Cocaine Preexposure Research Articles

Prenatal and postnatal cocaine exposure enhances the anxiety- and depression-like behaviors in rats during cocaine withdrawal.

Prenatal drug exposure is a public health problem, which results in profound behavioral problems during childhood and adolescence, mainly represented by an increase in the risk of cocaine abuse at an early age. In rodents, prenatal and postnatal cocaine exposure enhanced locomotor activity and cocaine- or nicotine-induced locomotor sensitization. Various authors consider that the adverse emotional states (anxiety and depression) that occur during cocaine withdrawal are the main factors that precipitate, relapse, and increase chronic cocaine abuse, which could increase the risk of relapse of cocaine abuse. Therefore, the objective of this study was to characterize anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal in rats born to females exposed prenatally and postnatally to cocaine. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine preexposure group), and another group of pregnant female rats was administered daily with saline (saline preexposure group). Of the litters resulting from the cocaine-pre-exposed and saline-pre-exposed pregnant female groups, only the male rats were used for the recording of the anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal The study found that prenatal and postnatal cocaine exposure dose-dependent enhanced anxiety- and depression-like behaviors. This suggests that prenatal and postnatal cocaine exposure can result in enhanced vulnerability to cocaine abuse in young and adult humans.

Prenatal and Postnatal Cocaine Enhances the Induction and Expression of Locomotor Sensitization to Nicotine in Male Rats.

Several studies mention that early consumption of cannabis, alcohol, or even cocaine is related to an increase in the prevalence of daily consumption of tobacco in adulthood. However, other factors, such as genetic comorbidity, social influences, and even molecular, neurochemical, and behavioral alterations induced by prenatal and postnatal cocaine exposure, could also explain these observations, since these factors together increase the vulnerability of the offspring to the reinforcing effects of nicotine. The objective of this study was to determine the effect of prenatal and postnatal exposure to cocaine on nicotine-induced locomotor sensitization in young and adult rats. The study was divided into two stages: prenatal and postnatal. In the prenatal stage, a group of pregnant female Wistar rats was administered cocaine daily from day GD0 to GD21 (cocaine preexposure group), and another group of pregnant female rats was administered saline daily (saline preexposure group). Of the litters resulting from the cocaine preexposed and saline preexposed pregnant female groups, in the postnatal stage, only the male rats were used for the recording of the locomotor activity induced by different doses of nicotine (0.2, 0.4, and 0.6 mg/kg) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90, and 120 days). Prenatal and postnatal cocaine exposure enhanced nicotine-induced locomotor activity and locomotor sensitization. This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to other drugs of abuse, such as nicotine, in humans. Several studies have shown that the abuse of a drug, such as cannabis, alcohol, or even cocaine, at an early age can progress to more severe levels of use of other drugs, such as nicotine, to adulthood. Our data are consistent with this hypothesis, since prenatal and postnatal cocaine exposure enhanced the nicotine-induced increase in locomotor activity and locomotor sensitization. This suggests that prenatal and postnatal exposure to cocaine enhances the drug's salience.

Cocaine preexposure enhances sexual conditioning and increases resistance to extinction in male Japanese quail.

The incentive-sensitization theory posits that drug addiction results from altered learning and motivational processes that stem from drug-induced changes in the brain's reward circuitry. Although it is generally accepted that problematic drug use results from these neuroadaptations, less research has focused on how these neural changes affect the incentive-motivational properties of naturally rewarding stimuli such as sex. The present set of experiments was conducted to investigate (1) dose-dependent effects of preexposure to chronic cocaine on sexual conditioning and (2) how prior cocaine exposure affects the extinction of sexually conditioned behavior in male Japanese quail. In Experiment 1, male quail were exposed to saline or to cocaine (5, 10, or 20 mg/kg ip) for 10 days, and their locomotor activity was measured. After a washout period, ten sexual-conditioning trials were conducted in which a light (CS) was presented prior to the presentation of a female quail (US) and approach to the light was measured. The results showed that cocaine dose-dependently enhanced sexually conditioned approach behavior and copulation. Experiment 2 was procedurally similar to Experiment 1, except that the quail received either saline or 10 mg/kg cocaine (ip) and 24 extinction trials were conducted. During extinction, no female was presented after the CS. The results showed that preexposure to cocaine delayed extinction. Therefore, cocaine may dose-dependently increase the strength of sexual conditioning, and this may subsequently increase resistance to extinction. These findings and their possible mechanisms are explored.

A Closer Look at the Effects of Repeated Cocaine Exposure on Adaptive Decision-Making under Conditions That Promote Goal-Directed Control.

It has been proposed that compulsive drug seeking reflects an underlying dysregulation in adaptive behavior that favors habitual (automatic and inflexible) over goal-directed (deliberative and highly flexible) action selection. Rodent studies have established that repeated exposure to cocaine or amphetamine facilitates the development of habits, producing behavior that becomes unusually insensitive to a reduction in the value of its outcome. The current study more directly investigated the effects of cocaine pre-exposure on goal-directed learning and action selection using an approach that discourages habitual performance. After undergoing a 15-day series of cocaine (15 or 30 mg/kg, i.p.) or saline injections and a drug withdrawal period, rats were trained to perform two different lever-press actions for distinct reward options. During a subsequent outcome devaluation test, both cocaine- and saline-treated rats showed a robust bias in their choice between the two actions, preferring whichever action had been trained with the reward that retained its value. Thus, it appears that the tendency for repeated cocaine exposure to promote habit formation does not extend to a more complex behavioral scenario that encourages goal-directed control. To further explore this issue, we assessed how prior cocaine treatment would affect the rats’ ability to learn about a selective reduction in the predictive relationship between one of the two actions and its outcome, which is another fundamental feature of goal-directed behavior. Interestingly, we found that cocaine-treated rats showed enhanced, rather than diminished, sensitivity to this action–outcome contingency degradation manipulation. Given their mutual dependence on striatal dopamine signaling, we suggest that cocaine’s effects on habit formation and contingency learning may stem from a common adaptation in this neurochemical system.

Aberrant approach-avoidance conflict resolution following repeated cocaine pre-exposure.

Addiction is characterized by persistence to seek drug reinforcement despite negative consequences. Drug-induced aberrations in approach and avoidance processing likely facilitate the sustenance of addiction pathology. Currently, the effects of repeated drug exposure on the resolution of conflicting approach and avoidance motivational signals have yet to be thoroughly investigated. The present study sought to investigate the effects of cocaine pre-exposure on conflict resolution using novel approach-avoidance paradigms. We used a novel mixed-valence conditioning paradigm to condition cocaine-pre-exposed rats to associate visuo-tactile cues with either the delivery of sucrose reward or shock punishment in the arms in which the cues were presented. Following training, exploration of an arm containing a superimposition of the cues was assessed as a measure of conflict resolution behavior. We also used a mixed-valence runway paradigm wherein cocaine-pre-exposed rats traversed an alleyway toward a goal compartment to receive a pairing of sucrose reward and shock punishment. Latency to enter the goal compartment across trials was taken as a measure of motivational conflict. Our results reveal that cocaine pre-exposure attenuated learning for the aversive cue association in our conditioning paradigm and enhanced preference for mixed-valence stimuli in both paradigms. Repeated cocaine pre-exposure allows appetitive approach motivations to gain greater influence over behavioral output in the context of motivational conflict, due to aberrant positive and negative incentive motivational processing.

Baseline-dependent effects of cocaine pre-exposure on impulsivity and D2/3 receptor availability in the rat striatum: possible relevance to the attention-deficit hyperactivity syndrome.

We have previously shown that impulsivity in rats predicts the emergence of compulsive cocaine seeking and taking, and is coupled to decreased D2/3 receptor availability in the ventral striatum. As withdrawal from cocaine normalises high impulsivity in rats, we investigated, using positron emission tomography (PET), the effects of response-contingent cocaine administration on D2/3 receptor availability in the striatum. Rats were screened for impulsive behavior on the five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [18F]fallypride, rats were trained to self-administer cocaine for 15 days under a long-access schedule. As a follow-up, rats were assessed for impulsivity and underwent a second [18F]fallypride PET scan. At baseline, we found that D2/3 receptor availability was significantly lower in the left, but not right, ventral striatum of high-impulsive rats compared with low-impulsive rats. While the number of self-administered cocaine infusions was not different between the two impulsivity groups, impulsivity selectively decreased in high-impulsive rats withdrawn from cocaine. This effect was accompanied by a significant increase in D2/3 receptor availability in the left, but not right, ventral striatum. We further report that D2/3 receptor availability was inversely related to baseline D2/3 receptor availability in the ventral striatum of high-impulsive rats, as well as to the left and right dorsal striatum of both low-impulsive and high-impulsive rats. These findings indicate that the reduction in impulsivity in high-impulsive rats by prior cocaine exposure may be mediated by a selective correction of deficient D2/3 receptor availability in the ventral striatum. A similar baseline-dependent mechanism may account for the therapeutic effects of stimulant drugs in clinical disorders such as ADHD.

Sensitization of rapid dopamine signaling in the nucleus accumbens core and shell after repeated cocaine in rats.

Repeated cocaine exposure and withdrawal leads to long-term changes, including behavioral and dopamine sensitization to an acute cocaine challenge, that are most pronounced after long withdrawal periods. However, the changes in dopamine neurotransmission after short withdrawal periods are less well defined. To study dopamine neurotransmission after 1-day withdrawal, we used fast-scan cyclic voltammetry (FSCV) to determine whether repeated cocaine alters rapid dopamine release and uptake in the nucleus accumbens (NAc) core and shell. FSCV was performed in urethane anesthetized male Sprague-Dawley rats that had previously received one or seven daily injections of saline or cocaine (15 mg/kg, ip). In response to acute cocaine, subjects showed increased dopamine overflow that resulted from both increased dopamine release and slowed dopamine uptake. One-day cocaine pre-exposure, however, did not alter dopaminergic responses to a subsequent cocaine challenge. In contrast, 7-day cocaine-treated subjects showed a potentiated rapid dopamine response in both the core and shell after an acute cocaine challenge. In addition, kinetic analysis during the cocaine challenge showed a greater increase in apparent K(m) of 7-day cocaine exposed subjects. Together, the data provide the first in vivo demonstration of rapid dopamine sensitization in the NAc core and shell after a short withdrawal period. In addition, the data clearly delineate cocaine's release and uptake effects and suggest that the observed sensitization results from greater uptake inhibition in cocaine pre-exposed subjects.

The effects of cross‐drug preexposure on cocaine‐ and fluoxetine‐induced conditioned taste aversions

Although cocaine‐induced CTAs are well documented, little is known about the basis for cocaine's aversive effects. To address a role of serotonin (5‐HT) in cocaine‐induced aversions, the present experiments used the cross‐drug preexposure design in which the effects of preexposure to fluoxetine (FLU), a selective 5‐HT transporter (SERT) inhibitor, were examined on aversions induced by cocaine (nonselective monoamine transport inhibitor) and the effects of cocaine preexposure were examined on FLU‐induced aversions. A FLU dose‐response function was established in male Sprague‐Dawley rats to determine a dose of FLU that would induce intermediate aversions comparable to those induced by 18 mg/kg cocaine (Experiment 1). Naïve rats were then exposed to FLU (10 mg/kg) prior to aversion conditioning with cocaine (18 mg/kg ; Experiment 2) and with cocaine (18 mg/kg) prior to aversion conditioning with FLU (10 mg/kg; Experiment 3). Although there was no effect of FLU preexposure on either cocaine‐ or FLU‐induced aversions, preexposure to cocaine attenuated aversions induced by itself and by FLU. One interpretation of this attenuation is that exposure to one drug produces cross‐tolerance to the aversion‐inducing effects of the second. These results suggest that these two compounds may induce aversions via a common mechanism, i.e., SERT inhibition. Supported by a Mellon Foundation grant to ALR.

Preexposure to cocaine attenuates aversions induced by both cocaine and fluoxetine: Implications for the basis of cocaine-induced conditioned taste aversions

Although cocaine-induced conditioned taste aversions (CTA) are well documented, little is known about the basis for cocaine's aversive effects. To address the role of serotonin (5-HT) in cocaine-induced aversions, the present experiments used the cross-drug preexposure design in which the effects of exposure to fluoxetine, a selective 5-HT reuptake inhibitor (SSRI) with 5-HT transporter (SERT) inhibitory properties, were examined on aversions induced by cocaine (a nonselective monoamine transport inhibitor) and the effects of cocaine preexposure were examined on fluoxetine-induced aversions. Prior to these assessments, a fluoxetine dose–response function (3.2, 5.6, 10, and 18 mg/kg) was established in male Sprague–Dawley rats to determine a dose of fluoxetine that would induce intermediate aversions that were comparable to those induced by 18 mg/kg cocaine (Experiment 1). Other groups of rats were then exposed to fluoxetine prior to aversion conditioning with cocaine (Experiment 2) and with cocaine prior to aversion conditioning with fluoxetine (Experiment 3). All drugs were administered subcutaneously (cocaine 18 mg/kg; fluoxetine 10 mg/kg). Although there was no effect of fluoxetine preexposure on either cocaine- or fluoxetine-induced aversions, preexposure to cocaine significantly attenuated aversions induced by itself and by fluoxetine. These results were discussed in terms of the possible role 5-HT might play in the mediation of aversions induced by cocaine.

Dopamine transporter down‐regulation following repeated cocaine: implications for 3,4‐methylenedioxymethamphetamine‐induced acute effects and long‐term neurotoxicity in mice

3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Mice received a course of cocaine (20 mg*kg(-1), x2 for 3 days) followed by MDMA (20 mg*kg(-1), x2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA.

Chronic Cocaine Enhances Corticotropin-Releasing Factor-Dependent Potentiation of Excitatory Transmission in Ventral Tegmental Area Dopamine Neurons

Current concepts suggest that stress-induced release of neuromodulators such as corticotropin-releasing factor (CRF) can drive drug-dependent behaviors. Although previous drug exposure can enhance behavioral and neurochemical responses to stress, it is unclear how such drug exposure alters the CRF modulation of excitatory synapses onto ventral tegmental area (VTA) dopamine neurons, a key locus of drug- and stress-induced neuroadaptation. Here, we demonstrate that, after repeated cocaine exposure, the magnitude and duration of the CRF-induced potentiation of NMDA receptor (NMDAR)-mediated neurotransmission was significantly increased compared with naive and saline-treated mice. Furthermore, CRF enhanced AMPA receptor (AMPAR)-mediated transmission only in mice that were exposed to cocaine. Increased frequency of AMPAR-mediated spontaneous miniature EPSCs and the intracellular blockade of CRF potentiation of AMPAR-mediated transmission suggest both presynaptic and postsynaptic effects of CRF. Importantly, pharmacological experiments revealed that CRF receptor 1 and protein kinase A pathways were newly recruited after repeated cocaine for the enhancement of CRF-induced NMDAR potentiation and the appearance of AMPAR potentiation. Thus, enhanced CRF-induced potentiation of excitatory synaptic transmission onto VTA dopamine neurons after cocaine preexposure is likely to produce an abnormal increase in dopamine release during stressful events and could augment activation of addictive behaviors in response to stress.

Individual differences in cocaine-induced locomotor activity in male Sprague–Dawley rats and their acquisition of and motivation to self-administer cocaine

Factors that increase an individual's susceptibility to cocaine dependence remain largely unknown. We have previously shown that adult outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following the administration of a single dose of cocaine (10 mg/kg, i.p.). Furthermore, LCR/HCR classification predicts dopamine transporter function/inhibition, cocaine-induced locomotor sensitization, and cocaine-conditioned place preference. The present study assessed LCR/HCR classification and the development of locomotor sensitization on the latency to acquire cocaine self-administration and motivation to self-administer cocaine. LCRs and HCRs did not differ in their latency to acquire low-dose cocaine self-administration (0.25 mg/kg/infusion over 12 s, fixed ratio 1 schedule of reinforcement). In a follow-up experiment, repeated experimenter-administered injections of cocaine (10 mg/kg, i.p.) resulted in locomotor sensitization for LCRs, but not HCRs; nonetheless, all rats exhibited decreased latency to acquire cocaine self-administration compared to the first experiment. Repeated cocaine preexposure and LCR/HCR classification predicted break point when rats responded for cocaine under a progressive ratio schedule of reinforcement (0.25, 0.5, and 1.0 mg/kg/infusion; multiple exposure>single exposure, LCR>HCR), but there was no interaction between these variables. Although LCR/HCR classification did not predict the rate of acquisition of cocaine self-administration under these conditions, LCR rats demonstrated greater responding for cocaine after acquisition (PR). Thus, these findings demonstrate the relevance of using the LCR/HCR model when studying susceptibility to cocaine dependence.

The effects of cocaine preexposure on cocaine-induced taste aversion learning in Fischer and Lewis rat strains

The Fischer (F344) and Lewis (LEW) inbred rat strains differ on a number of behaviors, including those induced by a variety of drugs of abuse. Although a number of physiological and biochemical differences between the strains have been reported following both single and repeated drug administration, studies assessing changes in the affective properties of drugs after repeated exposure are limited. To that end, using the F344 and LEW strains, the present study examined the effects of repeated exposure to cocaine on the subsequent acquisition of cocaine-induced conditioned taste aversions, a preparation often used in assessing the development of tolerance to the drug's aversive effects. Specifically, separate groups of male F344 and LEW rats received five injections of 32 mg/kg cocaine (or vehicle) prior to taste aversion conditioning with 32 mg/kg cocaine (or vehicle). Vehicle-preexposed subjects of both strains acquired aversions to the cocaine-associated taste with no differences in the strength of the aversions. Further, cocaine-preexposed subjects displayed significantly attenuated aversions, an effect consistent with prior work with outbred animals. There was no difference between the two strains in this attenuation, suggesting that there were no genotype-specific differences in tolerance to cocaine's aversive effects. The data were discussed in relation to genetic/environmental interactions in the vulnerability to drugs of abuse.

History of cocaine self-administration alters morphine reinforcement in the rat

It has been shown repeatedly that cocaine pre-exposure may sensitise neurochemical and behavioural responses to opioid drugs. The aim of the present study was to investigate effects of a prior history of cocaine self-administration on morphine reinforcement in the rat. Male Sprague–Dawley rats were allowed to acquire intravenous cocaine self-administration (0.3 mg/kg/infusion) for 20 days. When operant responding for cocaine had stabilised, morphine was introduced instead of cocaine in the next self-administration session. One group of cocaine-exposed rats was allowed to respond for 0.56 mg/kg/infusion of morphine (i.e. the dose which was willingly self-administered by drug-naive controls). The second group was allowed to respond for 0.056 mg/kg/infusion of morphine (i.e. the dose which did not maintain self-administration behaviour in the drug-naive rats). The subjects with the history of cocaine self-administration, in contrast to the drug-naive group, did not maintain operant responding for 0.56 mg/kg/infusion of morphine. These rats easily self-administered the ten times lower dose of the opioid (0.056 mg/kg/infusion). An opioid receptor antagonist, naltrexone (1 mg/kg i.p.) restored the positive reinforcing properties of the higher dose of morphine in the cocaine-exposed rats. Concluding, the present results suggest that prior history of cocaine self-administration sensitises rats to the positive reinforcing properties of morphine.

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 μg) 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 μg) 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.

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.

Effects of chronic cocaine exposure on corticotropin-releasing hormone binding protein in the central nucleus of the amygdala and bed nucleus of the stria terminalis

The neuropeptide, corticotropin-releasing hormone (CRH), has been shown to play a role in behavioral and neurobiological effects of drugs of abuse. An important modulator of CRH, the CRH binding protein (CRH-BP), has not, on the other hand, been assessed for its role in drug-associated effects. The primary objective of the present experiment was to assess whether prior, chronic exposure to cocaine modulates expression of CRH-BP, and to compare expression of the BP with that of the peptide itself. We assessed CRH-BP and CRH mRNA expression in two brain regions where CRH is known to affect responses to drugs of abuse; namely, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). Male Long-Evans rats were given 14 daily injections of cocaine (30 mg/kg, i.p.) or saline. One, 3, 10, 28, or 42 days post-treatment, animals were killed and adjacent brain sections through the CeA and BNST were processed for CRH-BP and CRH by in situ hybridization. In the CeA, cocaine pre-exposure increased both CRH and CRH-BP mRNA expression 1 day post-treatment. In the dorsal BNST, cocaine pre-exposure elevated levels of CRH-BP, but not CRH, mRNA 3 days post-treatment. Taken together, the results suggest that withdrawal-induced changes in the expression of the CRH-BP, and CRH itself, are relatively short-lived and that a dysregulation in basal expression of either gene is not likely responsible for long-lasting behavioral effects noted with cocaine and other drugs of abuse.

Conditioned Activity and Instrumental Reinforcement Following Long-Term Oral Consumption of Cocaine by Rats.

Food-reinforced conditioned activity and instrumental responding were measured in rats after 50 weeks of continuous access to a cocaine-saccharin solution in their home cages. The elevation of conditioned activity produced by acute access to the cocaine-saccharin solution in the home cage during testing was abolished by long-term preexposure to the cocaine solution, an effect that was reversed by systemic administration of cocaine immediately prior to testing. By contrast, chronic cocaine preexposure enhanced instrumental responding for both cocaine-sucrose and pure sucrose solutions. These results support the idea that long-term cocaine exposure enhances subsequent reinforcement.

Cocaine pre-exposure produces a sensitized and context-specific c-fos mRNA response to footshock stress in the central nucleus of the AMYGDALA

In recent years, there has been growing interest in the putative relationship between stress and vulnerability to relapse in former drug addicts. In animal studies aimed at exploring this relationship, it has been shown that brief exposure to intermittent footshock stress produces reliable reinstatement of drug seeking after prolonged drug-free periods. Whereas footshock reinstates drug seeking, it does not reinstate behaviors maintained by non-drug reinforcers, suggesting that prior drug experience may produce a form of sensitization within neuronal systems that mediate stress-induced reinstatement. The primary objective of the present experiments was to determine whether pre-exposure to cocaine produces a long-lasting, sensitized neuronal response to footshock stress within two brain regions known to mediate footshock-induced reinstatement; the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In experiment 1, animals were injected for 7 days with cocaine (days 1 and 7 in test chambers; days 2–6 in homecages) or saline. After 21 drug-free days, they were exposed to footshock or no footshock. In experiment 2, rats were injected daily for 7 days with cocaine in one of two contexts and saline in the alternate context. After 21 drug-free days, they were given footshock either in the same context that they were given cocaine in or the alternate context. In CeA, footshock produced enhanced expression of c-fos mRNA in cocaine, but not saline, pre-exposed animals. Furthermore, this effect was gated by the environmental context in which cocaine was given; footshock only enhanced c-fos mRNA expression when it was given in a context that had previously been paired with cocaine. Although footshock induced c-fos mRNA expression in the BNST, its effects in this region were not dependent on drug history. The major findings are that a history of cocaine exposure produces sensitization to an acute stressor within CeA, and this effect is gated by environmental context.

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. To study the effects of repeated cocaine exposure on locomotor activity induced by different doses of CRF after drug-free periods ranging from 24 h to 28 days. Male Wistar rats were injected once daily for 7 days with cocaine (15 mg/kg, IP on days 1 and 7 in locomotor chambers; 30 mg/kg, IP, on days 2-6 in home cages) or saline. In experiment 1, starting 10 days after the last injection, animals were tested for their locomotor response to intracerebroventricular (ICV) injections of vehicle and three doses of CRF (0.25, 0.5, and 5 microg). In experiment 2, animals were tested for their locomotor response to ICV injections of 0.5 microg CRF after drug-free periods of 1-2, 10-11 and 28-29 days. Compared to saline pre-exposed animals, cocaine pre-exposed animals showed a significantly greater locomotor response to CRF, relative to vehicle, at all doses tested (experiment 1) and after drug-free periods of up to 28 days (experiment 2). The effects were clear and extremely consistent in magnitude between experiments and conditions. These results suggest that cocaine pre-exposure induces long-term changes in the responsivity of the central nervous system to CRF.