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Find video protocols related to scientific articles indexed in Pubmed.
A choice-based screening method for compulsive drug users in rats.
Curr Protoc Neurosci
PUBLISHED: 07-16-2013
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We describe a protocol for screening compulsive drug users among cocaine self-administering rats, the most frequently used animal model in addiction research. Rats are first trained on several alternating days to self-administer either cocaine (i.v.) or saccharin-sweetened water (by mouth)--a potent, albeit nonessential, nondrug reward. Then rats are allowed to choose between the two rewards over several days until the preference stabilizes. Most rats choose to stop using cocaine and pursue the alternative reward. Only a minority of Wistar strain rats (generally 15%) persist in taking the drug, regardless of the severity of past cocaine use and even when made hungry and offered the possibility to relieve their physiological need. Persistence of cocaine use in the face of a high-stakes choice is a core defining feature of compulsion. This choice-based screening method for compulsive drug users is easy to implement, has several important applications, and compares well with other methods in the field.
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Intravenous nicotine injection induces rapid, experience-dependent sensitization of glutamate release in the ventral tegmental area and nucleus accumbens.
J. Neurochem.
PUBLISHED: 06-25-2013
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Although numerous data suggest that glutamate (GLU) is involved in mediating the neural effects of nicotine, direct data on nicotine-induced changes in GLU release are still lacking. Here, we used high-speed amperometry with enzyme-based GLU and enzyme-free GLU-null biosensors to examine changes in extracellular GLU levels in the ventral tegmental area (VTA) and nucleus accumbens shell (NAcc) induced by intravenous nicotine in a low, behaviorally active dose (30 ?g/kg) in freely moving rats. Using this approach, we found that the initial nicotine injection in drug-naive conditions induces rapid, transient, and relatively small GLU release (~ 90 nM; latency ~ 15 s, duration ~ 60 s) that is correlative in the VTA and NAcc. Following subsequent nicotine injections within the same session, this phasic GLU release was supplemented by stronger tonic increases in GLU levels (100-300 nM) that paralleled increases in drug-induced locomotor activation. GLU responses induced by repeated nicotine injections were more phasic and stronger in the NAcc than in VTA. Therefore, GLU is phasically released within the brains reinforcement circuit following intravenous nicotine administration. Robust enhancement of nicotine-induced GLU responses following repeated injections suggests this change as an important mediator of sensitized behavioral and neural effects of nicotine. By using high-speed amperometry with glutamate (GLU) biosensors, we show that i.v. nicotine at a low, behaviorally relevant dose induces rapid GLU release in the NAcc and VTA that is enhanced following repeated drug injections. This is the first study reporting second-scale fluctuations in extracellular GLU levels induced by nicotine in two critical structures of the motivation-reinforcement circuit and rapid sensitization of GLU responses coupled with locomotor sensitization.
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Rapid sensitization of physiological, neuronal, and locomotor effects of nicotine: critical role of peripheral drug actions.
J. Neurosci.
PUBLISHED: 06-14-2013
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Repeated exposure to nicotine and other psychostimulant drugs produces persistent increases in their psychomotor and physiological effects (sensitization), a phenomenon related to the drugs reinforcing properties and abuse potential. Here we examined the role of peripheral actions of nicotine in nicotine-induced sensitization of centrally mediated physiological parameters (brain, muscle, and skin temperatures), cortical and VTA EEG, neck EMG activity, and locomotion in freely moving rats. Repeated injections of intravenous nicotine (30 ?g/kg) induced sensitization of the drugs effects on all these measures. In contrast, repeated injections of the peripherally acting analog of nicotine, nicotine pyrrolidine methiodide (nicotine(PM), 30 ?g/kg, i.v.) resulted in habituation (tolerance) of the same physiological, neuronal, and behavioral measures. However, after repeated nicotine exposure, acute nicotine(PM) injections induced nicotine-like physiological responses: powerful cortical and VTA EEG desynchronization, EMG activation, a large brain temperature increase, but weaker hyperlocomotion. Additionally, both the acute locomotor response to nicotine and nicotine-induced locomotor sensitization were attenuated by blockade of peripheral nicotinic receptors by hexamethonium (3 mg/kg, i.v.). These data suggest that the peripheral actions of nicotine, which precede its direct central actions, serve as a conditioned interoceptive cue capable of eliciting nicotine-like physiological and neural responses after repeated nicotine exposure. Thus, by providing a neural signal to the CNS that is repeatedly paired with the direct central effects of nicotine, the drugs peripheral actions play a critical role in the development of nicotine-induced physiological, neural, and behavioral sensitization.
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Physiological fluctuations in brain temperature as a factor affecting electrochemical evaluations of extracellular glutamate and glucose in behavioral experiments.
ACS Chem Neurosci
PUBLISHED: 03-14-2013
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The rate of any chemical reaction or process occurring in the brain depends on temperature. While it is commonly believed that brain temperature is a stable, tightly regulated homeostatic parameter, it fluctuates within 1-4 °C following exposure to salient arousing stimuli and neuroactive drugs, and during different behaviors. These temperature fluctuations should affect neural activity and neural functions, but the extent of this influence on neurochemical measurements in brain tissue of freely moving animals remains unclear. In this Review, we present the results of amperometric evaluations of extracellular glutamate and glucose in awake, behaving rats and discuss how naturally occurring fluctuations in brain temperature affect these measurements. While this temperature contribution appears to be insignificant for glucose because its extracellular concentrations are large, it is a serious factor for electrochemical evaluations of glutamate, which is present in brain tissue at much lower levels, showing smaller phasic fluctuations. We further discuss experimental strategies for controlling the nonspecific chemical and physical contributions to electrochemical currents detected by enzyme-based biosensors to provide greater selectivity and reliability of neurochemical measurements in behaving animals.
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Neurobiology of addiction versus drug use driven by lack of choice.
Curr. Opin. Neurobiol.
PUBLISHED: 01-23-2013
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Research on the neurobiology of addiction often involves nonhuman animals that are given ready access to drugs for self-administration but without other choices. Here we argue using cocaine as an example that this standard setting may no longer be sufficient and can even lead to the formulation of unrealistic views about the neurobiology of addiction. Addiction as a psychiatric disorder is defined as resulting from brain dysfunctions that affect normal choice-making, not as an expectable response to lack of alternative choices. We encourage neurobiologists involved in addiction research to increase animals choice during drug access, preferably by supplying alternative rewarding pursuits. Only animals that continue to take and prefer drugs despite and at the expense of other available choices may be considered as having developed an addiction-like behavior in comparison to those that remain able to stop drug use for other pursuits, even after extended drug use. The systematic comparison of these two individual behaviors should reveal new insights about the neurobiology of drug choice and addiction. More generally, this research should also shed a unique light on how the brain chooses among qualitatively different kinds of pursuits.
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Extended heroin access increases heroin choices over a potent nondrug alternative.
Neuropsychopharmacology
PUBLISHED: 01-15-2013
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Epidemiological research shows that the proportion of drug users who become addicted to heroin is higher than to cocaine. Here we tested whether this difference could be due to a difference in the addiction liability between the two drugs. Addiction liability was assessed under a discrete-trials choice procedure by measuring the proportion of rats that prefer the drug over a potent alternative reward (ie, water sweetened with saccharin). Previous research on choice between self-administration of i.v. cocaine or sweet water showed that the proportion of cocaine-preferring rats remains relatively low and invariable (ie, 15%), even after extended drug access and regardless of past drug consumption (ie, total drug use before choice testing). By contrast, the present study shows that under similar choice conditions, the proportion of heroin-preferring rats considerably increases with extended heroin access (6-9?h per day for several weeks) and with past heroin consumption, from 11 to 51% at the highest past drug consumption level. At this level, the proportion of drug-preferring rats was about three times higher with heroin than with cocaine (51% vs 15%). This increase in the rate of heroin preference after extended heroin access persisted even after recovery from acute heroin withdrawal. Overall, these findings show that choice procedures are uniquely sensitive to different drugs and suggest that heroin is more addictive than cocaine. This higher addiction liability may contribute to explain why more drug users become addicted to heroin than to cocaine in epidemiological studies.
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Drug specificity in extended access cocaine and heroin self-administration.
Addict Biol
PUBLISHED: 10-13-2011
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Increased drug availability can precipitate a rapid escalation of drug consumption in both vulnerable humans and laboratory animals. Drug intake escalation is observed across a broad spectrum of drugs of abuse, including stimulants, opiates, ethanol and phencyclidine. Whether and to what extent the processes underlying escalated levels of drug intake vary across different substances is poorly understood. The present study sought to address this question in rats self-administering both cocaine and heroin-two addictive drugs with both common and different neurobiological effects. In experiment 1, we determined how cocaine intake is initially related to heroin intake in non-escalated rats with a limited access to both drugs. In experiment 2, two groups of rats were initially allowed to self-administer either cocaine or heroin for 1 hour per day and then after behavioral stabilization, for 6 hours per day to precipitate drug intake escalation. In each group, dose-injection functions for cocaine and heroin self-administration were generated. In experiment 1, regardless of the dose, rats with a high intake of one drug did not necessarily have a high intake of the alternate drug. In experiment 2, escalated levels of heroin or cocaine self-administration did not generalize to the other drug. This outcome was confirmed in a third drug substitution experiment following different access lengths to cocaine self-administration (i.e. 1, 4 and 8 hours). The processes underlying spontaneous and escalated drug overconsumption appear thus to vary across different drugs of abuse. More research should be devoted in the future to these differences.
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Critical role of peripheral actions of intravenous nicotine in mediating its central effects.
Neuropsychopharmacology
PUBLISHED: 06-08-2011
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In addition to its direct action on central neurons, nicotine (NIC) activates multiple nicotinic acetylcholine receptors localized on afferent terminals of sensory nerves at the sites of its administration. Although the activation of these receptors is important in mediating the primary sensory and cardiovascular effects of NIC, their role in triggering and maintaining the neural effects of NIC remains unclear. Using high-speed electroencephalography (EEG) and electromyography (EMG) recordings in freely moving rats, we showed that NIC at low intravenous (i.v.) doses (10-30 ?g/kg) induced rapid, strong, and prolonged EEG desynchronization both in the cortex and ventral tegmental area (with decreases in ? and robust increases in ? and ? frequencies) and neck EMG activation that began during the injection (?5 s). EEG and EMG effects of NIC were drastically reduced by pre-treatment with hexamethonium, a peripherally acting NIC antagonist, and the immediate EEG effects of NIC were strongly inhibited during urethane anesthesia. Although NIC pyrrolidine methiodide, a quaternary NIC analog that cannot enter the brain, also induced rapid EEG desynchronization, its effects were much shorter and weaker than those of NIC. Therefore, NIC by acting on peripheral nicotinic receptors provides a major contribution to its rapid, excitatory effects following i.v. administration. Since this action creates a sensory signal that rapidly reaches the brain via neural pathways and precedes the slower and more prolonged direct actions of NIC on brain cells, it could have a major role in associative learning and changes in the behavioral and physiological effects of NIC following its repeated use.
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Intravenous saline injection as an interoceptive signal in rats.
Psychopharmacology (Berl.)
PUBLISHED: 01-31-2011
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Addictive drugs are commonly delivered in the organism by means of intravenous (i.v.) injections. Since saline mimics the blood environment by basic ionic properties and pH, it is generally assumed that it should not have any physiological effects, serving as a control for the effects induced by drugs.
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Cocaine is low on the value ladder of rats: possible evidence for resilience to addiction.
PLoS ONE
PUBLISHED: 04-09-2010
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Assessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats--by far the most frequently used animal model in this field--suggest that the value of cocaine is lower than previously thought.
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Rapid fluctuations in extracellular brain glucose levels induced by natural arousing stimuli and intravenous cocaine: fueling the brain during neural activation.
J. Neurophysiol.
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Glucose, a primary energetic substrate for neural activity, is continuously influenced by two opposing forces that tend to either decrease its extracellular levels due to enhanced utilization in neural cells or increase its levels due to entry from peripheral circulation via enhanced cerebral blood flow. How this balance is maintained under physiological conditions and changed during neural activation remains unclear. To clarify this issue, enzyme-based glucose sensors coupled with high-speed amperometry were used in freely moving rats to evaluate fluctuations in extracellular glucose levels induced by brief audio stimulus, tail pinch (TP), social interaction with another rat (SI), and intravenous cocaine (1 mg/kg). Measurements were performed in nucleus accumbens (NAcc) and substantia nigra pars reticulata (SNr), which drastically differ in neuronal activity. In NAcc, where most cells are powerfully excited after salient stimulation, glucose levels rapidly (latency 2-6 s) increased (30-70 ?M or 6-14% over baseline) by all stimuli; the increase differed in magnitude and duration for each stimulus. In SNr, where most cells are transiently inhibited by salient stimuli, TP, SI, and cocaine induced a biphasic glucose response, with the initial decrease (-20-40 ?M or 5-10% below baseline) followed by a reboundlike increase. The critical role of neuronal activity in mediating the initial glucose response was confirmed by monitoring glucose currents after local microinjections of glutamate (GLU) or procaine (PRO). While intra-NAcc injection of GLU transiently increased glucose levels in this structure, intra-SNr PRO injection resulted in rapid, transient decreases in SNr glucose. Therefore, extracellular glucose levels in the brain change very rapidly after physiological and pharmacological stimulation, the response is structure specific, and the pattern of neuronal activity appears to be a critical factor determining direction and magnitude of physiological fluctuations in glucose levels.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.