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In JoVE (1)
Other Publications (18)
- Psychopharmacology
- Journal of Clinical and Experimental Neuropsychology
- Neuroscience Letters
- Psychopharmacology
- Neuroscience Letters
- Pharmacology, Biochemistry, and Behavior
- Psychopharmacology
- Behavioural Brain Research
- Pharmacology, Biochemistry, and Behavior
- Psychopharmacology
- Pharmacology, Biochemistry, and Behavior
- Psychopharmacology
- Brain Research
- Progress in Neuro-psychopharmacology & Biological Psychiatry
- Behavioural Brain Research
- British Journal of Pharmacology
- Behavioural Brain Research
- Behavioural Brain Research
Articles by Suzanne Erb in JoVE
JoVE Neuroscience
A Procedure for Studying the Footshock-Induced Reinstatement of Cocaine Seeking in Laboratory Rats
Psychology, University of Toronto Scarborough
Animal models of relapse, known as reinstatement procedures, have been used extensively to study the role of stress in relapse to drug seeking. Here, we report on a method for inducing the reinstatement of cocaine seeking in laboratory rats via acute exposures to mild, intermittent electric footshock.
Other articles by Suzanne Erb on PubMed
Prior, Repeated Exposure to Cocaine Potentiates Locomotor Responsivity to Central Injections of Corticotropin-releasing Factor (CRF) in Rats
There is considerable evidence that the stress-related neuropeptide, corticotropin-releasing factor (CRF), plays an important role in mediating behavioural changes induced by prior experience with cocaine. From this perspective, it is conceivable that repeated exposure to cocaine induces a form of sensitization in CRF systems that makes animals more responsive to CRF following prolonged drug-free periods.
Neurocognitive Deficits in Cocaine Users: a Quantitative Review of the Evidence
Studies on the neurocognitive effects of cocaine abuse are equivocal with respect to the specific types of deficits observed, although the vast majority of studies indicate that at least some deficits in certain broad functions such as attention, learning and memory, executive functions, and response speed exist. All of these studies based their results on null hypothesis statistical significance testing (NHSST). It is argued that effect size analysis, which provides information about the magnitude of difference, offers a more valid index of cognitive impairments in a population when compared to NHSST. Accordingly, the objective of the current study was to conduct an effect size analysis (or a meta-analysis in cases where the same test measure was utilized in more than one study) to determine the type and the magnitude of the specific cognitive deficits found as a result of cocaine use. Effect sizes were calculated for each test variable across 15 empirical studies that met inclusion criteria. The results from 481 cocaine users and 586 healthy normal controls revealed that cocaine use had the largest effect on several measures of attention (0.40 < d < 1.10). Moderate to large effect sizes (d > 0.50) were also obtained on tests of visual memory and working memory. Minimal effect sizes (d < 0.30) were obtained on tests of verbal fluency and other language functions and sensory-perceptual functions. Tests of executive functioning produced mixed findings and were interpreted in terms of degree rather than nature of impairment. The results are consistent with findings from neuroimaging and neurochemical studies that have found cocaine use to be associated with dysfunctions in the anterior cingulate gyrus and orbitofrontal cortex; these regions are highly implicated in the mediation of attentional and executive functions, respectively. Methodological limitations of the empirical studies included in the analysis are discussed.
Cocaine Pre-exposure Enhances CRF-induced Expression of C-fos MRNA in the Central Nucleus of the Amygdala: an Effect That Parallels the Effects of Cocaine Pre-exposure on CRF-induced Locomotor Activity
There is evidence that cocaine pre-exposure produces changes in the responsivity of central corticotropin-releasing factor (CRF) systems and that these systems mediate some of the drug-related behavioural effects of acute stressors. The present experiment was conducted to assess the effects of repeated cocaine exposure on CRF-induced neuronal activation within two regions of the extended amygdala, the central nucleus of the amygdala (CeA) and lateral bed nucleus of the stria terminalis (BNST). In addition, CRF-induced neuronal activation was compared with CRF-induced locomotor activity. Rats were injected for 7 days with cocaine (days 1 and 7 in test chambers; days 2-6 in homecages) or saline. After 10 drug-free days, locomotor responsiveness to intracerebroventricular (i.c.v.) injections of CRF and Vehicle was assessed over 2-h test periods. Twenty-four to 48 h following testing for locomotor activity, animals were injected with either CRF or Vehicle, 30 min before being sacrificed. Subsequently, the brains were processed by in situ hybridization for c-fos mRNA, a widely used marker of neuronal activation, in the CeA and BNST. In CeA, i.c.v. CRF enhanced the expression of c-fos mRNA in cocaine, but not saline, pre-exposed animals; in the same animals, i.c.v. CRF resulted in enhanced locomotor activity in cocaine, but not saline, pre-exposed animals. The results demonstrate that repeated exposure to cocaine changes the neuronal response to CRF in the CeA; furthermore, they suggest that these changes in the CeA could potentially be of functional significance in the effects of repeated cocaine exposure on CRF-induced locomotor activity.
Activation of Central Neurotensin Receptors Reinstates Cocaine Seeking in the Rat: Modulation by a D1/D5, but Not D2/D3, Receptor Antagonist
Neurotensin (NT) has been implicated in some of the behavioral effects of psychostimulants. Thus, there is reason to think that NT may play a role in the reinstatement of cocaine seeking, and that it may do so via an interaction with dopamine (DA).
Activation of Central Neurokinin-1 Receptors Induces Reinstatement of Cocaine-seeking Behavior
A number of neurochemical systems have been implicated in mediating relapse to drug-seeking behavior. Substance P (SP) is a neuropeptide that interacts with some of these systems, suggesting a possible role for SP and its preferred receptor, the neurokinin-1 (NK-1) receptor, in the mediation of relapse. In this study, we examined whether selective activation of NK-1 receptors induces reinstatement of cocaine-seeking behavior, and whether endogenous activity at these receptors is involved in mediating cocaine-induced reinstatement. For each experiment, rats were trained to self-administer cocaine for 8--10 days, and following a period of extinction, tests for reinstatement were given. To examine the effects of NK-1 receptor activation on reinstatement of cocaine-seeking behavior, animals received an intracerebroventricular (ICV) infusion of the selective NK-1 receptor agonist, [Sar(9)Met(O(2))(11)]-SP (0, 1, 3 microg), immediately prior to the test session. To examine the role of endogenous NK-1 receptor activity on cocaine-induced reinstatement, rats were pretreated with ICV infusions of the selective NK-1 receptor antagonists, RP 67580 (0, 0.1, 0.5, 2.5 nmol) or GR 82334 (0, 2, 10, 50 pmol), prior to systemic priming injections of cocaine (10mg/kg or 20mg/kg; i.p.). The results showed that [Sar(9)Met(O(2))(11)]-SP induced reinstatement of cocaine-seeking behavior, but that RP 67580 and GR 82334 had no effect on cocaine-induced reinstatement. These findings suggest that while activation of NK-1 receptors is capable of inducing reinstatement of cocaine-seeking behavior, endogenous activity at these receptors is not involved in mediating the priming effects of cocaine on reinstatement of drug-seeking behavior.
Effects of Central Neurokinin-1 Receptor Antagonism on Cocaine- and Opiate-induced Locomotor Activity and Self-administration Behaviour in Rats
The neuropeptide substance P (SP) and its preferred receptor, the neurokinin-1 (NK-1) receptor, have been implicated in some of the reward-related behavioural effects of abused drugs, including psychostimulants and opiates. The first objective of the present series of experiments was to assess the role of the NK-1 receptor in two reward-related behavioural effects of cocaine: locomotor activity and self-administration. In tests for locomotor activity, rats were given intracerebroventricular (ICV) infusions of the selective NK-1 receptor antagonist, GR82334 (0, 10, 50 pmol), prior to systemic injections of cocaine. In self-administration experiments, rats were trained to self-administer cocaine on a fixed-ratio 5 (FR5) schedule of reinforcement. Following acquisition of stable responding, animals were pretreated with GR82334 (0, 2, 10, 50 pmol; ICV) prior to subsequent self-administration sessions. Based on evidence suggesting a potentially selective role for NK-1 receptors in opiate reward, we also examined the effects of GR82334 on morphine-induced locomotor activity and heroin self-administration. Results showed that GR82334 had no effect on cocaine-induced locomotor activity or cocaine self-administration, but attenuated morphine-induced locomotor activity and increased heroin self-administration. These findings suggest that endogenous activity at NK-1 receptors may play a specific role in opiate-induced, but not cocaine-induced, locomotor activation and reinforcement.
Central Injections of CRF Reinstate Cocaine Seeking in Rats After Postinjection Delays of Up to 3 H: an Influence of Time and Environmental Context
In drug addicts, the induction of drug craving is not always associated with an immediate opportunity to take drugs again. It is, therefore, important to study how delays in opportunity for drug seeking affect the time-course of relapse. Intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) is a stressor that reinstates heroin and alcohol seeking in rats, when administered just before tests for reinstatement. It is not known whether CRF reinstates cocaine seeking; moreover, the effect of delaying testing for reinstatement, after CRF injection, has not been studied.
A Role for Corticotropin-releasing Factor in the Long-term Expression of Behavioral Sensitization to Cocaine
Corticotropin-releasing factor (CRF) has been implicated in a number of the behavioral and biochemical effects of cocaine. We recently reported that central injections of CRF produce a potentiated locomotor response in animals that had been given repeated injections of cocaine up to 4 weeks earlier. We now report that with as few as 1 or 3 exposures to cocaine (total of 45 mg/kg, i.p., per day), and a drug-free period of 28 days, i.c.v. injections of CRF (0.5 microg) produce augmented locomotor responses, similar to those induced by cocaine (10 mg/kg, i.p.) itself. In addition, in animals pre-exposed to cocaine for 3 days, pre-treatment with the CRF receptor antagonist, D-Phe CRF(12-41) (1 microg, i.c.v.), blocks the expression of behavioral sensitization to a cocaine challenge after a 28-day drug-free period. These results demonstrate that short-term exposure to cocaine produces a form of long-term sensitization within systems upon which CRF acts and that activation of CRF receptors is importantly involved in the expression of behavioral sensitization to cocaine.
A Study of the Lasting Effects of Cocaine Pre-exposure on Anxiety-like Behaviors Under Baseline Conditions and in Response to Central Injections of Corticotropin-releasing Factor
Anxiety-like behaviors emerge with repeated exposure to and short-term withdrawal from cocaine. The stress-related neuropeptide, corticotropin-releasing factor (CRF), has been implicated in the anxiogenic effects of cocaine withdrawal, as well as in some of the long-lasting effects of cocaine. One objective of the present experiments was to determine whether repeated exposures to cocaine, under conditions that induce anxiety in the initial withdrawal period, would induce longer-lasting anxiogenic responses. A second objective was to determine whether any such effects would be potentiated by CRF. In Experiment 1, animals were injected once daily for 7 days with cocaine (30 mg/kg, i.p.) or saline in the home cages and, after a 10-day drug-free period, were given an i.c.v. injection of CRF (0.5 or 5.0 micro g) or vehicle, followed by a 5-min test for anxiety in the elevated plus maze or light-dark transition apparatus. In Experiment 2, animals were given the cocaine or saline injections in a distinct environment. At test, they were placed in the distinct environment after the CRF (0.5 micro g) or vehicle injection and were subsequently tested for anxiety. Cocaine produced enhanced levels of anxiety when pre-exposures were given in a distinct environment, but not when they were given in the home cage. In neither case did cocaine differentially alter anxiety-like responses to CRF. The results suggest that a "reminder" of the drug experience, such as re-exposure to cocaine-paired contextual cues, may be necessary to induce elevated levels of anxiety after the initial withdrawal period. In addition, although the results do not rule out a role for endogenous CRF in lasting cocaine-induced anxiogenic responses, they suggest that an increased sensitivity of CRF receptors to the peptide is not responsible for the effect.
Footshock Stress Reinstates Cocaine Seeking in Rats After Extended Post-stress Delays
Exposure to footshock stress reinstates drug seeking in rats when tests for reinstatement are conducted immediately after termination of the stressor. It is not known, however, whether footshock is effective in inducing reinstatement if a post-stress delay is imposed before testing for reinstatement.
Effects of Repeated Yohimbine on the Extinction and Reinstatement of Cocaine Seeking
Acute exposure to the pharmacological stressor yohimbine (YOH) reinstates drug seeking in rats. The present experiments investigated whether repeated exposure to YOH during extinction training affects the time-course of extinction and the magnitude of subsequent YOH- or footshock-induced reinstatement of cocaine seeking. Rats trained to self-administer cocaine were given five days of extinction training, during which they were injected with YOH (1.25 mg/kg, i.p.) either before or after daily extinction sessions. Following additional extinction training in the absence of YOH, animals were tested for reinstatement to a YOH (1.25 mg/kg, i.p.) or footshock (20 min, intermittent, 0.9 mA per 0.5 s shock) challenge. Animals injected with YOH before daily extinction sessions showed an attenuated rate of extinction, relative to control animals. Following additional extinction training in the absence of YOH treatment, these same animals showed a marked attenuation of YOH-induced reinstatement of cocaine seeking. YOH treatment during extinction did not, however, affect the magnitude of reinstatement induced by footshock. These findings demonstrate that repeated exposure to a stressor during extinction training can modulate the processes governing extinction learning and the subsequent reinstatement of drug seeking induced by that stressor.
Interaction Between Noradrenaline and Corticotrophin-releasing Factor in the Reinstatement of Cocaine Seeking in the Rat
Corticotropin-releasing factor (CRF) and noradrenaline (NA) have been shown in independent studies to mediate stress-induced reinstatement of drug seeking. To date, however, a functional interaction between the systems in reinstatement has not been demonstrated.
Role of CRF and Other Neuropeptides in Stress-induced Reinstatement of Drug Seeking
A central problem in the treatment of drug addiction is high rates of relapse to drug use after periods of forced or self-imposed abstinence. This relapse is often provoked by exposure to stress. Stress-induced relapse to drug seeking can be modeled in laboratory animals using a reinstatement procedure. In this procedure, drug-taking behaviors are extinguished and then reinstated by acute exposure to stressors like intermittent unpredictable footshock, restraint, food deprivation, and systemic injections of yohimbine, an alpha-2 adrenoceptor antagonist that induces stress-like responses in humans and nonhumans. For this special issue entitled "The role of neuropeptides in stress and addiction", we review results from studies on the role of corticotropin-releasing factor (CRF) and several other peptides in stress-induced reinstatement of drug seeking in laboratory animals. The results of the studies reviewed indicate that extrahypothalamic CRF plays a critical role in stress-induced reinstatement of drug seeking; this role is largely independent of drug class, experimental procedure, and type of stressor. There is also limited evidence for the role of dynorphins, hypocretins (orexins), nociceptin (orphanin FQ), and leptin in stress-induced reinstatement of drug seeking.
Evaluation of the Relationship Between Anxiety During Withdrawal and Stress-induced Reinstatement of Cocaine Seeking
The initial termination of cocaine consumption in human addicts is associated with heightened anxiety states and low levels of craving. Craving, however, tends to increase progressively over time, remains high for extended periods of time, and can be exacerbated by stressors, leading to relapse. Laboratory rats, likewise, exhibit heightened states of anxiety after withdrawal from drug, and follow a time course of cocaine seeking that parallels the time course of craving reported in humans. In addition, laboratory rats show heightened susceptibility to relapse when exposed to stressors after extended periods of withdrawal, and exhibit persistent and heightened expressions of stress-induced anxiety. The general objective of this paper is to consider the relationship between anxiety states after withdrawal from cocaine and stress-induced reinstatement of cocaine seeking in laboratory rats, and to identify the neural substrates involved. The focus of the review is on studies addressing the roles of corticotropin-releasing factor (CRF) and noradrenaline pathways of the extended amygdala circuitry, and their direct or indirect interactions with the mesocorticolimbic dopamine system, in anxiety after withdrawal from cocaine and stress-induced reinstatement of cocaine seeking. Furthermore, the effects of time after withdrawal from cocaine and amount of cocaine exposure during self-administration on the activity of CRF, noradrenaline, and dopamine pathways of the extended amygdala and mesocorticolimbic systems will be considered. The review will highlight how changing levels of activity within these systems may serve to alter the nature of the relationship between anxiety and stress-induced reinstatement of cocaine seeking at different times after withdrawal from cocaine.
Age-related Effects of Acute Nicotine on Behavioural and Neuronal Measures of Anxiety
Adolescence is considered a period of enhanced vulnerability to the initiation of tobacco use. Biological differences in the sensitivity of adolescents and adults to the anxiogenic and anxiolytic effects of nicotine may contribute to this heightened vulnerability. Here, we investigated the age-dependency of the effects of acute nicotine on anxiety-related behaviour and neurotransmission. In Experiment 1, male adolescent (P33-37) and adult (P65-69) Long-Evans rats received nicotine (0, 0.4 or 0.8 mg/kg,s.c.) prior to testing using two measures of anxiety, the elevated plus maze (EPM) and light-dark (LD) transition box. In Experiment 2, in situ hybridization was used to assess, in different male adolescent and adult rats, CRF mRNA expression in the BNST, PVN and CeA in response to acute nicotine. In the EPM, adult rats displayed less anxious behaviour than adolescents. Nicotine (0.4, 0.8 mg/kg) increased open and closed arm entries in adolescent rats, suggesting increased general activity, but it did not affect behaviour in the LD box. CRF mRNA expression was elevated in PVN of adolescent rats, relative to adults. Nicotine, however, had no effect on CRF mRNA expression in the BNST, PVN or CeA. The present findings suggest that adolescents are more sensitive to the general activational, rather than anxiety-related, effects of nicotine, and that CRF mRNA expression in stress-related brain regions does not correlate with these effects. This work further characterizes the age-related differences in the anxiety-related effects of nicotine, and provides insight into potential factors influencing vulnerability to tobacco abuse.
Teneurin C-terminal Associated Peptide-1 Blocks the Effects of Corticotropin-releasing Factor on Reinstatement of Cocaine Seeking and on Cocaine-induced Behavioural Sensitization
The stress-related neuropeptide, corticotropin-releasing factor (CRF), has become an important focus of studies of cocaine addiction, and in particular, the effects of stress on cocaine-related behaviours. A recently discovered peptide system, the teneurin C-terminal associated peptides (TCAP), has been implicated in the regulation of the stress response, via a CRF-related mechanism. Here we have determined whether treatment with TCAP-1, a synthetic analogue of TCAP, modulated two cocaine-related behaviours induced by CRF: reinstatement of cocaine seeking, and expression of cocaine-induced behavioural sensitization.
Central Injections of Noradrenaline Induce Reinstatement of Cocaine Seeking and Increase C-fos MRNA Expression in the Extended Amygdala
We recently reported that central injections of noradrenaline (NA) induce reinstatement of cocaine seeking in rats. Here, we replicate and extend our finding to an additional dose of NA and show that it is associated with the induction of c-fos mRNA expression (a marker of neuronal activation) in functionally relevant brain regions, including the bed nucleus of the stria terminalis and central nucleus of the amygdala.
Expression and Resilience of a Cocaine-conditioned Locomotor Response After Brief and Extended Drug-free Periods
Conditioned associations between drug experience and its context are maintained long after drug use ceases, and may contribute to relapse after extended abstinence. These include operantly conditioned associations directed toward seeking drug, but also Pavlovian conditioned associations between drug reward and contextual cues present at the time of drug administration. The present study sought to determine whether expression of a Pavlovian conditioned locomotor (CL) response to a cocaine-associated context increases over time in the same manner observed for instrumental responses, and whether the CL memory is differentially susceptible to extinction and recovery after brief versus extended abstinence. Male rats received injections of cocaine (30mg/kg, i.p.) or vehicle once per day for 6 days. In Exp. 1, CL activity was measured 1, 7, 21, or 42 days later. Rats that had received cocaine injections displayed robust CL, regardless of when testing occurred. In Exp. 2, extinction and recovery of CL were assessed after 1 or 42 days. The CL response was more readily extinguished in rats tested 1 day after drug exposure, as compared to rats tested 42 days later. Exp. 3 confirmed that conditioning in the testing context was necessary for expression of CL. Overall, our results indicate that Pavlovian associations underlying the CL response are maintained long after drug experience. Although the expression of CL does not change with the passage of time, as has been observed for instrumental drug-related responses, the memory trace does appear to become more resilient over time.
