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The Journal of Visualized Experiments (JoVE) is a peer reviewed, PubMed-indexed video journal. Our mission is to increase the productivity of scientific research.

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Articles by Joseph P. Huston in JoVE

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Generation, Purification, and Characterization of Cell-invasive DISC1 Protein Species


JoVE 4132 8/30/2012

1, 1, 2, 2, 1

1Department of Neuropathology, Medical School Düsseldorf, Germany, 2Center of Behavioral Neuroscience, University of Düsseldorf

The generation, purification and cell invasion of intracellular, cytoplasmic full length DISC1 protein aggresomes from cell cultures and of a labeled, multimeric recombinant DISC1 protein fragment in E. coli are described. Cell invasiveness is shown for recipient cells in cell culture and for neurons in vivo after stereotactical brain inoculation.

Other articles by Joseph P. Huston on PubMed

The Sliding Window Correlation Procedure for Detecting Hidden Correlations: Existence of Behavioral Subgroups Illustrated with Aged Rats

Journal of Neuroscience Methods. Dec, 2002  |  Pubmed ID: 12468003

We developed the sliding window correlation procedure in order to examine populations for possible heterogeneity in the ways two variables are related with each other. This procedure involves computing correlation coefficients (R) for overlapping successive segments of the covariate scores. The distribution of resulting Rs reveals fluctuations in the degree and direction of R over the sample of ranked scores. This procedure is applied to behavioral data of aged rats, which were rank-ordered according to water maze performance, and correlated with open field exploration and conflict behavior in a light/dark chamber. Results revealed correlation coefficients of varying magnitudes and opposing directions for different segments of the population, which were obscured by overall correlation analysis. E.g. for the superior learners, the Rs were highest between maze learning ability, increased open field exploration and reduced anxiety in the conflict test, whereas for the intermediate learners the Rs were highest for maze learning ability related with reduced exploration and increased anxiety. Thus, the sliding window correlation distribution can be applied in conjunction with overall correlation analysis to provide information about the potential presence and locations of subgroups within a population, especially if overall correlation analysis does not yield significant results.

The Graded Anxiety Test: a Novel Test of Murine Unconditioned Anxiety Based on the Principles of the Elevated Plus-maze and Light-dark Test

Journal of Neuroscience Methods. Dec, 2002  |  Pubmed ID: 12535765

Standard tests of murine unconditioned anxiety such as the elevated plus-maze and light-dark test are based on a dichotomy of avoidance behaviour (walled vs. open arms and dark vs. light compartments). We combined the principles of both tests by modifying the elevated plus-maze as follows: one walled arm was made transparent and had a white floor (WTW), whereas the other walled arm was opaque-gray having a black floor (WOB). Furthermore, one open arm had a white floor (OW), while the other had a black one (OB). These modifications allow the distinction between more than two sub-compartments that elicit different degrees of avoidance behaviour, thus having a higher discriminative potency. Additionally, the paradigm was thought to permit the within-task detection of pharmacological side effects on the perception of the anxiogenic stimuli provided. The degree of avoidance of the sub-compartments exhibited by saline-treated mice for the distal parts of the four arms was distributed as follows: WOB

Non-linear Dynamics of Operant Behavior: a New Approach Via the Extended Return Map

Reviews in the Neurosciences. 2002  |  Pubmed ID: 12013025

Previous efforts to apply non-linear dynamic tools to the analysis of operant behavior revealed some promise for this kind of approach, but also some doubts, since the complexity of animal behavior seemed to be beyond the analyzing ability of the available tools. We here outline a series of studies based on a novel approach. We modified the so-called 'return map' and developed a new method, the 'extended return map' (ERM) to extract information from the highly irregular time series data, the inter-response time (IRT) generated by Skinner-box experiments. We applied the ERM to operant lever pressing data from rats using the four fundamental reinforcement schedules: fixed interval (FI), fixed ratio (FR), variable interval (VI) and variable ratio (VR). Our results revealed interesting patterns in all experiment groups. In particular, the FI and VI groups exhibited well-organized clusters of data points. We calculated the fractal dimension out of these patterns and compared experimental data with surrogate data sets, that were generated by randomly shuffling the sequential order of original IRTs. This comparison supported the finding that patterns in ERM reflect the dynamics of the operant behaviors under study. We then built two models to simulate the functional mechanisms of the FI schedule. Both models can produce similar distributions of IRTs and the stereotypical 'scalloped' curve characteristic of FI responding. However, they differ in one important feature in their formulation: while one model uses a continuous function to describe the probability of occurrence of an operant behavior, the other one employs an abrupt switch of behavioral state. Comparison of ERMs showed that only the latter was able to produce patterns similar to the experimental results, indicative of the operation of an abrupt switch from one behavioral state to another over the course of the inter-reinforcement period. This example demonstrated the ERM to be a useful tool for the analysis of IRT accompanying intermittent reinforcement schedules and for the study of the non-linear dynamics of operant behavior.

Fischer 344 and Wistar Rats Differ in Anxiety and Habituation but Not in Water Maze Performance

Neurobiology of Learning and Memory. Jul, 2002  |  Pubmed ID: 12071664

The fact that various neuropharmacological substances have anxiolytic as well as amnesic effects suggests that neuronal mechanisms of anxiety and learning/memory closely interact. Hence, we hypothesized that differences in anxiety-related behavior could be accompanied with differences in cognition or habituation. Two rat strains with different levels of anxiety, more anxious Fischer 344 rats by Charles River (FC) and less anxious Wistar rats by Winkelmann (WW), were tested in the Morris water maze task and an open field test for habituation learning. Additionally, we investigated the effect of different light intensities on the performance in the Morris water maze and the elevated plus maze. The results of the water maze task indicate that differences in anxiety-related behavior do not go along with differences in this performance of learning/memory. Moreover, the test was not affected by different light intensities. In contrast, illumination did affect performance in the elevated plus maze test, wherein dim light provoked an anxiolytic effect in both rat strains. The findings that neither different baseline levels of anxiety nor fear modulating light conditions were accompanied by changes in the performance of rats in the Morris water maze led us to the suggestion that there is no connection between anxiety and learning/memory in this task. Contrarily, anxiety might be associated with habituation learning in the open field test, shown by the superior habituation of the anxious FC rats in comparison to the less anxious WW rats. In sum, these results indicate that anxiety and learning/memory seem to be independently regulated behaviors, whereas habituation might be more closely correlated with anxiety. Nevertheless, a general statement about the relation between emotionality and learning/memory mechanisms would be premature and the link between behaviors remains to be clarified.

Anxiolytic-like Effects of Substance P Fragment (SP(1-7)) in Non-human Primates (Callithrix Penicillata)

Peptides. May, 2002  |  Pubmed ID: 12084529

The behavioral effects of the amino (N)-terminal fragment of substance P (SP(1-7)) on the marmoset (Callithrix penicillata) predator confrontation test of fear/anxiety were investigated. The test apparatus consisted of a figure-eight maze with three parallel arms interconnected at each extremity to a perpendicular arm. A taxidermized oncilla cat (Felis tigrina) was placed outside the maze facing one of its corners. Subjects were submitted to seven 30 min maze habituation trials (HTs), in the absence of the 'predator', and then to six 30 min treatment trials (TTs), in the presence of the 'predator', consisting of four doses of SP(1-7) (5, 50, 250 and 500 microg/kg; IP), saline and sham injection. SP(1-7) treatment reversed, in a dose-dependent way, the fear-induced avoidance behavior due to the predator's presence and increased the frequency of exploratory behaviors. Locomotor activity decreased during successive HTs, yet increased after all SP(1-7) treatments. These results indicate that systemic administration of SP(1-7) produces anxiolytic-like effects in marmosets tested in the predator confrontation model of fear/anxiety.

Cocaine Increases Serotonergic Activity in the Hippocampus and Nucleus Accumbens in Vivo: 5-HT1a-receptor Antagonism Blocks Behavioral but Potentiates Serotonergic Activation

Synapse (New York, N.Y.). Aug, 2002  |  Pubmed ID: 12112399

The hippocampus is an important mediator of learning and reinforcement, but its role in cocaine effects has received little attention. Neuronal activity in the hippocampus and the nucleus accumbens (Nac) depend on serotonergic (5-HT) transmission. Here we describe for the first time a cocaine-induced increase in 5-HT concentration in the hippocampus and the Nac parallel to behavioral activation. In addition, pretreatment with the 5-HT(1A)-receptor antagonist WAY 100635 blocked the behavioral activation after cocaine while potentiating the 5-HT increase in the hippocampus and the Nac. In vivo microdialysis was used in behaving rats to measure extracellular concentration of 5-HT in the hippocampus and the Nac. Four groups of animals received one of the following drug combinations: WAY 100635 (0.4 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), WAY 100635 (0.4 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 30 min apart. It was found that 1.) cocaine, at a dose that activates behavior, increases 5-HT levels in the hippocampus and in the Nac, and 2.) 5-HT(1A)-receptor antagonism can cause a dissociation of the hippocampal and Nac 5-HT activity from behavioral activation after cocaine. These results are discussed within the framework of the hippocampal-accumbens projection and its contribution to behavioral activity. They suggest that the hippocampus may have a role in mediating the behavioral and neurochemical effects of cocaine.

The Selective Serotonin(1A)-receptor Antagonist WAY 100635 Blocks Behavioral Stimulating Effects of Cocaine but Not Ventral Striatal Dopamine Increase

Behavioural Brain Research. Aug, 2002  |  Pubmed ID: 12191821

An increase in the extracellular dopamine (DA) concentration is generally accepted as an important neurochemical mediator of the behavioral effects of cocaine. Cocaine induced increases in serotonergic (5-HT) activity also appears to be involved in these effects. Here we describe the effects of the 5-HT(1A)-receptor antagonist WAY 100635 on the behavioral and neurochemical effects of cocaine. In-vivo microdialysis was used in behaving rats to measure extracellular concentration of DA in the nucleus accumbens (Nac). Four groups of animals received one of the following drug combinations: WAY 100635 (0.4 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), WAY 100635 (0.4 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 20 min apart. The pretreatment with WAY 100635 significantly attenuated the locomotor stimulant effects of cocaine without altering the DA overflow in the Nac. WAY 100635 itself did not modify locomotion or the extracellular DA concentration in the Nac. These results indicate that (1) the 5-HT(1A)-receptor is an important component in the mediation of cocaine locomotor stimulant effects, and (2) an increase in the extracellular DA concentration in the Nac might be a necessary but is not a sufficient condition for the locomotor stimulant effects of cocaine.

Circadian Variation of Brain Histamine in Goldfish

Brain Research Bulletin. Jan, 2003  |  Pubmed ID: 12464402

Teleosts may make an excellent model to study brain histamine function. Fishes are phylogenetically closer to the basic vertebrate blueprint than higher vertebrates. They appear to have a simpler histaminergic system in terms of central nervous system distribution and, contrary to higher vertebrates, brain histamine appears to be strictly neuronal. In this preliminary study, we examined circadian variation of brain histamine in goldfish, Carassius auratus, as this neurotransmitter correlates with circadian behavior of some mammals. Two groups of juvenile goldfish were held in 24 60L aquaria, six fish per aquarium, on reversed photoperiods; L:D 12:12 with light onset either at 0700 or 1900h. Fish were sampled every 4h. At a sampling time, all the fish in a tank were taken; each sampling, for both groups, was done in replicate. Brain histamine was determined by immunoassay. There was a significant circadian variation in histamine on both photoperiod regimes with the highest levels during the photophase. These results support the hypothesis of an early phylogenic role for histamine in vertebrate circadian physiology.

The Relevance of Neuronal Substrates of Defense in the Midbrain Tectum to Anxiety and Stress: Empirical and Conceptual Considerations

European Journal of Pharmacology. Feb, 2003  |  Pubmed ID: 12600713

The medial hypothalamus, amygdala, and dorsal periaqueductal gray constitute the main neural substrates for the integration of aversive states in the brain. More recently, some regions of the mesencephalon, such as the superior and inferior colliculi have also been proposed as part of this system. In fact, fear-like behaviors often result when these sites are electrically or chemically stimulated. Both the behavioral and autonomic consequences of electrical stimulation of the mesencephalic tectum have been shown to be attenuated by minor tranquilizers, probably through enhancement of gamma-aminobutyric acid (GABA)-mediated neurotransmission, which exerts a tonic inhibitory control on the neural circuits responsible for the so-called defense behavior repertoire. Besides GABA, also 5-hydroxy tryptamine serotonin (5-HT), opioids, neuropeptides, histaminergic and excitatory amino acids have all been implicated in the regulation of anxiety-related behaviors induced by stimulation of midbrain tectum. Efforts have been made to characterize how these neurotransmitters interact with each other in the organization of these reactions to aversive stimulation. In this review, we summarize the evidence linking the brain's defense response systems to the concept of fear-anxiety. Furthermore, a case is made for the consideration of the relevance of this body of data to the search for the physiological underpinnings of depression and its consequences.

Chromosomal Loci Influencing the Susceptibility to the Parkinsonian Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2003  |  Pubmed ID: 12967986

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of the nigrostriatal dopaminergic pathway. Although its etiology is not yet fully understood, an interaction of genetic predisposition and environmental factors is frequently discussed. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can evoke PD-like symptoms and neuropathological changes in various species, including mice. It was found repeatedly that mouse strains differ in their susceptibility to MPTP, which might serve as a model for genetic predisposition to neurodegeneration of the nigrostriatal system. In the present study, F2 intercross mice, derived from parental strains with high (C57BL/6J) versus low (BALB/cJ) MPTP susceptibility, were treated with MPTP and phenotyped for dopamine (DA) loss in the neostriatum, a highly sensitive marker of nigrostriatal dysfunction. A subsequent quantitative trait loci analysis revealed a gender-dependent locus for DA loss on chromosome 15 and a putative locus on chromosome 13. A number of potential candidate genes, including the membrane dopamine transporter, are located in the respective areas. Several mechanisms that are possibly involved in the control of the action of MPTP on the nigrostriatal system are discussed.

Serotonin As an Important Mediator of Cocaine's Behavioral Effects

Drugs of Today (Barcelona, Spain : 1998). Jul, 2003  |  Pubmed ID: 12973400

Although the dopaminergic system still plays an important role in the investigation of the behavioral effects of cocaine, a broad literature emerged parallel to this research that provided significant evidence for an important contribution of the serotonergic (5-hydroxytryptamine, 5-HT) system. It has been known for a long time that the 5-HT transporter is one of the primary targets of cocaine within the brain and that cocaine causes an increase in the 5-HT activity in many brain regions. In general, the 5-HT system plays an important role in the organization of spontaneous behaviors, like locomotion, eating, drinking or grooming, and is also involved in emotion and mood. This review provides an overview of the role of 5-HT and 5-HT receptors in the acute behavioral and subjective effects of cocaine. There is broad evidence for a contribution of the 5-HT system to cocaine-induced hyperactivity in animals and to the subjective hedonic effects in humans. Studies with selective 5-HT receptor-ligands suggest the contribution of a large number of different 5-HT receptor subtypes to these effects. In order to fully understand the behavioral effects of cocaine and the mechanisms of their mediation, the 5-HT system needs to be considered, either parallel to or in interaction with the dopaminergic system.

Mice with Astrocyte-directed Inactivation of Connexin43 Exhibit Increased Exploratory Behaviour, Impaired Motor Capacities, and Changes in Brain Acetylcholine Levels

The European Journal of Neuroscience. Oct, 2003  |  Pubmed ID: 14622192

Gap junctions mediate communication between many cell types in the brain. Gap junction channels are composed of membrane-spanning connexin (Cx) proteins, allowing the cell-to-cell passage of small ions and metabolites. Cx43 is the main constituent of the brain-spanning astrocytic gap junctional network, controlling activity-related changes in ion and glutamate concentrations as well as metabolic processes. In astrocytes, deletion of Cx43-coding DNA led to attenuated gap junctional coupling and impaired propagation of calcium waves, known to influence neuronal activity. Investigation of the role of Cx43 in behaviour has been impossible so far, due to postnatal lethality of its general deletion. Recently, we have shown that deletion of Cx30, which is also expressed by astrocytes, affects exploration, emotionality, and neurochemistry in the mouse. In the present study, we investigated the effects of the astrocyte-directed inactivation of Cx43 on mouse behaviour and brain neurochemistry. Deletion of Cx43 in astrocytes increased exploratory activity without influencing habituation. In the open field, but not in the elevated plus-maze, an anxiolytic-like effect was observed. Rotarod performance was initially impaired, but reached control level after further training. In the water maze, Cx43 deficient mice showed a steeper learning course, although final performance was similar between groups. Cx43 inactivation in astrocytes increased acetylcholine content in the frontal cortex of water maze-trained animals. Results are discussed in terms of altered communication between astrocytes and neurons, possible compensation processes, and differential effects of Cx30- and astrocyte-specific Cx43 deletion.

Histidine-decarboxylase Knockout Mice Show Deficient Nonreinforced Episodic Object Memory, Improved Negatively Reinforced Water-maze Performance, and Increased Neo- and Ventro-striatal Dopamine Turnover

Learning & Memory (Cold Spring Harbor, N.Y.). Nov-Dec, 2003  |  Pubmed ID: 14657262

The brain's histaminergic system has been implicated in hippocampal synaptic plasticity, learning, and memory, as well as brain reward and reinforcement. Our past pharmacological and lesion studies indicated that the brain's histamine system exerts inhibitory effects on the brain's reinforcement respective reward system reciprocal to mesolimbic dopamine systems, thereby modulating learning and memory performance. Given the close functional relationship between brain reinforcement and memory processes, the total disruption of brain histamine synthesis via genetic disruption of its synthesizing enzyme, histidine decarboxylase (HDC), in the mouse might have differential effects on learning dependent on the task-inherent reinforcement contingencies. Here, we investigated the effects of an HDC gene disruption in the mouse in a nonreinforced object exploration task and a negatively reinforced water-maze task as well as on neo- and ventro-striatal dopamine systems known to be involved in brain reward and reinforcement. Histidine decarboxylase knockout (HDC-KO) mice had higher dihydrophenylacetic acid concentrations and a higher dihydrophenylacetic acid/dopamine ratio in the neostriatum. In the ventral striatum, dihydrophenylacetic acid/dopamine and 3-methoxytyramine/dopamine ratios were higher in HDC-KO mice. Furthermore, the HDC-KO mice showed improved water-maze performance during both hidden and cued platform tasks, but deficient object discrimination based on temporal relationships. Our data imply that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms and further indicate that these opposed effects are related to the task-inherent reinforcement contingencies.

Effects of Chronic Intraventricular Infusion of Heparin Glycosaminoglycan on Learning and Brain Acetylcholine Parameters in Aged Rats

Behavioural Brain Research. Dec, 2003  |  Pubmed ID: 14659577

We reported previously that the glycosaminoglycan heparin (HP) has the facility to improve learning in adult rodents when administered into the nucleus basalis of the ventral pallidum. Here we gauged the effects of chronic intraventricular infusion of HP (20 ng per day over 28 days) in 26-month-old rats in terms of Morris water maze performance, habituation to a novel open field, retention of a step-through inhibitory avoidance task and changes in forebrain acetylcholine (ACh) levels. Control groups included vehicle-infused old and adult (3-month-old) rats. The chronic infusion of HP did not significantly influence the performance of the old animals in any of the learning and memory tasks employed. HP only slightly facilitated the retention of the inhibitory avoidance task and the rate of habituation in the open-field paradigm. In the water maze, the glycosaminoglycan did not counteract the navigation deficits observed for aged controls and even impaired performance during the initial place-learning trials. After behavioural testing, tissue levels of ACh were determined in frontal cortex, ventral striatum, neostriatum and hippocampus without detecting any obvious neurochemical differences between groups. The current results, together with our previous work, indicate that HP differentially affects learning and memory parameters in adult and aged rats. Thus, whereas the glycosaminoglycan proved effective in facilitating mnemonic functions in normal adult animals, no such a clear-cut beneficial effect was observed in behaviourally impaired old rats.

Anxiolytic-like Effects of the Selective 5-HT1A Receptor Antagonist WAY 100635 in Non-human Primates

European Journal of Pharmacology. Dec, 2003  |  Pubmed ID: 14660023

Non-human primates provide important insights into the potential use of 5-HT(1A) receptor antagonists in treating human anxiety disorders and as research tools, given the existent inconsistencies in rodent tests. This study investigated the effects of the selective silent 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane-carboxamide trihydrochloride (WAY 100635), administered systemically, in an ethologically based fear/anxiety test in marmoset monkeys (Callithrix penicillata). Subjects were tested using a figure-eight maze and a taxidermized wild cat as 'predator' stimulus. After seven 30-min maze habituations in the absence of the 'predator', each animal was submitted to four pseudo-randomly assigned 30-min treatment trials in the presence of the 'predator': three WAY 100635 (0.2, 0.4 and 0.8 mg/kg, i.p.) sessions and a saline control trial. The 'predator' stimulus caused a significant fear-induced avoidance of the maze sections closest to where it was presented, indicating an anxiogenic effect. However, WAY 100635 treatment reversed, significantly and dose-dependently, this fear-induced avoidance behavior, while increasing maze exploration. Sedation was not observed. This is the first study to suggest an anxiolytic-like effect of the selective silent 5-HT(1A) receptor antagonist WAY 100635 in non-human primates, indicating its potential use as a therapeutic agent.

The 5-HT1A Receptor and Behavioral Stimulation in the Rat: Effects of 8-OHDPAT on Spontaneous and Cocaine-induced Behavior

Psychopharmacology. Dec, 2004  |  Pubmed ID: 15167982

The contribution of the 5-HT(1A) somato-dendritic autoreceptor populations to spontaneous and cocaine-induced locomotion is unclear.

Multibehavioral Analysis of Fear and Anxiety Before, During, and After Experimentally Induced Predatory Stress in Callithrix Penicillata

Pharmacology, Biochemistry, and Behavior. Jun, 2004  |  Pubmed ID: 15219778

A detailed behavioral analysis of nine Callithrix penicillata was conducted in the Marmoset Predator Confrontation Test (MPCT) during (a) four habituation trials with no "predator," (b) six confrontation trials with the predator (taxidermized oncilla cat, Felis tigrina), and (c) four trials with the predator removed. The marmosets habituated to the test apparatus with significant decreases in locomotion, exploration and long calls. Initial exposure to the predator elicited mainly fear-related behaviors (proximic avoidance, tsik-tsik vocalization, swaying/tongue in-out), whereas repeated confrontations attenuated these behaviors, concomitant to an increase in anxiety-associated responses (scratching/grooming/scent marking). The initial behavioral repertoire, observed before confrontations, was fully restored only upon removal of the predator. This easily discernable complex defensive behavioral repertoire is hoped to provide a comprehensive baseline for studying the biological substrates of fear/anxiety parameters in nonhuman primates.

Dopaminergic and Serotonergic Autoreceptor Stimulation Effects Are Equivalent and Additive in the Suppression of Spontaneous and Cocaine Induced Locomotor Activity

Brain Research. Sep, 2004  |  Pubmed ID: 15306247

We used the D(2) receptor agonist, apomorphine (APO) and the 5-HT(1A) receptor agonist, 8-OHDPAT (8OH) in a low dose range to stimulate autoreceptors and in this way assess the separate and combined effects of reduced DA and 5-HT activity upon spontaneous and cocaine induced locomotor behavior. Two separate experiments were conducted. In the first experiment, separate groups of rats (N=10) were tested with either saline, 8OH, APO or 8OH plus APO (0.01, 0.025, 0.05 mg/kg). At 0.05 mg/kg, 8OH and APO induced similar dose related decreases (up to approximately 50%) in locomotor activity. The combined 8OH plus APO treatment induced dose-related decreases in locomotion (approximately 90%). At the 0.05 mg/kg dose level, the drug treatments given separately blocked cocaine induced increases in activity and the 8OH and APO inhibitory effects were again additive. In the second experiment, separate groups (N=10) received saline, 0.05 mg/kg APO, 0.05 mg/kg 8OH or 0.05 mg/kg APO plus 0.05 mg/kg 8OH. As in the first experiment, the 8OH and APO given separately reduced locomotor activity by approximately 50% and when given together, locomotor activity was virtually eliminated (reduced 80-90%). When the combined APO/8OH group also received the 5-HT(1A) antagonist, WAY 100635 (0.05 mg/kg), the effect on activity was equivalent to 0.05 mg/kg APO alone. Ex vivo neurochemical measurement of dopamine (DA) and serotonin (5-HT) metabolism confirmed that the APO decreased DA turnover, 8OH decreased 5-HT turnover and the combined treatment reduced both the DA and 5-HT turnover. Thus, for both spontaneous and cocaine induced locomotor behavior, the low dose 8OH and APO treatments suppressed locomotor activity and these effects were additive. These findings indicate that DA and 5-HT systems contribute separately to motoric activation. These results suggest that it is important to consider both DA and 5-HT contributions to disorders of motoric impoverishment such as Parkinson's disease as well as to hyperkinetic states such as those induced by stimulant drugs.

Hippocampus 5-HT(1A)-receptors Attenuate Cocaine-induced Hyperlocomotion and the Increase in Hippocampal but Not Nucleus Accumbens 5-HT

Hippocampus. 2004  |  Pubmed ID: 15318330

Cocaine induces an increase in hippocampal and nucleus accumbens (Nac) serotonin (5-HT) concentration parallel to locomotor activation. Both effects can be modulated by systemic 5-HT(1A)-receptor agonism/antagonism. Given the contribution of the hippocampus to spontaneous behavioral activity, these observations suggest a role for hippocampal 5-HT as well in the modulation of cocaine effects on behavior. To determine the role of hippocampal 5-HT(1A)-receptors in cocaine effects on behavior and hippocampal 5-HT release, we used in vivo microdialysis in freely moving rats. The 5-HT(1A)-receptor agonist, 8-OH-DPAT (0, 0.1, 1 and 10 microM), was applied locally into the hippocampus by reversed dialysis followed by a cocaine (10 mg/kg) or saline i.p. injection. The hippocampal 5-HT(1A)-receptor activation attenuated cocaine-induced hyperlocomotion and rearing behavior dose-dependently. Parallel to that, the cocaine-induced 5-HT increase was attenuated dose-dependently in the hippocampus but was left unaffected in the Nac. The intra-hippocampal application of 8-OH-DPAT affected neither behavioral activity nor 5-HT concentration in the hippocampus and in the Nac. In accord with these findings, hippocampal 5-HT(1A)-receptors may not be directly involved in the regulation of spontaneous behavior or basal 5-HT concentration in the hippocampus and Nac. However, the results indicate an inhibitory role of hippocampal 5-HT(1A)-receptors in cocaine-induced hyperactivity and in the 5-HT increase evoked by cocaine in the hippocampus but not in the Nac.

Extinction-induced Immobility in the Water Maze and Its Neurochemical Concomitants in Aged and Adult Rats: a Possible Model for Depression?

Neurobiology of Learning and Memory. Sep, 2004  |  Pubmed ID: 15341798

Extinction of escape behavior in the water maze due to the removal of the platform, was hypothesized to induce a negative state, including the development of immobility, which is held to reflect a state of "despair" when measured in the forced swimming test. 27 aged and 8 adult animals (26 and 3 months old Wistar rats, respectively) were tested in the water maze during nine days with a platform hidden, followed by 7 days of extinction trials with the platform absent. As expected, both age groups developed immobility over the extinction trials, with the aged showing more than the adults. To examine whether the age difference in immobility was related to performance differences during acquisition, the aged were subdivided into superior, intermediate and inferior learners (n = 9 per group) on the basis of overall times to platform during acquisition, and compared with each other and the adults. Results showed that the aged inferior learners displayed the highest levels of immobility among the aged. Immobility scores were then correlated with post-mortem neurotransmitter contents in the hippocampus and ventral striatum. In the ventral striatum, levels of immobility were correlated with levels of acetylcholine, dopamine and the metabolite dihydroxyphenylacetic acid in the aged, and with norepinephrine in the adults. The data support the hypothesis that multiple extinction trials in the water maze result in immobility that may indicate "behavioral despair," and that striatal neurotransmitter systems correlate with the degree of its expression. The concept of extinction-induced despair is held to provide the promise of a conceptual and empirical model of human depression that is the consequence of loss of reinforcers.

Neurokinin-1 Receptor Antagonism by SR140333: Enhanced in Vivo ACh in the Hippocampus and Promnestic Post-trial Effects

Peptides. Nov, 2004  |  Pubmed ID: 15501528

Substance P (SP) has memory-promoting, reinforcing and anxiolytic-like effects when applied systemically or centrally. Such effects may be mediated by the neurokinin-1 (NK-1) receptor, since SP preferentially binds to this receptor. We measured the effects of a selective non-peptide NK-1 receptor antagonist, SR140333 (1, 3 and 9 mg/kg i.p.) on ACh levels in frontal cortex, amygdala and hippocampus by microdialysis and HPLC. Levels of ACh in the hippocampus increased dose-dependently immediately after treatment. The same doses of SR140333 given post-trial had minor facilitative effects on inhibitory avoidance learning and open-field habituation, but did not have reinforcing effects in a conditioned place preference (CPP) task. The selective action of NK-1 receptor antagonism on hippocampal ACh may be related to its positive influence on learning.

Higher Order Memories for Objects Encountered in Different Spatio-temporal Contexts in Mice: Evidence for Episodic Memory

Reviews in the Neurosciences. 2004  |  Pubmed ID: 15526548

The ability to build higher order multi-modal memories comprising information about the spatio-temporal context of events has been termed 'episodic memory'. Deficits in episodic memory are apparent in a number of neuropsychiatric diseases. Unfortunately, the development of animal models of episodic memory has made little progress. Towards the goal of such a model we devised an object exploration task for mice, providing evidence that rodents can associate object, spatial and temporal information. In our task the mice learned the temporal sequence by which identical objects were introduced into two different contexts. The 'what' component of an episodic memory was operationalized via physically distinct objects; the 'where' component through physically different contexts, and, most importantly, the 'when' component via the context-specific inverted sequence in which four objects were presented. Our results suggest that mice are able to recollect the inverted temporal sequence in which identical objects were introduced into two distinct environments. During two consecutive test trials mice showed an inverse context-specific exploration pattern regarding identical objects that were previously encountered with even frequencies. It seems that the contexts served as discriminative stimuli signaling which of the two sequences are decisive during the two test trials.

Contralateral Increase in Thigmotactic Scanning Following Unilateral Barrel-cortex Lesion in Mice

Behavioural Brain Research. Feb, 2005  |  Pubmed ID: 15617769

Adult C57BL/6 mice received uni- or bilateral cryogenic or sham-lesions over the barrel field and their exploratory behaviour was assessed in an open field between 1 and 7 days post-lesion. Bilateral cortical lesions produced a short-lasting increase in thigmotactic scanning with both sides of the face on the first day of testing. Mice with a unilateral barrel-cortex lesion showed more contralateral wall scanning with a recovery to behavioural symmetry after 5-7 days. Furthermore, the increase in contralateral thigmotaxis was most pronounced in animals with damage to the left barrel field, indicative of a lateralization of the lesion-induced behavioural changes. The cortical lesions did not influence locomotor activity and the rate of habituation to the open field (habituation 'learning'). Referring to recent electrophysiological findings, we hypothesize that the lesion established a lateralized source of increased neuronal excitability within the affected barrel-cortex, leading to more behaviour with its corresponding vibrissae. Alternatively, if the lesion results in contralateral 'neglect' in terms of input, the increased scanning with the affected vibrissae may reflect an attempt of the system to compensate for this with an increase in usage.

Evidence That the 5-HT1A Autoreceptor is an Important Pharmacological Target for the Modulation of Cocaine Behavioral Stimulant Effects

Brain Research. Feb, 2005  |  Pubmed ID: 15713268

The psychostimulant effects of cocaine critically depend on the serotonergic (5-HT) system, of which the 5-HT1A receptor is an essential component. We recently showed divergent contributions of various pre- and postsynaptic 5-HT1A receptor populations to the behavioral effects of cocaine. Here, we further investigate the role of 5-HT1A autoreceptors in the acute and chronic stimulant effects of cocaine using 5-HT1A receptor ligands in autoreceptor preferring doses. In experiment 1, four groups of rats (N = 10) received either saline or the 5-HT1A agonist, 8-OHDPAT (0.05 mg/kg) 20 min prior to a saline or cocaine (10 mg/kg) injection on 9 consecutive days. In experiment 2, six groups (N = 10) were given either saline, the 5-HT1A antagonist, WAY 100635 (0.05 mg/kg) or 8-OHDPAT (0.05 mg/kg) plus WAY 100635 (0.05 mg/kg) 20 min before a saline or cocaine (10.0 mg/kg) treatment on 9 consecutive days. Initially, both the 8-OHDPAT and WAY 100635 pretreatments completely blocked the locomotor stimulant effects of cocaine whereas the combined 8-OHDPAT plus WAY 100635 pretreatment had no effect. In saline treated groups, neither the WAY 100635 nor the 8-OHDPAT plus WAY 100635 pretreatment influenced spontaneous activity levels, whereas the 8-OHDPAT alone severely reduced spontaneous activity. These effects persisted over the course of the 9 test sessions. A different pattern of results was obtained for the cocaine treatment groups. With repeated treatments, the WAY 100635 treatment always blocked the locomotor activation effect of cocaine, whereas the effects of 8-OHDPAT were transformed from an inhibition to an enhancement of cocaine locomotor stimulation. The combined 8-OHDPAT plus WAY 100635 pretreatment did not affect the stimulant effect of cocaine. These findings demonstrate that low dose autoreceptor preferring treatments with a 5-HT1A agonist and antagonist can strongly modify the behavioral stimulant effects of cocaine and suggest that the 5-HT1A autoreceptor may be an important pharmacological target for the development of treatments for cocaine addiction.

Aged and Adult Rats Compared in Acquisition and Extinction of Escape from the Water Maze: Focus on Individual Differences

Behavioral Neuroscience. Feb, 2005  |  Pubmed ID: 15727519

Individual differences in water maze and open-field performance of aged and adult rats were compared in a cross-sectional study. Three- and 24-month-old rats were classified into superior, moderate, and inferior groups on the basis of escape latencies during hidden platform acquisition and were compared regarding water maze acquisition and extinction, and open-field behavior. Unexpectedly, subgroup differences were invariant across age: The inferior and superior maze learners differed in (a) thigmotactic swimming during water maze acquisition and extinction and (b) open-field rearings. Thus, although aging has a detrimental effect on water maze acquisition and extinction, the degree of impairment might be partly determined by individual novelty-induced rearing activity and thigmotactic swimming at adult ages.

Serotonin1A-receptor Antagonism Blocks Psychostimulant Properties of Diethylpropion in Marmosets (Callithrix Penicillata)

European Journal of Pharmacology. Mar, 2005  |  Pubmed ID: 15777778

Diethylpropion (1-phenyl-2-diethylamine-1-propanone hydrochloride) is a stimulant drug with reinforcing properties that is used to treat obesity in humans. While the anorectic properties of diethylpropion are mediated by a noradrenergic mechanism, stimulant properties depend on its effects on the serotonergic (5-HT) and/or dopaminergic systems. In this study we investigated the role of the 5-HT1A-receptor in the acute behavioral effects of diethylpropion in marmosets (Callithrix penicillata). Animals were pretreated with the selective 5-HT1A-receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide trihydrochloride (WAY 100635; 0.2, 0.4, 0.8 mg/kg, i.p.) or saline (i.p.) and received a treatment with diethylpropion (10 mg/kg, i.p) or saline (i.p.). Diethylpropion induced an increase in locomotor activity in 60% of the monkeys, which were classified as diethylpropion sensitive, but did not affect locomotion in 40% of the monkeys (diethylpropion insensitive). Sensitivity analysis revealed two types of responders to diethylpropion. In the sensitive animals (type A) diethylpropion increased locomotor activity and anxiogenic-like behavior, but decreased bodycare activities. In the insensitive animals (type B) diethylpropion did not affect locomotor and bodycare activity after diethylpropion, but led to a strong increase in anxiogenic-like behavioral responses. Selective 5-HT1A-receptor antagonism modulated the acute diethylpropion effects responder type specifically. In the sensitive (type A) monkeys WAY 100635 blocked the diethylpropion-induced increase in locomotor activity, while not affecting anxiogenic-like behavioral responses or the suppression of bodycare activities. In the insensitive monkeys, WAY 100635 had no effect on locomotor activity after diethylpropion, but blocked diethylpropion effects on some anxiogenic-like behavioral responses. In conclusion, these results suggest an essential contribution of the 5-HT1A-receptor to the stimulant effects of diethylpropion, which is responder type specific. It also suggests the 5-HT1A-receptor to be a source of the interindividual variance in the acute behavioral response to the stimulant diethylpropion in monkeys.

Pharmacological Inhibition of DA- and 5-HT Activity Blocks Spontaneous and Cocaine-activated Behavior: Reversal by Chronic Cocaine Treatment

Brain Research. Jun, 2005  |  Pubmed ID: 15896723

Recently it was shown that the combined pretreatment with low autoreceptor preferring dose levels of apomorphine (0.05 mg/kg) and 8-OHDPAT (0.05 mg/kg), which decrease dopaminergic and serotonergic activity, induces a profound behavioral inhibition and also blocks the stimulant effects of cocaine. In two experiments, we report that the acute blockade of spontaneous and cocaine locomotor stimulant effects by pretreatment with 8-OHDPAT (0.05 mg/kg) plus apomorphine (0.05 mg/kg) is dose-dependently (0.0 2.5, 5.0, and 10.0 mg/kg cocaine) reversed with repeated cocaine treatments. Using a paired vs. unpaired Pavlovian conditioning protocol, we found that this reversal by cocaine (10 mg/kg) of the inhibition by the combined 8-OHDPAT plus apomorphine pretreatment occurred for the paired but not the unpaired cocaine treatment. The findings suggest that this reversal of behavioral inhibition is mediated by the transformation of the drug cues generated by 8-OHDPAT and apomorphine into cocaine-conditioned stimuli which can activate behavior.

Integrated Memory for Objects, Places, and Temporal Order: Evidence for Episodic-like Memory in Mice

Neurobiology of Learning and Memory. Nov, 2005  |  Pubmed ID: 16102980

Human episodic memory refers to the recollection of an unique past experience in terms of what happened, and where and when it happened. Factoring out the issue of conscious recollection, episodic memory, even at the behavioral level, has been difficult to demonstrate in non-human mammals. Although, it was previously shown that rodents can associate what and when or what and where information given on unique trials, it proved to be difficult to demonstrate memory for what, where, and when simultaneously in mammals, without using extensive training procedures, which might induce semantic rather than episodic memory recall. Towards the goal of an animal model of human episodic memory we designed an three-trial object exploration task in which different versions of the novelty-preference paradigm were combined to subsume (a) object recognition memory, (b) the memory for locations in which objects were explored, and (c) the temporal order memory for object presented at distinct time points. We found that mice spent more time exploring two "old familiar" objects relative to two "recent familiar" objects, reflecting memory for what and when and concomitantly directed more exploration at a spatially displaced "old familiar" object relative to a stationary "old familiar" object, reflecting memory for what and where. These results suggest that during a single test trial the mice were able to (a) recognize previously explored objects, (b) remember the location in which particular objects were previously encountered, and (c) to discriminate the relative recency in which different objects were presented. According to the currently discussed behavioral criteria for episodic-like memory in animals, our results suggest that mice are capable to form such higher order memories.

Episodic-like Memory in Mice: Simultaneous Assessment of Object, Place and Temporal Order Memory

Brain Research. Brain Research Protocols. Dec, 2005  |  Pubmed ID: 16185914

Episodic memory refers to the conscious recollection of a unique past experience in terms of "what" happened and "where" and "when" it happened. Since deficits in episodic memory are found in a number of neuropsychiatric diseases, such as Alzheimer's disease, for which several pharmacological, lesion and genetic animal models are available, there is a need for animal models of episodic-like memory, which can be used to devise appropriate treatments. However, even when the problem of conscious recollection in animals is factored out, episodic memory has been difficult to demonstrate in nonhuman mammals because it has not yet been possible to demonstrate an integrated memory for "what",-"where"-and-"when". We designed a three-trial "what",-"where"-and-"when" object exploration task in which different versions of the novelty preference paradigm were combined to subsume (a) object recognition memory, (b) the memory for locations in which objects were explored and (c) the temporal order memory for objects presented at distinct time points. Our results suggest that mice are able to (a) recognize previously explored objects, (b) remember the location in which particular objects were previously encountered and (c) discriminate the relative recency in which different objects were presented. We suggest that our protocol providing the simultaneous assessment of object memory for "what",-"where"-and-"when" in mice might be useful in the search for the neural substrates of episodic memory, the screening for promnestic drugs and the behavioral phenotyping of genetic models of neuropsychiatric diseases affecting episodic memory.

Wistar Rats Show Episodic-like Memory for Unique Experiences

Neurobiology of Learning and Memory. Mar, 2006  |  Pubmed ID: 16290193

Human episodic memory refers to the recollection of an unique past experience in terms of its details, its locale, and temporal occurrence. Episodic memory, even in principle, has been difficult to demonstrate in non-verbal mammals. Previously, we provided evidence that mice are able to form an integrated memory for "what," "where," and "when" aspects of single experiences by combining different versions of the novelty-preference paradigm, i.e., object recognition memory, the memory for locations in which objects were explored, and the temporal order memory for objects presented at distinct time points. In the present series of experiments we evaluated whether this paradigm, with minor modifications, also works with rats. We found that rats spent more time exploring an "old familiar" object relative to a "recent familiar" object, suggesting that they recognized objects previously explored during separate trials and remembered their order of presentation. Concurrently, the rats responded differentially to spatial object displacement dependent on whether an "old familiar" or "recent familiar" object was shifted to a location, where it was not encountered previously. These results provide strong evidence that the rats established an integrated memory for "what," "where," and "when." We also found that acute stress impaired the animal's performance in the episodic-like memory task, which, however, could be partially reversed by the N-Methyl-D-aspartate-receptors agonist D-cycloserine.

Determining the Region-specific Contributions of 5-HT Receptors to the Psychostimulant Effects of Cocaine

Trends in Pharmacological Sciences. Feb, 2006  |  Pubmed ID: 16406129

Cocaine is a drug of abuse that has complex neurochemical and behavioural profiles. When it became evident that models that involve only dopamine do not fully explain the complex effects of cocaine on behaviour, the focus of research expanded to include the 5-hydroxytryptamine (5-HT) system in the brain. The 5-HT system comprises several subtypes of 5-HT receptors, which contribute differentially to the various behavioural effects of cocaine. In this article, we describe which subtypes regulate behaviours that are related to cocaine addiction and how they might provide new therapeutic approaches. Numerous subpopulations of each 5-HT receptor can be distinguished according to their location in the brain. We also discuss how these subpopulations relate to the effects of 5-HT-receptor stimulation at the systemic level. These insights provide a new receptor-based approach for understanding the 5-HT mechanisms that subserve the actions of cocaine and possible pharmacotherapies against cocaine addiction.

Operant Behavior of Rats Under Fixed-interval Reinforcement Schedules: a Dynamical Analysis Via the Extended Return Map

Nonlinear Dynamics, Psychology, and Life Sciences. Apr, 2006  |  Pubmed ID: 16519866

The extended-return-map was employed to analyze the inter-response time data of operant experiments using fixed-interval schedules and food reinforcement. After intensive training over numerous sessions, rats gradually developed several types of temporal patterns of lever pressing behaviors, which were visualized through different patterns of data point distributions in the extended-return-map. Analyses with randomly shuffled data sets confirmed that these patterns depended on the sequential order of the inter-response time data, indicating that they reflected dynamics of the behavior. A procedure was developed to quantify the difference between patterns in the extended-return-maps, thus, enabling the comparison between sessions, and between animals. Simulations suggested that, in addition to the two-state break-and-burst responding, both multiple switches of behavioral states during the inter-reinforcement periods and the acceleration of lever pressing rate should be taken into consideration for the dynamics found in the data.

The Tachykinin NK3 Receptor Antagonist SR142801 Blocks the Behavioral Effects of Cocaine in Marmoset Monkeys

European Journal of Pharmacology. May, 2006  |  Pubmed ID: 16603151

Brain neuropeptide transmitters of the tachykinin family are involved in the organization of many behaviors. However, little is known about their contribution to the behavioral effects of drugs of abuse. Recently, the tachykinin NK3 receptor, one of the three tachykinin receptors in the brain, was shown to attenuate the acute and chronic behavioral effects of cocaine in rats. In order to test if these findings can be generalized to primates we investigated the role of the tachykinin NK3 receptor in the acute behavioral effects of cocaine in marmoset monkeys (Callithrix penicillata) using a figure-eight maze procedure. Animals were pretreated with the tachykinin NK3 receptor antagonist, (R)-(N)-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]propyl]-4-phenylpiperidin-4-yl]-N-methylacetamide (SR142801; 0, 0.02, 0.2, 2.0 mg/kg, i.p.), and received either a treatment with cocaine (10 mg/kg, i.p) or saline (i.p.). Cocaine increased locomotor activity and aerial glance behavior, but reduced exploratory and bodycare activities, scent marking and terrestrial scanning behavior. A sensitivity analysis revealed that two responder types can be differentiated in relation to the occurrence of a hyperlocomotor response to cocaine. SR142801 blocked the actions of cocaine on several behaviors dose-dependently for each responder type, respectively. There was no effect of SR142801 alone on any behavior measured. These data suggest that the tachykinin NK3 receptor contributes to the individual behavioral response to cocaine in marmoset monkeys. Having no behavioral effects on its own, but blocking the cocaine effects, might suggest the tachykinin NK3 receptor antagonist, SR142801, as a potential treatment of cocaine addiction in humans.

Interaction of the Tachykinin NK3 Receptor Agonist Senktide with Behavioral Effects of Cocaine in Marmosets (Callithrix Penicillata)

Peptides. Sep, 2006  |  Pubmed ID: 16621146

Brain neuropeptide transmitters of the tachykinin family are involved in the organization of many behaviors. However, little is known about their contribution to the behavioral effects of drugs of abuse. Recently, antagonism of the tachykinin NK3-receptor (NK3-R), one of the three tachykinin receptors in the brain, was shown to attenuate the acute and chronic behavioral effects of cocaine in rats and the acute effects in non-human primates. In order to expand these findings we investigated the effects of the NK3-R agonist, succinyl-[Asp6, Me-Phe8]SP(6-11) (senktide), on the acute behavioral effects of cocaine in marmoset monkeys (Callithrix penicillata) using a figure-eight maze procedure. Animals were pretreated with senktide (0, 0.1, 0.2, 0.4 mg/kg, s.c.), and received either a treatment with cocaine (10 mg/kg) or saline (i.p.). Cocaine increased locomotor activity and the duration of aerial scanning behavior, but reduced exploratory activity, bodycare activity, the frequency of aerial scanning, and terrestrial glance behavior. Senktide blocked the effects of cocaine on locomotor activity, but enhanced the cocaine effects on exploratory activity, aerial scanning frequency, and terrestrial glance behavior. Senktide alone did not significantly influence monkey behavior in this study. These data expand previous findings suggesting a complex role of the NK3-R in the acute behavioral effects of cocaine in non-human primates.

Neurokinin Receptor Antagonism Attenuates Cocaine's Behavioural Activating Effects Yet Potentiates Its Dopamine-enhancing Action in the Nucleus Accumbens Core

The European Journal of Neuroscience. Sep, 2006  |  Pubmed ID: 17004936

Several lines of evidence indicate a role for neurokinin3 receptors (NK3-Rs) in behavioural activation and mechanisms governing reinforcement processes. In this study we investigated the effect of pretreatment with the NK3-R antagonist, SR142801, (0.2 and 2.0 mg/kg) on the cocaine-induced (10.0 mg/kg i.p.) increase in extracellular dopaminergic activity in the nucleus accumbens (NAc). In vivo microdialysis in the NAc of freely moving rats showed that cocaine increased concentrations of dopamine (DA) to approximately 350% in the core and approximately 450% in the shell. Pre-treatment with SR142801 significantly potentiated this effect in the core (to approximately 550%), whereas this effect was not found in the shell. We also investigated the effects of NK3-Rs antagonism on cocaine-induced hyperactivity and conditioned place preference. SR142801 blocked the hyperactivity, but neither the conditioned place preference nor the conditioned locomotor activity induced by cocaine, although there was a slight tendency towards a reduced place preference. When given alone, SR142801 had no effects on behaviour or extracellular dopamine concentrations in any of the structures investigated. These data provide evidence for a contribution of NK3-Rs in the acute behavioural and neurochemical effects of cocaine, involving dopaminergic activity in the core of the nucleus accumbens.

Reinstatement of Episodic-like Memory in Rats by Neurokinin-1 Receptor Antagonism

Neurobiology of Learning and Memory. Mar, 2007  |  Pubmed ID: 17079168

We previously showed that a systemic administration of the selective non-peptide neurokinin-1-receptor (NK-1-R) antagonist SR140333 increases hippocampal acetylcholine levels and facilitates long term memory. In the present study, we investigated whether systemic SR140333 has beneficial effects on episodic-like memory for unique experiences. Rats received either no injection, a vehicle injection or SR140333 at doses of 1, 3 and 9 mg/kg (i.p.) prior to the acquisition of an object memory for what, where and when. In line with previous results, untreated rats showed episodic-like memory, while vehicle-injected rats were impaired. A low dose of 1mg/kg SR140333 reinstated episodic-like memory. This result might be related to the effects of SR140333 on hippocampal cholinergic transmission and/or on the stress-response elicited by the injection procedure. Higher doses of SR140333 (3 and 9 mg/kg) induced psychomotor effects, including stereotypic behaviors and arched posture. Since NK-1-R antagonists have anxiolytic and promestic properties and induce hippocampal acetylcholine release at lower doses, they might be effective in the alleviation of the cognitive deficits and increased anxiety seen in early stages of Alzheimer's disease.

"Despair" Induced by Extinction Trials in the Water Maze: Relationship with Measures of Anxiety in Aged and Adult Rats

Neurobiology of Learning and Memory. Mar, 2007  |  Pubmed ID: 17079170

We have previously reported that extinction of escape behavior in the water maze due to the removal of the platform coincided with the development of behavioral "despair" in aged and adult rats, as assessed by immobility. The present study examines further predictions derived from the hypothesis that the withholding of reinforcement induces behaviors akin to depression. We tested for correlations between extinction performance and immobility, as well as between immobility and measures of anxiety in aged and adult rats. Age comparisons were also performed on these variables. Forty aged and 29 adult male Wistar rats (24 and 3 months old, respectively) were examined in the open field, black/white box and elevated-plus maze followed by 6 days of training in the water maze hidden platform task and 8 days of extinction without the platform. Indices of immobility increased over trials of extinction, with the aged showing higher levels, earlier onsets and larger slope increases of immobility than the adults. A lower resistance-to-extinction was predictive of more "despair" in both age groups. Between-group differences in the open field, black/white box and elevated-plus maze indicated that the aged showed more anxiety-like behavior than the adults and/or explored these environments less. Within the aged group, indicators of fearfulness in the three tests were predictive of higher levels of "despair". The extinction-despair model is held to provide the promise of a conceptual and empirical model of human depression that is the consequence of withdrawal of reinforcement.

Double Dissociating Effects of Sensory Stimulation and Cocaine on Serotonin Activity in the Occipital and Temporal Cortices

Neuropharmacology. Mar, 2007  |  Pubmed ID: 17116310

Visual cues that become associated with the consumption of psychostimulant drugs energize craving and the intake of the drug by mechanisms of which little is known. In two experiments using in vivo microdialysis in freely moving rats we compared the effects of visual and auditory stimulation with that of cocaine (0, 5, 10, 20mg/kg; i.p.) on the extracellular serotonin (5-HT) activity in the occipital and temporal cortices in relation to behavior. Visual stimulation increased 5-HT in the occipital, but not temporal cortex, parallel to an increase in locomotion. Auditory stimulation decreased 5-HT in the auditory, but not occipital cortex, thus, showing a double dissociated 5-HT response. These data suggest that a locally restricted 5-HT response to sensory stimulation may gate behavioral activity sense-modality selectively. Cocaine affected 5-HT in the occipital cortex and behavioral activity in the same direction as visual stimulation, but in an amplified and prolonged way. In the temporal cortex cocaine also caused an increase in 5-HT. The findings demonstrate common effects of visual stimulation and cocaine on 5-HT activity in the occipital cortex in relation to locomotor activity. The results suggest that concepts of how neutral visual cues become powerful energizers of addiction-related behaviors should be expanded to incorporate not only an acute enhancement of reward processing mechanisms, but, in parallel, also an amplified processing of visual stimuli in the occipital cortex.

Extinction-induced "despair" in the Water Maze, Exploratory Behavior and Fear: Effects of Chronic Antidepressant Treatment

Neurobiology of Learning and Memory. May, 2007  |  Pubmed ID: 17223365

In former studies, we found evidence for the hypothesis that withdrawal of negative reinforcement presents a major source for stress and despair. Specifically, the removal of a hidden platform in the water maze induced extinction of previously reinforced escape behavior and behavioral immobility, indicative of "despair", which also correlated with indices of fear. Here, we tested the effects of antidepressants on extinction in the water maze, and expected that such drugs would attenuate the rate of extinction of a conditioned place preference (CPP) and also any emotionally relevant behavior that is induced by the loss of reinforcement, such as immobility. Adult male Wistar rats were trained to escape onto a hidden platform for 10 days. Daily treatment with desipramine hydrochloride (DMI, 10mg/kg) or fluoxetine (FLX, 10 mg/kg) commenced 1 day before the first of 11 extinction trials without the platform, administered 48 h apart, and continued thereafter, as the rats were tested in an open field and elevated-plus maze. As compared to controls, DMI increased the resistance-to-extinction of CPP, attenuated immobility, and increased wall climbing behavior. In the open field, DMI reduced activity levels, but was without effect on traditional fear parameters in the elevated-plus maze. FLX, by contrast, increased immobility during the extinction trials and fear in the elevated-plus maze. The withdrawal of reinforcement induced "despair" that was alleviated by the noradrenaline reuptake inhibitor DMI. The effects of the selective serotonin reuptake inhibitor FLX on immobility and fear may be explained in terms of its side effect profile.

Dopamine Activity in the Occipital and Temporal Cortices of Rats: Dissociating Effects of Sensory but Not Pharmacological Stimulation

Synapse (New York, N.Y.). Apr, 2007  |  Pubmed ID: 17230551

Little is known about the functional role of DA in other cortical areas than in the prefrontal cortex. Here we demonstrate that visual stimulation increases DA activity as measured by in vivo microdialysis in the occipital, but not in the temporal cortex of freely moving rats. Auditory stimulation neither acutely affected DA in the occipital nor in the temporal cortex. A pharmacological challenge with cocaine (0, 5, 10, 20 mg/kg; i.p.) increased DA levels in both areas dose-dependently. These data suggest that DA might play a role in visual processing selectively in the occipital cortex. Furthermore, the results indicate that DA in both regions may contribute to cocaine's behavioral effects.

Serotonin and Psychostimulant Addiction: Focus on 5-HT1A-receptors

Progress in Neurobiology. Feb, 2007  |  Pubmed ID: 17316955

Serotonin(1A)-receptors (5-HT(1A)-Rs) are important components of the 5-HT system in the brain. As somatodendritic autoreceptors they control the activity of 5-HT neurons, and, as postsynaptic receptors, the activity in terminal areas. Cocaine (COC), amphetamine (AMPH), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine ("Ecstasy", MDMA) are psychostimulant drugs that can lead to addiction-related behavior in humans and in animals. At the neurochemical level, these psychostimulant drugs interact with monoamine transporters and increase extracellular 5-HT, dopamine and noradrenalin activity in the brain. The increase in 5-HT, which, in addition to dopamine, is a core mechanism of action for drug addiction, hyperactivates 5-HT(1A)-Rs. Here, we first review the role of the various 5-HT(1A)-R populations in spontaneous behavior to provide a background to elucidate the contribution of the 5-HT(1A)-Rs to the organization of psychostimulant-induced addiction behavior. The progress achieved in this field shows the fundamental contribution of brain 5-HT(1A)-Rs to virtually all behaviors associated with psychostimulant addiction. Importantly, the contribution of pre- and postsynaptic 5-HT(1A)-Rs can be dissociated and frequently act in opposite directions. We conclude that 5-HT(1A)-autoreceptors mainly facilitate psychostimulant addiction-related behaviors by a limitation of the 5-HT response in terminal areas. Postsynaptic 5-HT(1A)-Rs, in contrast, predominantly inhibit the expression of various addiction-related behaviors directly. In addition, they may also influence the local 5-HT response by feedback mechanisms. The reviewed findings do not only show a crucial role of 5-HT(1A)-Rs in the control of brain 5-HT activity and spontaneous behavior, but also their complex role in the regulation of the psychostimulant-induced 5-HT response and subsequent addiction-related behaviors.

The Pharmacology, Neuroanatomy and Neurogenetics of One-trial Object Recognition in Rodents

Neuroscience and Biobehavioral Reviews. 2007  |  Pubmed ID: 17368764

Rats and mice are attracted by novel objects. They readily approach novel objects and explore them with their vibrissae, nose and forepaws. It is assumed that such a single explorative episode leaves a lasting and complex memory trace, which includes information about the features of the object explored, as well as where and even when the object was encountered. Indeed, it has been shown that rodents are able to discriminate a novel from a familiar object (one-trial object recognition), can detect a mismatch between the past and present location of a familiar object (one-trial object-place recognition), and can discriminate different objects in terms of their relative recency (temporal order memory), i.e., which one of two objects has been encountered earlier. Since the novelty-preference paradigm is very versatile and has some advantages compared to several other memory tasks, such as the water maze, it has become a powerful tool in current neurophamacological, neuroanatomical and neurogenetical memory research using both rats and mice. This review is intended to provide a comprehensive summary on key findings delineating the brain structures, neurotransmitters, molecular mechanisms and genes involved in encoding, consolidation, storage and retrieval of different forms of one-trial object memory in rats and mice.

Neurokinin 3 Receptor Activation Potentiates the Psychomotor and Nucleus Accumbens Dopamine Response to Cocaine, but Not Its Place Conditioning Effects

The European Journal of Neuroscience. Apr, 2007  |  Pubmed ID: 17445241

Neurokinin(3) receptors (NK(3)-Rs) have been implicated in psychomotor activity and reinforcement mechanisms. Recently, we showed that NK(3)-R antagonism blocked the psychostimulant properties of cocaine both in rats and in primates. Here, using in vivo microdialysis in the nucleus accumbens (NAc) of freely moving rats, we investigated the effect of the NK(3)-R agonist senktide (0.2 and 0.4 mg/kg s.c.) on the cocaine-evoked increase in dopamine. Cocaine (10 mg/kg i.p.) increased dopamine levels to 404 and 480% of baseline in the core and shell of the NAc, respectively. Pretreatment with senktide at a dose of 0.2 mg/kg potentiated this effect to 666 (core) and 869% (shell) of baseline, without having any effect on dopamine when given alone. Behavioural measurements revealed that 0.2 mg/kg senktide also potentiated the cocaine-induced increase in horizontal and vertical activity. Senktide alone induced a short-lasting increase in activity that was not accompanied by any alterations of the neurochemical parameters. In conditioned place preference (CPP) experiments, senktide pretreatment did not alter CPP induced by cocaine (5 and 10 mg/kg i.p.), and had no effect when given alone. Likewise, cocaine-conditioned locomotor activity was not affected by the NK(3)-R agonist. However, as in the microdialysis studies, cocaine-induced (5 and 10 mg/kg i.p.) hyperactivity was potentiated by senktide, and there was evidence for a facilitation of sensitization to the hyperlocomotor effects of cocaine by senktide. These data provide evidence that NK(3)-Rs are involved in the control of the hyperlocomotor and NAc DA response to cocaine, but not in cocaine-induced CPP.

NMDA Receptor Modulation by D-cycloserine Promotes Episodic-like Memory in Mice

Psychopharmacology. Sep, 2007  |  Pubmed ID: 17497136

NMDA-R (N-methyl-D-aspartate receptors) have been implicated in synaptic plasticity underlying one-trial learning of event-place associations. In rodents, episodic-like memory (ELM) of personally experienced events can be inferred from behavior that reflects the remembrance of the content (what kind of object was presented), place (where was this object placed), and temporal context (when was the object presented). We have previously shown that that D-cycloserine (DCS), an NMDA-R agonist, ameliorates stress-induced deficits in ELM.

Behavior on the Water Maze Platform: Relationship to Learning and Open Field Exploration in Aged and Adult Rats

Brain Research Bulletin. Sep, 2007  |  Pubmed ID: 17720541

In the present study we examined whether age-related deficits in the water maze could be accounted for by changes in the behavior on the platform, and whether platform behavior represents some form of exploration, akin to that seen in the open field. Twenty-seven aged and 8 adult rats (26 and 3 months old Wistar rats, respectively) were tested in an empty open field and spatial object exploration task, followed by 9 days of escape learning in a water maze. The aged as compared to the adults exhibited lower levels of open field activity and were deficient in the object displacement task. Escape deficits in the water maze and reduced activity levels on the platform were also found. In the aged, water maze performance was correlated with behavior on the platform, including quiescence, orienting-like activity and turning behavior, a form of axial rotation. In both age groups, turning behavior was also correlated with exploratory activity in the open field. In conclusion, the results support the hypothesis that age-related impairments in the water maze relate to changes in platform behavior, which, in turn, might reflect exploratory activity.

Characterization of Connexin30.3-deficient Mice Suggests a Possible Role of Connexin30.3 in Olfaction

European Journal of Cell Biology. Dec, 2007  |  Pubmed ID: 17728008

We have generated connexin30.3-deficient mice in which the coding region of the connexin30.3 gene was replaced by the lacZ reporter gene. The expression pattern of this connexin was characterized using beta-galactosidase staining and immunoblot analyses. In skin, beta-galactosidase/connexin30.3 protein was expressed in the spinous and granulous layers of the epidermis. Specific beta-galactosidase/connexin30.3 expression was also detected in the thin ascending limb of Henle's loop in the kidney. In addition, we found beta-galactosidase/connexin30.3 in progenitor cells of the olfactory epithelium and in a subpopulation of cells in the apical layer of the vomeronasal organ. Connexin30.3-deficient mice were fertile and displayed no abnormalities in the skin or in the chemosensory systems. Furthermore, they showed normal auditory thresholds as measured by brain stem evoked potentials. These mice did, however, exhibit reduced behavioural responses to a vanilla scent.

Effects on Spontaneous and Cocaine-induced Behavior of Pharmacological Inhibition of Noradrenergic and Serotonergic Systems

Pharmacology, Biochemistry, and Behavior. Mar, 2008  |  Pubmed ID: 18155756

Cocaine-induced increases in dopamine (DA) contribute importantly to cocaine effects on behavior but, the role of concomitant increases in norepinephrine (NE) and serotonin (5-HT) is less well understood. In order to selectively block the increases in NE and 5-HT evoked by cocaine, autoreceptor preferring low doses (0.01, 0.025 and 0.05 mg/kg) of the a2 agonist, Clonidine or the 5-HT1A agonist, 8-OHDPAT were given as pretreatments 20 min prior to saline or cocaine (10.0 mg/kg) in separate groups of rats (N=10). With pharmacological stimulation of NE and 5-HT autoreceptors, release of these neurotransmitters would be suppressed and, therefore, less available for re-uptake blockade by cocaine. With increasing dose levels, Clonidine had marked inhibitory effects on spontaneous and cocaine-induced locomotion, grooming and rearing. 8-OHDPAT pretreatment also suppressed spontaneous locomotion, grooming and rearing; but, in contrast, did not reduce the cocaine locomotor stimulant effects. 8-OHDPAT, however, did suppress central zone entry and rearing in cocaine treated rats. Using ex vivo methods, we found that 8-OHDPAT selectively reduced 5-HT metabolism in the medial frontal cortex (MFC) and subcortical limbic brain. Clonidine selectively reduced NE metabolism in the MFC, but decreased both DA and 5-HT metabolism in the subcortical limbic brain without affecting NE metabolism. This diverse and broad spectrum of Clonidine effects upon neurotransmitters and behavior is striking and points-up the important, complex and integrative role of NE in brain function. While both Clonidine and 8-OHDPAT can substantially attenuate a number of cocaine behavioral effects, these inhibitory effects appear to be secondary to reductions in the behavioral baseline rather than reversals of cocaine effects.

Behavioral Actions of Intranasal Application of Dopamine: Effects on Forced Swimming, Elevated Plus-maze and Open Field Parameters

Neuropsychobiology. 2008  |  Pubmed ID: 18515976

Recently, we found evidence that intra-nasally administered dopamine (DA), can enter the brain, leading to an immediate increase in extracellular DA levels in striatal subregions. This offers a potential alternative approach to target the brain with exogenous DA, which otherwise cannot cross the blood-brain barrier. Here, we examined whether intra-nasally applied DA also exerts behavioral activity on mesocortical and nigrostriatal dopaminergic functions.

NK(3) Receptor Agonism Promotes Episodic-like Memory in Mice

Neurobiology of Learning and Memory. Sep, 2008  |  Pubmed ID: 18556225

The mammalian tachykinins are a family of closely related peptides including substance P, neurokinin A, neurokinin B and, recently, also hemokinin-1. They are present in the peripheral and central nervous systems, and bind to three known neurokinin (NK) receptors, the NK(1)-, NK(2)- and NK(3) receptors. In both rodents and humans, NK(3) receptors are expressed in brain structures which have been associated with learning and memory. Evidence for a role of NK(3) receptors in learning and memory has been found in NK(3) receptor knockout mice. Here, we investigated the influence of the NK(3) receptor agonist, senktide (0.1, 0.2 and 0.4 mg/kg), on the performance of C57BL/6 mice in a recently developed episodic-like memory task. Since a promnestic effect of senktide was expected, we employed an experimental protocol that provided sub-optimal learning conditions for episodic-like memory. The results indicate that senktide promotes episodic-like memory in mice in a dose-dependent manner, providing, for the first time, evidence for an involvement of NK(3) receptors in episodic-like memory.

Frequency of Network Synchronization in the Hippocampus Marks Learning

The European Journal of Neuroscience. Jun, 2008  |  Pubmed ID: 18588541

The synchronization of neuronal networks may be instrumental in plasticity and learning. Hippocampal high-frequency oscillations (140-200 Hz, 'ripples') characteristic of consummatory behaviours are thought to promote memory formation. We recorded ripple oscillations from the CA1 area in temporal learning tasks. Rats learned to adjust their operant response to the timing of food reward delivery [fixed interval schedule (FI)]. The intrinsic frequency of ripples was elevated following the switch in reinforcement timing. Learning, as assessed from the response pattern, correlated with fluctuations of intraripple frequency and amplitude. Changes in motor activity did not account for the variability of ripple oscillations. At the same time, features of ripples were unaltered when the fixed interval of reward delivery was changed but did not depend on the lever press response. Thus, in addition to the known replay of neuronal firing patterns during ripple oscillations, the rhythm itself appears to be modulated in an experience-specific way and represents a direct correlate of learning.

Behavior Selectively Elicited by Novel Stimuli: Modulation by the 5-HT1A Agonist 8-OHDPAT and Antagonist WAY-100635

Behavioural Pharmacology. Jul, 2008  |  Pubmed ID: 18622186

The serotonergic system has a broad influence on behavior, but its specific contribution to novel object exploration remains to be examined. Toward this end, we assessed the impact of the 5-HT1A agonist, 8-OHDPAT (0.01-0.05 mg/kg) and the 5-HT1A antagonist, WAY-100635 (0.01-0.05 mg/kg) on novel object exploration in a familiar open-field environment. 8-OHDPAT produced a dose-related inhibition of responding to the novel object, whereas, WAY-100635 treatment induced a dose-related increase in the investigatory response to the novel object. Combined, the effects of WAY and 8-OHDPAT treatments were statistically indistinguishable from saline. In terms of locomotor activity, only the highest dose of 8-OHDPAT (0.05 mg/kg) altered locomotor activity and the effect was inhibitory. These findings provide evidence for an involvement of the serotonergic system in the response to novel stimuli and indicate that this effect can be dissociated from effects on overall activity including locomotor, rearing and grooming behaviors.

Extinction-induced "despair" in Aged and Adult Rats: Links to Neurotrophins in Frontal Cortex and Hippocampus

Neurobiology of Learning and Memory. Oct, 2008  |  Pubmed ID: 18662794

In the search for animal models of human geriatric depression, we found that operant extinction of escape from water results in the expression of immobility in different age groups, indicative of behavioral "despair", which was also associated with the resistance-to-extinction (RTE) expressed by these animals. With respect to the neurotrophin hypothesis of depression, nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein levels in frontal cortex (FC) and hippocampus (HP) were examined and related to behavioral immobility and RTE in the water maze in aged and adult Wistar rats. Age-related increases in levels of NGF were found in HP and of NT-3 in FC. Indices of immobility showed relationships in the aged with NGF and, in adults, with BDNF, pointing to a dissociation of neurotrophic involvement in extinction trial-induced "despair" in aged and adult rats. The present results support the hypothesis, that extinction-induced immobility in the water maze reflects a state akin to behavioral despair and point to age-related differences of neurotrophic involvement in depressive-like symptoms. The concept of extinction-induced behavioral "despair" in the aged subsumes several aspects of human geriatric depression, such as co-morbidity of learning impairment and anxiety, and, thus could represent a useful paradigm to examine the neuronal mechanisms underlying depression, especially in aged rodents.

Predatory Stress As an Experimental Strategy to Measure Fear and Anxiety-related Behaviors in Non-human Primates

Reviews in the Neurosciences. 2008  |  Pubmed ID: 18751522

Natural defense-inducing stimuli are being increasingly exploited as a means to investigate the neural mechanisms underlying normal and pathological anxiety, as well as for the screening of new compounds with potential therapeutic use in human anxiety disorders. Such an approach, frequently used in rodents, has recently been employed in the Marmoset Predator Confrontation Test (MPCT). In this method, marmoset monkeys are individually confronted with a taxidermized predator (wild oncilla cat) in a previously habituated maze environment, while several easily discernable fear/anxiety-related behaviors are measured. Confrontation with the cat stimulus significantly altered ongoing behaviors, each habituating distinctively during repeated exposures; e.g. complete rapid habituation (alarm call), complete slow habituation (exploration, vigilance) or only partial habituation (proximity avoidance). Pharmacological validating studies with diazepam and buspirone induced a significant dose-dependent reversal of the fear-induced proximic avoidance and scratching/scent-marking behaviors, while exploration (smell/lick the maze, leg stand) was found to increase. The neuropeptide substance P and the selective 5-HT1A receptor antagonist WAY100635 resulted in a similar anxiolytic-like profile. The response pattern observed was not influenced by social isolation, handling/manual restraint, novel environment exposure or habituation to the stimulus or its location. Persistent defensive behavior and response pattern to diazepam was observed when naive versus MPCT-experienced marmosets were tested following a recent predatory stress. Taken together, the results indicate that the MPCT is a valuable experimental procedure to measure fear and anxiety-related behaviors in nonhuman primates.

Pharmacological Inhibition of Dopamine and Serotonin Activity Blocks Spontaneous and Cocaine-activated Behaviour

Progress in Brain Research. 2008  |  Pubmed ID: 18772041

The dopaminergic (DA) and serotonergic (5-HT) systems are modulatory transmitter systems that can influence a wide range of behavioural functions. Psychostimulant drugs increase both DA and 5-HT activity by substance-specific mechanisms and, consequently, can broadly influence behavioural and emotional processes in humans and animals. In this chapter, we examine psychostimulant drug effects from the perspective of DA-5-HT and environmental context interactions and anchor this analysis to changes in spontaneous behaviour. In our consideration of the DA and 5-HT transmitter systems, we focus on pharmacological manipulations that target DA and 5-HT autoreceptors. Autoreceptors provide negative feedback inhibitory control of DA and 5-HT neuronal activity so that pharmacological treatments that act on autoreceptors can regulate DA and 5-HT availability. Since psychostimulant drug effects are linked to DA and 5-HT availability, our analysis focuses on investigations that use autoreceptor pharmacology to unravel the complexity of psychostimulant drug action. The overall findings from the experimental manipulations of autoreceptor pharmacology were then used to discuss issues pertinent to drug development for the treatment of psychostimulant drug addiction.

Differential Susceptibility to Extinction-induced Despair and Age-dependent Alterations in the Hypothalamic-pituitary-adrenal Axis and Neurochemical Parameters

Neuropsychobiology. 2008  |  Pubmed ID: 19088491

Clinical studies point to structural differences in the neurobiological mechanisms underlying early versus late onset of depression. However, studies examining the neuropathology of depressive-like behavior induced in the aged rodent are sparse. Extinction of learned behavior induces be- havioral 'despair', and is held to provide a conceptual and empirical model of human depression resulting from the withdrawal of reinforcement. We tested whether the neuroendocrinological and chemical concomitants of susceptibility to extinction-induced despair in aged animals differed from adult ones. Following the withholding of reinforcement (extinction of escape from a water maze), a number of aged and adult rats are prone to develop depressive-like behavior, i.e. immobility. Analysis of hypothalamus-pituitary-adrenal (HPA) axis markers revealed an increase in the mineralocorticoid/glucocorticoid receptor (MR/GR) mRNA ratio in the CA1 region of the hippocampus in aged and adult despair animals; however, in dependence on age, divergent changes contributed to the enhanced ratio. While aged despair rats had less GR mRNA, adult despair rats had more MR mRNA. Furthermore, age- and despair-related interactions with hippocampal and cortical steroid receptor co-activators and neurotransmitter contents in diverse brain areas were found. For instance, adult despair rats had an increased, and aged despair rats a decreased, DOPAC/dopamine turnover compared to the respective non-despair group. These results show that neurobiological underpinnings of depression in the aged differ from those of adults, and underline the importance of investigating age-related alterations in HPA axis dynamics in conjunction with neurotransmitter systems to advance our knowledge about neuronal mechanisms of late-life and/or late-onset depression.

Intranasal Application of Dopamine Reduces Activity and Improves Attention in Naples High Excitability Rats That Feature the Mesocortical Variant of ADHD

European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. Oct, 2009  |  Pubmed ID: 19328660

Based on findings of a profound action of intranasally applied dopamine (DA) on dopamine release in the striatum, we examined the possibility that intranasal application of DA would influence indices of attention and activity in juvenile male rats of the Naples High Excitability line. This rat model features the main aspects of Attention Deficit/Hyperactivity Disorder (ADHD). Juvenile NHE rats received an intranasal application of either DA (0.075 mg/kg, 0.15 mg/kg and 0.3 mg/kg) or vehicle into both nostrils daily for 15 days. On day 14, 1 h after treatment, they were tested in the Làt maze, and one day later, in the eight arm radial maze. Activity in the Làt maze: The highest dose of DA (0.3 mg/kg) decreased horizontal (HA) and vertical (VA) activity during the first 10 min of the test. No effect was found for rearing duration (RD), which indexes non-selective attention (NSA). Activity in the radial maze: No treatment effects were found for HA and VA components, and for RD. Attention indices: The intermediate dose of DA (0.15 mg/kg) significantly improved the number of arms visited before the first repetitive arm entry in the radial maze, an index of selective spatial attention (SSA). In conclusion, intranasal application of DA reduced hyperactivity at the highest dose used, whereas the intermediate dose improved attention in an animal model of ADHD. These results suggest the potential of employing intranasal DA for therapeutic purposes.

Toward an Animal Model of Extinction-induced Despair: Focus on Aging and Physiological Indices

Journal of Neural Transmission (Vienna, Austria : 1996). Aug, 2009  |  Pubmed ID: 19350220

Behaviors that are under the control of positive or negative reinforcers undergo extinction when the anticipated reward/reinforcer is withheld. Despair, an important symptom of environmentally determined depression in humans, can be generated by extinction, or the failure of expected reward to accrue. Although well known to clinicians dealing with depressive patients, an animal model has not been available for extinction-induced depression. We have made a beginning towards validating such a model, based on the extinction of negatively reinforced behavior in the rat, i.e., upon removal of the possibility to escape onto a safety platform in the water maze. As a marker for despair, we employed behavioral immobility, i.e., the cessation of swimming in the attempt to find safety from the water, presumably, a type of learned helplessness. This measure was sensitive to antidepressants and correlated with neurotransmitter contents, neurotrophins and hypothalamus-pituitary adrenal axis markers in selected sites of the brain. Given that some cases of depression in the elderly may be biologically distinct from others and from early-onset depression, and since particularly the aged are prone to experience extinction-induced despair, we compared aged (ca. 24 months old) animals with adults in most of our studies. We found a number of distinct differences in behavioral and biological measures, indicative of differences in propensity to, as well as response to, extinction-induced despair between aged and adults. Our results add to the body of evidence for differences in the neurobiological substrates of depressive disorders between aged and adults, with the implication for the requirement of different treatment strategies in these two populations.

Binding of [123I]iodobenzamide to the Rat D2 Receptor After Challenge with Various Doses of Methylphenidate: an in Vivo Imaging Study with Dedicated Small Animal SPECT

European Journal of Nuclear Medicine and Molecular Imaging. Apr, 2011  |  Pubmed ID: 21110190

The effect of various doses of methylphenidate on the binding of [(123)I]iodobenzamide ([(123)I]IBZM) to the rat D(2) receptor was assessed using small animal SPECT.

The Neural Foundations of Aesthetic Appreciation

Progress in Neurobiology. Jun, 2011  |  Pubmed ID: 21421021

The study of the cognitive and neural underpinnings of aesthetic appreciation by means of neuroimaging techniques has yielded a wealth of fascinating information. Although the results of these studies have been somewhat divergent, here we provide an integrative view of the early approaches, which identified some of the core mechanisms involved in aesthetic preference. Then, a number of more specific issues under the perspective of recent work are addressed. Finally, we propose a framework to accommodate these findings and we explore future prospects for the emerging field of neuroaesthetics.

The Value of Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Anxiety Disorders: an Integrative Review

CNS & Neurological Disorders Drug Targets. Aug, 2011  |  Pubmed ID: 21631403

Unlike for depression, only few studies are available today investigating the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) for anxiety disorders. This review aims to provide information on the current research approaches and main findings regarding the therapeutic use of rTMS in the context of various anxiety disorders. Although positive results have frequently been reported in both open and randomized controlled studies, our review of all identified studies indicates that at present no conclusive evidence of the efficacy of rTMS for the treatment for anxiety disorders is provided. Several treatment parameters have been used, making the interpretation of the results difficult. Moreover, sham-controlled research has often been unable to distinguish between response to rTMS and sham treatment. However, there is a limitation in the rTMS methods that likely impacts only the superficial cortical layers. It is not possible to directly stimulate more distant cortical areas, and also subcortical areas, relevant to the pathogenesis of anxiety disorders, though such effects in subcortical areas are thought to be indirect, via trans-synaptic connections. We thus recommend further studies to clearly determine the role of rTMS in the treatment of anxiety disorders. Key advances in combining TMS with neuroimaging technology may aid in such future developments.

The in Vivo Neurochemistry of the Brain During General Anesthesia

Journal of Neurochemistry. Nov, 2011  |  Pubmed ID: 21883214

Anesthesia describes a complex state composed of immobility, amnesia, hypnosis (sleep or loss of consciousness), analgesia, and muscle relaxation. Bottom-up approaches explain anesthesia by an interaction of the anesthetic with receptor proteins in the brain, whereas top-down approaches consider predominantly cortical and thalamic network activity and connectivity. Both approaches have a number of explanatory gaps and as yet no unifying view has emerged. In addition to a direct interaction with primary target receptor proteins, general anesthetics have massive effects on neurotransmitter activity in the brain. They can change basal transmitter levels by interacting with neuronal activity, transmitter synthesis, release, reuptake and metabolism. By that way, they can affect a great number of neurotransmitter systems and receptors. Here, we review how different general anesthetics affect extracellular activity of neurotransmitters in the brain during induction, maintenance, and emergence from anesthesia and which functional consequences this may have. Commonalities and differences between different groups of anesthetics in their action on neurotransmitter activity are discussed. We also review how general anesthetics affect the response dynamics of the neurotransmitter systems after sensory stimulation. More than 30 years of research have now yielded a complex picture of the effects of general anesthetics on brain neurotransmitter basal activity and response dynamics. It is suggested that analyzing the effects on neurotransmitter activity is the logical next step after protein interactions in a bottom-up analysis of anesthetic action in the brain on the way to a unifying view of anesthesia.

Decreased Methylation of the NK3 Receptor Coding Gene (TACR3) After Cocaine-induced Place Preference in Marmoset Monkeys

Addiction Biology. Nov, 2011  |  Pubmed ID: 22070124

Epigenetic processes have been implicated in neuronal plasticity following repeated cocaine application. Here we measured DNA methylation at promoter CpG sites of the dopamine transporter (DAT1) and serotonin transporter (SERT) and neurokinin3-receptor (NK3-R)-receptor (TACR3) coding genes in marmoset monkeys after repeated cocaine injections in a conditioned place preference paradigm. We found a decrease in DNA methylation at a specific CpG site in TACR3, but not DAT1 or SERT. Thus, TACR3 is a locus for DNA methylation changes in response to repeated cocaine administration and its establishment as a reinforcer, in support of other evidence implicating the NK3-R in reinforcement- and addiction-related processes.

Pharmacological Challenge and Synaptic Response - Assessing Dopaminergic Function in the Rat Striatum with Small Animal Single-photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET)

Reviews in the Neurosciences. 2011  |  Pubmed ID: 22103308

Disturbances of dopaminergic neurotransmission may be caused by changes in concentrations of synaptic dopamine (DA) and/or availabilities of pre- and post-synaptic transporter and receptor binding sites. We present a series of experiments which focus on the regulatory mechanisms of the dopamin(DA)ergic synapse in the rat striatum. In these studies, DA transporter (DAT) and/or D(2) receptor binding were assessed with either small animal single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after pharmacological challenge with haloperidol, L-DOPA and methylphenidate, and after nigrostriatal 6-hydroxydopamine lesion. Investigations of DAT binding were performed with [(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([(123)I]FP-CIT). D(2) receptor bindingd was assessed with either [(123)I](S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([(123)I]IBZM) or [(18)F]1[3-(4'fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine ([(18)F]FMB). Findings demonstrate that in vivo investigations of transporter and/or receptor binding are feasible with small animal SPECT and PET. Therefore, tracers that are radiolabeled with isotopes of comparatively long half-lives such as (123)I may be employed. Our approach to quantify DAT and/or D(2) receptor binding at baseline and after pharmacological interventions inducing DAT blockade, D(2) receptor blockade, and increases or decreases of endogenous DA concentrations holds promise for the in vivo assessment of synaptic function. This pertains to animal models of diseases associated with pre- or postsynaptic DAergic deficiencies such as Parkinson's disease, Huntington's disease, attention-deficit/hyperactivity disorder, schizophrenia or drug abuse.

Intranasally Applied L-DOPA Alleviates Parkinsonian Symptoms in Rats with Unilateral Nigro-striatal 6-OHDA Lesions

Brain Research Bulletin. Feb, 2012  |  Pubmed ID: 22108632

l-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of L-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied L-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN L-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN L-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20 min after the treatment. IN L-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that L-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model.

The NK3 Receptor Agonist Senktide Ameliorates Scopolamine-induced Deficits in Memory for Object, Place and Temporal Order

Neurobiology of Learning and Memory. Feb, 2012  |  Pubmed ID: 22209911

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schäble et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK3-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK3-R agonists and their activating influence on ACh suggest a possible role of the NK3-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK3-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous--s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object-place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object-place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine-induced memory impairments and indicate that the promnestic action of NK3-R agonists is mediated by muscarinic cholinergic mechanisms.

Human and Rat Brain Lipofuscin Proteome

Proteomics. Aug, 2012  |  Pubmed ID: 22707227

The accumulation of an autofluorescent pigment called lipofuscin in neurons is an invariable hallmark of brain aging. So far, this material has been considered to be waste material without particular relevance for cellular pathology. However, two lines of evidence argue that lipofuscin may play a yet unidentified role for pathological cellular functions: (i) Genetic forms of premature accumulation of similar autofluorescent material in neuronal ceroid lipofuscinosis indicate a direct disease-associated link to lipofuscin; (ii) Retinal pigment epithelium cell lipofuscin is mechanistically linked to age-associated macular degeneration. Here, we purified autofluorescent material from the temporal and hippocampal cortices of three different human individuals by a two-step ultracentrifugation on sucrose gradients. For human brain lipofuscin, we could identify a common set of 49 (among > 200 total) proteins that are mainly derived from mitochondria, cytoskeleton, and cell membrane. This brain lipofuscin proteome was validated in an interspecies comparison with whole brain rat lipofuscin (total > 300 proteins), purified by the same procedure, yielding an overlap of 32 proteins (64%) between lipofuscins of both species. Our study is the first to characterize human and rat brain lipofuscin and identifies high homology, pointing to common cellular pathomechanisms of age-associated lipofuscin accumulation despite the huge (40-fold) difference in the lifespan of these species. Our identification of these distinct proteins will now allow research in disturbed molecular pathways during age-associated dysfunctional lysosomal degradation.

Repeated Cocaine Administration in Marmoset Monkeys Induces Hypervigilance-related Behaviors, but No Changes in Locomotion and Cortisol Levels

Pharmacology, Biochemistry, and Behavior. Aug, 2012  |  Pubmed ID: 22921767

Although cocaine induces several behavioral and hormonal effects, little is known about non-contingent repeated administrations in non-human primates. Therefore, we analyzed behavioral (locomotion, vigilance) and hormonal (cortisol) responses of adult black tufted-ear marmosets during repeated administrations and withdrawal trials. The subjects were divided into two groups (saline or cocaine 5mg/kg, ip) and submitted to nine treatment trials and four withdrawal trials in the absence of any treatment in an open-field arena. Blood samples were obtained on five different time points of the procedure to evaluate the effects of repeated cocaine treatment on basal cortisol levels. Cocaine repeatedly administered to drug-naïve marmosets induced a slow-onset hypervigilance effect (i.e., scan - long-lasting sweeping movements of the head directed at the environment; and glance - single rapid movement of the head directed at the environment), with no concomitant change in locomotion. Treatment cessation during withdrawal immediately reversed the cocaine-induced hypervigilance effect. Cortisol levels remained constant throughout the procedure. Therefore, marmosets seem to have a similar behavioral - but not hormonal - response as humans and other nonhuman primates repeatedly injected with cocaine, but differ from rats in their absence of hyperlocomotor activity. The development of hypervigilance with repeated application may constitute a unique measure to assess cocaine-induced changes in behavior in the marmoset and other nonhuman primates.

Neurokinin2-R in Medial Septum Regulate Hippocampal and Amygdalar ACh Release Induced by Intraseptal Application of Neurokinins A and B

Hippocampus. May, 2012  |  Pubmed ID: 20882546

The neurokinin receptors (NK-R), NK(2)- and NK(3)-R, have been implicated in behavioral processes, but apparently in opposite ways: while NK(2)-R agonism disrupts memory and has anxiogenic-like action, NK(3) -R agonists facilitate memory and display anxiolytic-like effects. Systemic application of NK(2)-R antagonists block the release of acetylcholine (ACh) in the hippocampus, which is induced by intraseptal administration of the NK(2)-R ligand, neurokinin A (NKA). We investigated the effects of medial septal injection of NKA and a preferred ligand of NK(3)-R, neurokinin B (NKB), on the activity of cholinergic neurons of the basal forebrain and assessed the role of the medial septal NK(2)-R in the control of extracellular ACh levels in cholinergic projection areas. ACh was dialysed in the frontal cortex, amygdala and hippocampus of anesthetized animals and was analysed by HPLC-EC. ACh levels in hippocampus and amygdala, but not in frontal cortex were increased after intraseptal injection of either NKA or NKB (0.1, 1, 10 μM). Application of the nonpeptidic NK(2)-R antagonist, saredutant SR48968 (1, 10, 100 pM), followed by NKA (1 μM) or NKB (10 μM) injection into the medial septum, blocked the ACh increase in hippocampus and amygdala. These results indicate that medial septal NK(2)-R have an important role in mediating ACh release, for one, via the septal-hippocampal cholinergic projection and, secondly, via direct or indirect route to the amygdala, but not frontal cortex. They also support the hypothesis that hippocampal cholinergic neurotransmission controls amygdala function suggesting that this interaction is regulated via NK(2)-R in the medial septum.

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