5-HT2 receptor antagonists given in the acute withdrawal from daily cocaine injections can reverse established sensitization

Male Sprague-Dawley rats were given two separate sensitizing regimens of cocaine (7 days on, 7 days off, 7 days on at 40 mg/kg/day, s.c.) or saline injections. Half of the animals also received a drug with 5-hydroxytryptamine-2 (5-HT2) receptor antagonist properties (clozapine, 3 mg/kg; mianserin 6 mg/kg; ketanserin 1 mg/kg, all s.c.) or saline during the second cocaine dosing regimen in the acute withdrawal period, 3.5 h after each cocaine injection. On day 10 of withdrawal animals were challenged with cocaine (7.5 mg/kg, i.p.) and assessed by a behavioral rating scale and locomotor activity monitoring. The 5-HT2 receptor antagonists, but not saline, reversed behavioral sensitization and had little effect on behavior in the control animals. 5-HT2 receptor antagonists, therefore, may be a useful treatment for cocaine addicts that have undergone previous sensitization periods. The pharmacological profile of these antagonists suggests that the 5-HT2A receptor subtype may mediate this effect.     

Conditioned rewarding stimulus associated with cocaine self-administration reverses the depression of catecholamine brain systems following cocaine withdrawal in rats

Craving phenomena are related to induction of substance-seeking behaviour by stimuli associated with the availability of the drug. We investigated the changes in monoamine metabolism in regions of the brains of rats that, following a period of training of cocaine self-administration, were either killed 2 h after the last session or underwent extinction trials, during which cocaine was withdrawn. During the training, acoustic and visual stimuli announced the availability of cocaine. After 10 d of daily extinction trials, rats were re-introduced into the cage, and a signal associated with cocaine availability was applied to half of the animals. The rats were immediately killed and concentrations of dopamine and serotonin and their metabolites in various brain areas, and the concentration of noradrenaline and MHPG in the brainstem were assessed to calculate their metabolism rate indices. In rats self-administering cocaine, the levels of metabolites of all three amines were depressed, indicating a depression of the activity of monoaminergic systems. In the period of extinction, the dopamine levels in the nucleus accumbens and striatum and the level of the noradrenaline metabolite, MHPG, in the brainstem were reduced, suggesting a long-lasting disturbance of the catecholaminergic system, while serotonin levels and metabolism returned to normal values. The presence of the signal associated with previous cocaine availability, which invariably caused the reinstatement of cocaine-seeking behaviour annulled the changes observed in the group receiving no stimulus, bringing the concentration values of dopamine, and dopamine and noradrenaline metabolites to yoked-saline control rats. The results suggest that the stabilized self-administration of cocaine depresses the activity of all biogenic amine systems, and the changes in serotonin system are reversible, in contrast to those observed in catecholaminergic systems, which show the signs of a long-lasting impairment. The stimulus associated with cocaine availability activates the catecholaminergic system in animals after extinction procedure.     

Accumbal neurons that are activated during cocaine self-administration are spared from inhibitory effects of repeated cocaine self-administration.

Hypoactivity of the accumbens is induced by repeated cocaine exposure and is hypothesized to play a role in cocaine addiction. However, it is difficult to understand how a general hypoactivity of the accumbens, which facilitates multiple types of motivated behaviors, could contribute to the selective increase in drug-directed behavior that defines addiction. Electrophysiological recordings, made during sessions in which rats self-administer cocaine, show that most accumbal neurons that encode events related to drug-directed behavior achieve and maintain higher firing rates during the period of cocaine exposure (Task-Activated neurons) than do other accumbal neurons (Task-Non-Activated neurons). We have hypothesized that this difference in activity makes the neurons that facilitate drug-directed behavior less susceptible than other neurons to the chronic inhibitory effects of cocaine. A sparing of neurons that facilitate drug-directed behavior from chronic hypoactivity might lead to a relative increase in the transmission of neuronal signals that facilitate drug-directed behavior through accumbal circuits and thereby contribute to changes in behavior that characterize addiction (ie differential inhibition hypothesis). A prediction of the hypothesis is that neurons that are activated in relation to task events during cocaine self-administration sessions will show less of a decrease in firing across repeated self-administration sessions than will other neurons. To test this prediction, rats were exposed to 30 daily (6 h/day) cocaine self-administration sessions. Chronic extracellular recordings of single accumbal neurons were made during the second to third session and the 30th session. Between-session comparisons showed that decreases in firing were exhibited by Task-Non-Activated, but not by Task-Activated, neurons. During the day 30 session, the magnitude of the difference in firing rate between the two groups of neurons was positively related to the propensity of animals to seek and take cocaine. The findings of the present study are consistent with a basic prediction of the differential inhibition hypothesis and may be relevant to understanding cocaine addiction.     

Access to a running wheel inhibits the acquisition of cocaine self-administration

Physical activity decreases cocaine self-administration in laboratory animals and is associated with positive outcomes in substance abuse treatment programs; however, less is known about its efficacy in preventing the establishment of regular patterns of substance use in drug-naive individuals. The purpose of the present study was to examine the effects of access to a running wheel on the acquisition of cocaine self-administration in experimentally naive rats. Male, Long-Evans rats were obtained at weaning and assigned to sedentary (no wheel) or exercising (access to wheel) conditions immediately upon arrival. After six weeks, rats were surgically implanted with intravenous catheters and placed in operant conditioning chambers for 2 h/day for 15 consecutive days. Each session began with a noncontingent priming infusion of cocaine, followed by a free-operant period in which each response on the active lever produced an infusion of cocaine on a fixed ratio (FR1) schedule of reinforcement. For days 1-5, responding was reinforced with 0.25 mg/kg/infusion cocaine; for days 6-15, responding was reinforced with 0.75 mg/kg/infusion cocaine. In addition, all rats were calorically restricted during days 11-15 to 85% to 95% of their free-feeding body weight. Compared to sedentary rats, exercising rats acquired cocaine self-administration at a significantly slower rate and emitted significantly fewer active lever presses during the 15 days of behavioral testing. These data indicate that access to a running wheel inhibits the acquisition of cocaine self-administration, and that physical activity may be an effective intervention in substance abuse prevention programs.     

Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration.

Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine self-administration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens c-fos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGR1. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence. Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.     

Bromocriptine reverses the elevation in intracranial self-stimulation thresholds observed in a rat model of cocaine withdrawal.

Cocaine use frequently occurs in episodic prolonged binges. Following such a cocaine binge, the user suffers from severe depression mixed with irritability, anxiety, anergia and anhedonia. These symptoms constitute the cocaine withdrawal syndrome. Since cocaine's rewarding effects are mediated by enhanced dopaminergic neurotransmission in the mesocorticolimbic system, it is possible that a long-acting dopamine agonist might block the withdrawal effects associated with the termination of a prolonged bout of cocaine self-administration. An animal model of post-cocaine anhedonia was developed using the elevation in intracranial self-stimulation (ICSS) thresholds following the termination of prolonged periods of cocaine self-administration as a measure of an animal's "anhedonic" state. In the present study, an attempt was made to reverse the postcocaine elevation in ICSS thresholds with acute administration of a dopaminergic agonist, bromocriptine. Rats were allowed to self-administer cocaine for 24 hours continuously. Four hours after the termination of the self-administration session, animals were injected with either vehicle or bromocriptine (1, 2, or 4 mg/kg, IP). Two hours later (6 hours post cocaine), the animals' self-stimulation thresholds were assessed. Confirming previous work, treatment with the vehicle following a cocaine "binge" resulted in elevated ICSS thresholds compared to predrug baseline levels or to control rats' thresholds. Bromocriptine, at doses that had no effect on ICSS thresholds in control rats, reversed the postcocaine anhedonia in a dose-related manner. These results indicate that bromocriptine-like drugs (pharmacological agents that enhance dopaminergic neurotransmission) may be able to ameliorate some of the effects of cocaine withdrawal on mood and motivational state. In addition, the results of the present study indicate that the proposed animal model of cocaine withdrawal could be useful in the discovery and development of new pharmacotherapies for cocaine withdrawal.     

Decreased activity of rat A10 dopamine neurons following withdrawal from repeated cocaine.

Electrophysiological techniques were used to determine the basal activity of A10 dopamine (DA) neurons in the rat ventral tegmental area after a 10-14 day withdrawal from repeated cocaine treatment (10.0 mg/kg i.p. twice daily for 14 days). The number of spontaneously active A10 DA cells was significantly decreased (42%) in the cocaine-treated rats. This decreased activity may underlie the diminished basal levels of synaptic DA within the nucleus accumbens previously reported in cocaine-withdrawn rats and may account for anhedonia, anergia and cocaine craving reported by withdrawn cocaine addicts.     

Discrete-trials heroin self-administration produces sensitization to the reinforcing effects of cocaine in rats

Rationale The prevalence of cocaine use in opioid-dependent individuals is reportedly high, and the associated negative health and social consequences are severe and well documented. Sensitization of the reinforcing effects of cocaine has been demonstrated following noncontingent opioid exposure in animals; however, no preclinical studies have investigated the impact of opioid self-administration on cocaine’s reinforcing effects. Objective Experiments were designed to investigate whether access to heroin self-administration altered the subsequent reinforcing effects of cocaine. Methods Baseline responding for cocaine under a progressive ratio schedule was first established. Heroin was then self-administered under a 24-h discrete-trials procedure (DT5; access to heroin five times per hour). Subsequently, cocaine-maintained responding was reassessed. Results Here we demonstrate that 10 days of DT5 heroin self-administration (50 μg/kg per infusion) resulted in an increase in cocaine’s reinforcing effects at several doses across the cocaine dose–effect curve (0.38–3.0 mg/kg per infusion). These increases were relatively long lasting, exceeding the time course of a mild withdrawal syndrome. Conclusions The DT5×10-day history of heroin self-administration resulted in an upward shift in the cocaine dose–effect curve, suggesting that DT5 heroin self-administration produced an increase in potency and sensitization of the maximal effectiveness with which cocaine functions as a reinforcer. The present experiments contribute to a growing amount of preclinical evidence suggesting an impact of opioid exposure on the reinforcing effects of cocaine, which may partially explain the high incidence of cocaine use in opioid-dependent individuals.     

Binge self-administration and deprivation produces sensitization to the reinforcing effects of cocaine in rats

Rationale Behavioral procedures that incorporate dynamic changes in drug-maintained behavior are needed to model the development of cocaine addiction in humans.Objectives Because sensitization may occur to some aspects of drug administration during the addiction process, the objective of the present study was to define the critical features of self-administration histories that result in subsequent increases in the reinforcing efficacy of cocaine (measured using the progressive ratio (PR) schedule).Methods Animals were trained to self-administer cocaine on a fixed ratio (FR) schedule, baseline performance on a PR schedule was determined, and animals were given various histories of cocaine self-administration and drug deprivation. PR performance was reassessed following this experience.Results Cocaine self-administration under a discrete-trials procedure (24 h/day) for 10 days, followed by a 7-day deprivation period resulted in sensitization to the reinforcing effects of cocaine as assessed by the PR schedule (increases in maximal breakpoints maintained by cocaine with no change in sensitivity at lower doses). Similar levels of daily cocaine intake on a FR schedule (typically completed within 6 h) coupled with a deprivation period failed to produce changes in breakpoint. Providing access to cocaine during the deprivation period by repeated testing on a PR schedule prevented the sensitization.Conclusions These data suggest that these self-administration-induced changes in breakpoint reflect sensitization, and show that a drug-free deprivation period is necessary, but not sufficient, to produce this increase.     

Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response

Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.     

Estrous cyclicity and behavioral sensitization in female rats following repeated intravenous cocaine administration.

Repeated intermittent administration of cocaine is well known to produce behavioral sensitization in male animals. The present studies explored whether intact adult female rats maintained normal estrous patterns in response to repeated IV cocaine administration and whether behavioral sensitization occurred with this route of administration. Adult female Sprague-Dawley rats (N = 48) were surgically implanted with an intravenous access port. Animals received 3.0 mg/kg IV cocaine once/day for 14 days. Daily vaginal lavages indicated that female rats continued to cycle normally throughout the experiment. Estimates of statistical power for detecting alterations in estrous cycle length ranged from 0.61-0.95 for small (0.1) to large (0.4) effect sizes. Moreover, no cocaine-treated animals displayed persistent vaginal estrus or were acyclic and cocaine treatment did not decrease body weight. Immediately after the cocaine injection, animals were placed in IR photocell activity chambers for 60 min. Female rats displayed a significant 75% increase in locomotor activity across the 14-day time course of IV cocaine injections. These data indicate that 3.0 mg/kg of IV cocaine does not interfere with normal estrous cyclicity, and that behavioral sensitization occurs in female rats following repeated daily IV cocaine dosing. Collectively, these data suggest that the IV cocaine-dosing model may be particularly useful in exploring the gender-dependent effects of cocaine using intact female rats.     

Effects of repeated withdrawal from chronic ethanol on oral self-administration of ethanol on a progressive ratio schedule

Male hooded Lister rats were trained using a sucrose-fading technique, to perform an operant lever press response to obtain ethanol. Initial training, using an FR4 schedule in which each reinforcement required four lever presses, included varying the concentration of ethanol in the liquid reinforcer. Changes in reinforcer concentration between 7 and 15% (vol/vol) had little effect on either numbers of lever pressing responses, or reinforcers obtained during the 3h session. Increasing the reinforcer concentration to 20% caused a decline in responding. The effects of varying reinforcer concentration (0-20% ethanol) were also studied in the same animals performing a progressive ratio schedule, in which the number of responses required to obtain a reinforcer was successively increased during the session. In these experiments the point at which rats ceased to respond (breaking point) was taken as a measure of their motivation to obtain ethanol. The function describing the relationship between ethanol concentration and number of responses, and number of reinforcers obtained in a session was an inverted U, with the maximum values occurring at an ethanol concentration of 10%. The value of the breaking point (highest ratio achieved) depended on the criterion used to define cessation of responding, but was between 15 and 22. Rats performing for ethanol showed higher breaking points than when responding for water, but there was no statistically reliable effect of ethanol concentration on the breaking point parameter. The effects of feeding the rats a liquid diet containing ethanol, and its subsequent withdrawal, on progressive ratio responding for 5% ethanol, were studied over four cycles of exposure and withdrawal. Intakes of ethanol of 11 g/kg/day had no effect on the animals' breaking point on the progressive ratio schedule, but withdrawal from the ethanol diet resulted in breaking points significantly higher than those in a control group pair-fed a nutritionally equivalent, ethanol-free diet. Although there was no further effect of repeated exposure and withdrawal on responding during the acute withdrawal phase, baseline levels of responding were elevated in the animals which had received multiple cycles of ethanol diet and withdrawal. These results are discussed in the context of the consequences of sensitization to repeated withdrawal from ethanol in dependent animals and humans.     

Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered during withdrawal from intermittent and continuous cocaine

 The present experiment evaluated the ability of the 5-HT₃ antagonist, ondansetron, administered during withdrawal from chronic cocaine administration, to block the expression of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg/per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered via osmotic minipump. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily SC injection of 0–1.0 mg/kg ondansetron. On day seven of with-drawal from the cocaine pretreatment (2 days after the final ondansetron injection) all subjects received a 15.0 mg/kg IP cocaine challenge. Their behavior was then rated according to the Ellinwood and Balster (1974) scale for 60 min. The results indicated that daily injections of ondansetron, on days 1–5 of withdrawal from the pretreatment regimen, had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron, on days 1–5 of withdrawal from intermittent cocaine administration, significantly blocked the expression of sensitization. In the continuous cocaine group, ondansetron injections, on days 1–5 of withdrawal from continuous cocaine administration, also blocked the expression of behavioral tolerance. The results therefore indicate that changes in 5-HT₃ receptor function are associated with the expression of tolerance and sensitization, respectively. Received: 1 April 1997/Final version: 28 July 1997     

Comparison of sensitization to ambulation-increasing effects of cocaine and methamphetamine after repeated administration in mice.

The effects of repeated (5 times) subcutaneous administration of cocaine (10, 20 or 40 mg kg-1) and methamphetamine (1, 2 or 4 mg kg-1) at 3-4 day intervals have been compared in mice placed individually into tilting activity cages. A progressive enhancement of the ambulation-increasing effect was noted for 3-4 h after each administration, indicating that sensitization occurred. This occurrence and the existence of an optimal dose producing sensitization were similar for both drugs. However, enhancement of the effect after cocaine progressed rapidly and maximum sensitization was observed earlier than after methamphetamine administration. Moreover, the higher doses of cocaine (40 mg kg-1) caused stereotypies concurrent with preconvulsive signs of short duration that were enhanced by serial administration. In contrast, methamphetamine caused a more progressive enhancement, but stereotypies with no preconvulsive signs were produced by the higher dose (4 mg kg-1). The respectively, effective doses for the development of enhancement suggested that cocaine was less potent than methamphetamine in producing sensitization. Cross-sensitization occurred between both drugs. Thus, sensitization to cocaine was distinct from that to methamphetamine due to differences in its rapidity, intensity, and the presence or absence of preconvulsive changes.     

Protracted withdrawal: sensitization of the anxiogenic response to cocaine in rats concurrently treated with ethanol.

Rats were trained to respond on one lever following an injection of saline and the alternate lever after the anxiogenic drug pentylenetetrazol (PTZ 20 mg/kg), according to a fixed ratio (FR10) schedule of food reinforcement. The trained animals were then administered dependence-producing regimens of either cocaine (20 mg/kg, [IP], three times daily for 7 days) or ethanol (mixed 4.5% w/v with sweetened liquid diet given for 5 days). Separate groups of trained rats were given either subthreshold regimens of cocaine (20 mg/kg, IP, three times daily for 5 days), ethanol (2.25% w/v of the diet given for 5 days), or both. Additional groups were matched for control groups. After discontinuation of these regimens, rats were administered test injections of either saline or cocaine, and tested for elicitation of the PTZ-stimulus at selected intervals of withdrawal. After a saline injection, maximum elicitation of the PTZ-stimulus was observed 12 hours following chronic treatment with the higher dose of ethanol, and 120 hours following longer treatment with cocaine. During those periods of withdrawal when a saline injection failed to produce a PTZ-like stimulus, a test injection of cocaine (10 mg/kg) elicited the PTZ-stimulus in the ethanol withdrawn rats, although only partially eliciting the PTZ-stimulus in the cocaine withdrawn group. In the pair-fed controls, or rats withdrawn from the smaller dosage of either ethanol or cocaine, the test dose of saline or cocaine did not elicit the PTZ-stimulus; only 30% of rats selected the PTZ-appropriate level at the highest dose of cocaine tested (10 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice

RATIONALE: The novel antipsychotic aripiprazole in use for treatment of schizophrenia is a partial agonist at dopamine D2 receptors with actions at a variety of other receptors as well. Cocaine is believed to exert an important part of its rewarding effect by increasing extracellular levels of dopamine that subsequently act at dopamine D2 receptors. OBJECTIVES: As a partial agonist, aripiprazole may antagonize effects at D2 receptors and we accordingly tested whether aripiprazole could antagonize self-administration of cocaine. Because D2-like receptor agonists are self-administered, a D2 receptor partial agonist like aripiprazole might itself be reinforcing. Thus, we also assessed whether mice would acquire self-administration of aripiprazole. MATERIALS AND METHODS: A single session, mouse self-administration procedure was used. RESULTS: Oral pretreatment with aripiprazole dose-dependently decreased cocaine self-administration under a fixed ratio 1 schedule at the peak cocaine dose (0.03 mg/kg/infusion), reaching significance at 0.2 and 0.4 mg/kg of aripiprazole. Using 0.4 mg/kg, aripiprazole decreased rates of cocaine self-administration without shifting the peak of the dose-response function. There was no effect of aripiprazole per se, suggesting that its inhibitory action was due to effects on cocaine self-administration rather than non-specific motor effects. Aripiprazole was not found to be self-administered in the tested dose range (0.0003-0.3 mg/kg/infusion). The three highest doses (0.03, 0.1, and 0.3 mg/kg/infusion) even caused significant decreases in nose-poking activity, possibly due to extrapyramidal side effects. CONCLUSIONS: These data are consistent with a potential role for aripiprazole in treatment of cocaine addiction without abuse potential per se.     

Extinction of cocaine self-administration produces a differential time-related regulation of proenkephalin gene expression in rat brain.

The purpose of this study was to examine the time course effects of extinction of cocaine self-administration behavior on proenkephalin (PENK) gene expression in caudate-putamen nucleus (ST), nucleus accumbens (Acc), olfactory tubercle (Tu), piriform cortex (Pir), ventromedial hypothalamic nucleus (VMN), and central amygdala (Ce) as measured by in situ hybridization histochemistry. Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (1) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT); (2) noncontingent injections of either 1 mg/kg/injection of cocaine (NONCONT); or (3) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a FR5 schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (day 0) and 1-, 5-, and 10-day after the second extinction period, animal brains in each triad were removed to be processed for in situ hybridization. PENK mRNA levels were significantly higher in the cocaine groups when compared with SALINE group in the ST, Acc, Pir, and Tu regions on days 0, 1, 5, and 10 of the extinction and lower in the Ce region of CONT group when compared to NONCONT and SALINE groups on days 1, 5, and 10 of the extinction period. In the VMN nucleus, PENK mRNA content in CONT group versus NONCONT and SALINE groups was also lower, but there were statistically significant differences only on day 5. These results suggest that changes in PENK gene expression after contingent cocaine administration might be involved in cocaine withdrawal states.     

Prenatal and postnatal cocaine exposure enhances the induction and expression of locomotor sensitization to cocaine in rats

Prenatal and postnatal exposure to cocaine can affect the development and function of the central nervous system in offspring. It also produces changes in cocaine-induced dopamine release and increases cocaine self-administration and cocaine-induced conditioned place preference. Further, prenatal cocaine exposure involves greater risk for development of a substance use disorder in adolescents. Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on locomotor sensitization in rats. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine pre-exposure group) and another group pregnant female rats were administered daily with saline (saline pre-exposure group). During lactation (PND0 to PND21) pregnant rats also received cocaine administration or saline, respectively. Of the litters resulting of the cocaine pre-exposed and saline pre-exposed pregnant female groups, only the male rats were used for the recording of the locomotor activity induced by different doses of cocaine (1, 5, 10, 20 and 40 mg/Kg/day) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90 and 120 days), representative of adolescence and adult ages. The study found that prenatal and postnatal cocaine exposure enhanced locomotor activity and locomotor sensitization, and such increase was dose- and age-dependent. This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to cocaine abuse in young and adult humans.     

Stimulation of adenosine receptors in the nucleus accumbens reverses the expression of cocaine sensitization and cross-sensitization to dopamine D(2) receptors in rats

Adenosine receptors co-localize with dopamine receptors on medium spiny nucleus accumbens (NAc) neurons where they antagonize dopamine receptor activity. It remains unclear whether adenosine receptor stimulation in the NAc restores cocaine-induced enhancements in dopamine receptor sensitivity. The goal of these studies was to determine whether stimulating A₁ or A_2A receptors in the NAc reduces the expression of cocaine sensitization. Rats were sensitized with 7 daily treatments of cocaine (15 mg/kg, i.p.). Following one-week withdrawal, the effects of intra-NAc microinjections of the adenosine kinase inhibitor (ABT-702), the adenosine deaminase inhibitor (deoxycoformycin; DCF), the specific A₁ receptor agonist (CPA) and the specific A_2A receptor agonist (CGS 21680) were tested on the behavioral expression of cocaine sensitization. The results indicate that intra-NAc pretreatment of ABT-702 and DCF dose-dependently blocked the expression of cocaine sensitization while having no effects on acute cocaine sensitivity, suggesting that upregulation of endogenous adenosine in the accumbens is sufficient to non-selectively stimulate adenosine receptors and reverse the expression of cocaine sensitization. Intra-NAc treatment of CPA significantly inhibited the expression of cocaine sensitization, which was reversed by both A₁ and A_2A receptor antagonism. Intra-NAc treatment of CGS 21680 also significantly inhibited the expression of cocaine sensitization, which was selectively reversed by A_2A, but not A₁, receptor antagonism. Finally, CGS 21680 also inhibited the expression of quinpirole cross-sensitization. Together, these findings suggest that adenosine receptor stimulation in the NAc is sufficient to reverse the behavioral expression of cocaine sensitization and that A_2A receptors blunt cocaine-induced sensitization of postsynaptic D₂ receptors.     

Abstinence from cocaine self-administration heightens neural encoding of goal-directed behaviors in the accumbens.

Cocaine addiction in humans is characterized by cycles of abstinence from drug-taking and relapse. Here, electrophysiological recording procedures were used to determine whether nucleus accumbens (Acb) neuronal firing properties are altered following interruption and resumption of cocaine self-administration. Rats (n = 12) were trained to self-administer cocaine (2 h daily sessions) then divided into two groups. Acb activity was recorded for Group 1 (controls) during two additional self-administration sessions completed over the next 2 days (test sessions 1 and 2). Acb activity was recorded for Group 2 (1-month) during one self-administration session completed the next day (test 1), and during a second self-administration session 1 month later (test 2). As in prior reports, a subset of Acb neurons exhibited patterned discharges (short duration and/or long-term cyclic alterations, termed 'phasically active') relative to cocaine-reinforced responding during test session 1. Remarkably, the percentage of phasically active cells dramatically increased (nearly two-fold) following 1-month abstinence, in the core but not the shell of the Acb. Likewise, the strength of the neural correlates (determined via signal-to-baseline ratios) also increased as a function of abstinence. Extinction experiments in another set of rats (n = 12) revealed an increased motivational state for the drug following abstinence. The results show that abstinence from cocaine self-administration causes a dramatic increase in the number and strength of Acb neurons that encode cocaine-related information, thus representing the first neurophysiological correlate of heightened activation of the 'brain reward system' following abstinence and resumption (relapse) of cocaine consumption.