Reinstatement and spontaneous recovery of cocaine-seeking following extinction and different durations of withdrawal

Stimuli paired with drug use can acquire powerful motivational properties that are believed to induce relapse to drug-seeking in abstinent humans. Behavioural interventions for drug addiction, that have attempted to reduce the probability of relapse by extinguishing the motivational impact of drug-associated conditioned stimuli (CS), have had limited success. One explanation for the ready propensity to relapse to drug-seeking even following extinction of these stimuli may be that abstinence by humans can increase the ability of conditioned stimuli and drug primes to reinstate responding. In the present study, we sought to determine the effects on cocaine-seeking of imposing different periods of drug unavailability on rats, with or without extinction of the drug-seeking response and non-reinforced exposure to drug-associated stimuli. Rats were trained to self-administer cocaine under a second-order schedule of reinforcement, under which high response rates are maintained by drug-paired conditioned reinforcers, prior to extinction of the operant response alone or in combination with contingent presentation of the CS. Comparison of cocaine-seeking behaviour during a test session conducted either 1 day or 21 days after a 7-day period of extinction revealed that responding was significantly decreased the day after extinction, but spontaneously recovered following a further imposed period of 21 days during which cocaine and cocaine cues were not available. Self-administered cocaine further potentiated reinstated responding following all withdrawal periods. These findings are discussed with reference to interactions between drug unavailability, conditioned stimuli and cocaine self-administration, on the reinstatement of drug-seeking and the potential utility of extinction therapies for drug addiction.     

Contextual renewal of nicotine seeking in rats and its suppression by the cannabinoid-1 receptor antagonist Rimonabant (SR141716A)

Nicotine-associated paraphernalia such as cigarettes and ashtrays are potent smoking relapse triggers. In addition to these discrete cues, environmental contexts previously associated with smoking elicit strong cigarette craving, indicating that contextual stimuli also contribute to high smoking relapse rates. Nonetheless, little is known about the precise role of these stimuli in smoking relapse and the neuropharmacological mechanisms implicated herein.To address this issue, we determined whether re-exposure to the nicotine self-administration context after long-term extinction reinstates nicotine seeking behavior in rats. Further, we examined the effects of SR141716A (Rimonabant), a selective cannabinoid CB1 receptor antagonist which has been shown to attenuate cue-induced relapse to nicotine seeking, on context-induced reinstatement of nicotine seeking.Rats were trained to self-administer nicotine intravenously (30 μg/kg/infusion). Nicotine infusions were paired with an audiovisual compound stimulus. Subsequently, nose poking behavior was extinguished in the presence of this discrete cue in a context different from the self-administration context. Hereafter, rats were injected with 0, 1, or 3 mg/kg Rimonabant (i.p.) prior to re-exposure to either the self-administration or the extinction context.Re-exposure to the self-administration context, but not to the extinction context robustly reinstated responding for the discrete nicotine cues, an effect that was dose-dependently attenuated by Rimonabant.This is the first demonstration of contextual renewal of nicotine seeking in rodents after prolonged withdrawal. Further, our results indicate that the endocannabinoid system is involved in context-induced relapse to nicotine seeking, and as such these data provide further evidence for the use of CB1 antagonists in smoking cessation.     

The CB1 antagonist rimonabant (SR141716) blocks cue-induced reinstatement of cocaine seeking and other context and extinction phenomena predictive of relapse

Cannabinoid CB1 antagonists decrease self-administration of palatable food and several abused drugs in animals and modulate extinction of conditioned fear responses. Less is known, however, about whether and how CB1 antagonists might modulate the extinction of appetitive behavior. Therefore, this study examined the effects of the CB1 receptor antagonist rimonabant (SR141716) during extinction of responding maintained either by cocaine or by palatable foods (corn oil or Ensure), as well as responding elicited by stimulus cues that had been paired with the presentation of cocaine (i.e., cue-induced reinstatement) or a prime (presentation of cocaine or food). The effect of rimonabant on high rate responding in water-deprived mice trained to self-administer water was also examined. In mice self-administering cocaine, rimonabant attenuated cue-induced reinstatement of cocaine self-administration, the initial burst of responding during cocaine extinction and responding during spontaneous recovery. In mice self-administering corn oil, rimonabant decreased responding during extinction and also attenuated responding that had been reinstated by a priming presentation of corn oil. Moreover, mice treated with rimonabant required fewer daily sessions to reach criterion for extinction of cocaine-maintained responding than vehicle treated mice. Also, rimonabant had no effect on the rate of operant responding in mice trained to respond for water under an FR5 schedule of reinforcement. Taken together, these data suggest that in addition to attenuating the primary reinforcing effects of both palatable foods and drugs of abuse, CB1 receptor antagonism can attenuate context and cue reactivity during extinction learning and potentially enhance extinction learning in this way.     

Cue dependency of nicotine self-administration and smoking

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.     

Cortico-limbic circuitry for conditioned nicotine-seeking behavior in rats involves endocannabinoid signaling

Rationale The endocannabinoid system plays an important role in conditioned drug seeking, but the neuronal mechanisms involved in this behavior are unclear. Objectives Here, we evaluate the role of endogenous cannabinoids in the cortico-limbic circuitry in cue-induced nicotine-seeking behavior in rats. Methods Animals were first trained to self-administer nicotine (0.03 mg/kg/injection, IV) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and audiovisual stimuli. During subsequent sessions, nicotine was withdrawn and responding was reinforced by contingent presentation of the stimuli only. One month after nicotine removal, the cannabinoid CB1 receptor antagonist, rimonabant, was injected bilaterally into the shell of the nucleus accumbens (ShNAcc, 0.3, 3, or 30 ng/0.5 μl), the basolateral amygdala (BLA, 30 ng/0.5 μl), or the prelimbic cortex (PLCx, 30 ng/0.5 μl). Results Rimonabant injected into the ShNAcc dose-dependently reduced nicotine-seeking behavior without modifying spontaneous locomotor activity. Similar results were obtained when the drug (30 ng) was injected into the BLA or the PLCx. The anatomical specificity was confirmed in a control experiment using [³H]rimonabant. Fifteen minutes after drug injection, when the behavioral effects of rimonabant were already achieved, radioactivity was detected at the site of injection and had not diffused to adjacent regions. Conclusions These findings demonstrate that increased endocannabinoid transmission critically triggers conditioned nicotine-seeking behavior in key cortico-limbic regions.     

Potentiated reinstatement of cocaine-seeking behavior following D-amphetamine infusion into the basolateral amygdala.

Reinstatement of extinguished drug-seeking behavior following chronic drug self-administration has been demonstrated in rats in the presence of conditioned cues. This experimental model of cue-induced relapse can be used to assess the neural circuitry involved in relapse. We have previously shown that blockade of dopamine D1 receptors in the basolateral amygdala (BLA) abolishes conditioned cue-induced reinstatement of cocaine-seeking behavior. The present study tested the hypothesis that D-amphetamine-induced facilitation of monoamine neurotransmission in the BLA would potentiate conditioned cue-induced reinstatement of extinguished drug-seeking behavior. During daily self-administration sessions over 10 consecutive days, rats pressed a lever to receive cocaine infusions (0.2 mg/0.05 ml) paired with a light+tone compound stimulus. Following self-administration, rats underwent daily extinction sessions, during which no stimuli were presented. On the test days, rats received intra-BLA D-amphetamine (10 or 30 micro g/side) or vehicle infusions followed by extinction or conditioned cue-induced reinstatement testing. D-amphetamine infusions did not alter extinction responding relative to vehicle infusions. During reinstatement testing, conditioned cue presentation significantly increased responding over extinction levels, and intra-BLA D-amphetamine produced a dose-dependent increase in lever responding relative to vehicle infusions. These findings suggest that enhanced monoamine tone in the BLA potentiates the motivational effect and/or salience of cocaine-paired cues during reinstatement.     

Environmental stimuli promote the acquisition of nicotine self-administration in rats

RATIONALE: Environmental stimuli associated with drugs of abuse are believed to play a major role in the motivation to take drugs, drug dependence, and relapse. Previous work from this laboratory demonstrated that the response-contingent presentation of drug-related, visual cues was at least as important as nicotine in the maintenance, extinction and reacquisition of self-administration in experienced rats. OBJECTIVES: In the present research, we asked whether these same visual cues are effective in promoting the acquisition of operant responding in drug naive rats. METHODS: Male Sprague-Dawley rats were tested for self-administration of IV nicotine (0.03 mg/kg, free base) in 1-h daily sessions when infusions were or were not paired with two lighting events: a 1-s cue light, followed by a 1-min period during which the chamber light was turned off and responding was not reinforced. RESULTS: Rats tested with cues plus nicotine rapidly acquired self-administration and increased their lever pressing rates as the schedule progressed from FR1 to FR5. Without cues, the rate of nicotine self-administration was low and no adjustments were made in response to increasing schedule demands. While one of the stimuli, turning off the chamber light, was shown to have primary reinforcing properties, its association with nicotine produced a synergistic enhancement of lever pressing. Acquisition of operant responding was also enhanced, but to a lesser extent, by a previously neutral compound stimulus, i.e. the nicotine-paired cue light presented with a 1-s tone. CONCLUSIONS: These results illustrate a powerful interaction between environmental stimuli and nicotine in the acquisition of operant responding and indicate that both intrinsically reinforcing and previously neutral cues can participate in this effect.     

Naltrexone attenuation of conditioned but not primary reinforcement of nicotine in rats

RATIONALE: Opioid neurotransmission has been implicated in reinforcement-related processes for several drugs of abuse, including opiates, stimulants, and alcohol. However, less is known about its role in the motivational effects of nicotine and nicotine-associated environmental cues. OBJECTIVE: This study investigated whether pretreatment with naltrexone, an opioid receptor antagonist, alters conditioned incentive salience of nicotine cues under two conditions: cue-induced reinstatement of nicotine-seeking after extinction and cue-maintained responding during extinction. The effect of naltrexone on nicotine self-administration during the maintenance phase was also examined. MATERIALS AND METHODS: Male Sprague-Dawley rats were trained in daily 1-h sessions to self-administer nicotine (0.03 mg/kg/infusion, i.v.) on a fixed-ratio 5 schedule and associate a conditioned stimulus (CS) with each nicotine delivery. Once responding was extinguished by saline substitution for nicotine and omission of the CS, the reinstatement tests were conducted following subcutaneous administration of naltrexone (0, 0.25, 1, 2 mg/kg). In separate groups of rats, naltrexone (0, 2 mg/kg) was chronically given before each extinction sessions, where responses on the active lever resulted in presentations of the CS without nicotine infusion (saline substitution). Self-administration/naltrexone tests were conducted in different groups of rats receiving similar nicotine self-administration training. RESULTS: Naltrexone significantly attenuated the CS-reinstated responding on the active, previously nicotine-reinforced lever in the reinstatement tests and the CS-maintained active lever responding during the extinction tests. In contrast, neither acute nor chronic naltrexone produced an effect on nicotine self-administration behavior. CONCLUSIONS: These results indicate that activation of opioid receptors is implicated in mediation of the conditioned incentive properties of nicotine cues but not in the maintenance of nicotine self-administration. Therefore, these findings suggest that opioid receptor antagonists might have clinical potential for prevention of smoking relapse associated with exposure to environmental cues.     

The importance of a compound stimulus in conditioned drug-seeking behavior following one week of extinction from self-administered cocaine in rats

Previous studies have demonstrated that conditioned stimuli can increase responding on a drug-associated lever after extinction from drug self-administration. The present study investigated singular stimuli (tone or light) or a compound stimulus (tone + light) for their ability to increase extinguished responding following chronic cocaine self-administration. Rats self-administered cocaine for 2 weeks on a fixed ratio (FR1) schedule of reinforcement, in which lever responding resulted in varied presentation of a tone, light, or tone + light combination. The rats were then exposed to 1 week of daily extinction sessions. Presentation of the tone + light on day 8 of extinction in the absence of cocaine reinforcement resulted in a significant increase in responding, while either stimulus component alone was much weaker or failed to produce any changes from extinction rates of responding. In addition, changing the duration of the single elements of the compound did not affect the magnitude of increased responding to the compound. Following three final extinction sessions, robust lever responding for cocaine infusions on day 12 of extinction was seen across all groups. These findings suggest that compound stimuli may be critical to fully activate drug-seeking behavior in conditions of craving and relapse following prolonged extinction.     

Nicotine reinstatement of nicotine self-administration after long-term extinction

The effect of non-contingent priming injections of nicotine on the reinstatement of drug-seeking behaviour was studied in rats following the long-term extinction of nicotine self-administration. Male rats were trained to lever press for 0.03 mg/kg per infusion of intravenous nicotine. Nicotine maintained a robust self-administration behaviour (11.5±1.2; mean±SEM infusions/1-h session). When nicotine availability was discontinued, and only a non-contingent saline infusion was presented to the experimental subjects at the beginning of each daily session, responding for the drug-paired lever decreased to low values. After 4–13 sessions, responding extinguished. During this “extinction” period, non-contingent priming infusions of nicotine 0.001, 0.003, 0.01 or 0.03 mg/kg per infusion induced reinstatement of responsing for the drug-paired lever. The increased responding, compared with the corresponding previous day on saline, was observed at all four nicotine doses but was not statistically significant for the higher priming dose (0.03 mg/kg per infusion). These preliminary results indicate that nicotine priming is able to induce reinstatement of drug-seeking behaviour in rats similarly to other reinforcing drugs. The present findings show analogies with similar phenomena described in ex-smokers and support the addictive role of nicotine in tobacco smoking.     

Reinstatement of MDMA (ecstasy) seeking by exposure to discrete drug-conditioned cues

The widely used recreational drug MDMA (ecstasy) supports self-administration in animals, but it is not known whether MDMA-associated cues are able to reinstate drug seeking in a relapse model of drug addiction. To assess this possibility, drug-na?ve rats were trained to press a lever for MDMA infusions (0.30 mg/kg/infusion, i.v.) paired with a compound cue (light and tone) in daily 2 h sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. Conditioned cue-induced reinstatement tests were conducted after lever pressing was extinguished in the absence of MDMA and the conditioned cues. Conditioned cues reinstated lever pressing after extinction, and the magnitude of reinstatement was positively correlated with the level of responding during MDMA self-administration. These results show for the first time that conditioned cues can trigger reinstatement of MDMA-seeking behavior in rats, and that individual differences in the pattern of MDMA self-administration can predict the magnitude of reinstatement responding.     

Control of the reinforcing effects of nicotine by associated environmental stimuli in animals and humans

Tobacco dependence through cigarette smoking is the leading preventable cause of death in the world and kills nearly 4 million people annually. Nicotine, a psychoactive component of tobacco, is thought to have a major role in tobacco dependence by acting directly as a reinforcer of drug-seeking and drug-taking behavior. However, recent findings obtained with two procedures that are used widely to assess reinforcing effects of drugs in experimental animals, intravenous drug self-administration and conditioned place-preference procedures, demonstrate that environmental factors have a major influence on the reinforcing effects of nicotine. Under some experimental conditions, nicotine is also self-administered reliably by humans. Environmental stimuli that have been associated previously with the self-administration of nicotine can reinstate extinguished drug-seeking behavior in animals and precipitate relapse to smoking behavior in ex-smokers. Innovative medications that target cannabinoid CB(1) and dopamine D(3) receptors and might block specifically the influence of such conditioned environmental stimuli in smokers are in development.     

The observing-response procedure: a novel method to study drug-associated conditioned reinforcement

In this experiment, the observing-response procedure was adapted for use with drug self-administration. Rats' responding for oral ethanol was sometimes reinforced on a random-ratio schedule, whereas at other times it had no effect (i.e., extinction). Behavior producing stimuli associated with the otherwise unsignaled random-ratio and extinction periods (i.e., observing behavior) was acquired and maintained. In a vehicle control condition, both self-administration and observing behavior decreased, but observing decreased less rapidly proportionally to baseline than vehicle consumption. Thus, conditioned reinforcers may have persistent effects that are relatively independent of the current status of the primary reinforcer. The procedure allows long-term study of drug-associated conditioned reinforcement and provides independent indexes of the conditioned reinforcing and discriminative stimulus effects of drug stimuli.     

Factors that determine a propensity for cocaine-seeking behavior during abstinence in rats.

Individual differences in locomotor responses to novelty and psychostimulants, and sensitization following repeated drug exposure, predict increased sensitivity to the reinforcing effects of psychostimulants and are thought to underlie vulnerability to drug addiction. This study tested whether these factors determine another core feature of drug addiction, the propensity for drug-seeking behavior during abstinence in rats with prior cocaine-self-administration experience. Low and high response groups for each of these factors were determined in outbred rats by the median locomotor response to novelty and amphetamine prior to cocaine self-administration (pre-test), and to amphetamine during abstinence (post-test). Cocaine-seeking behavior during abstinence was measured by the level of drug-paired lever responding during extinction, and also during reinstatement induced by cocaine-associated cues, an amphetamine priming injection, and footshock stress. Animals with low and high locomotor responses to novelty and the amphetamine pre-test showed similar levels of cocaine-seeking behavior during extinction and reinstatement testing. Locomotor responses to amphetamine following cocaine self-administration (post-test) also failed to determine amphetamine's ability to reinstate cocaine-seeking behavior. Conversely, high levels of amphetamine-induced reinstatement were associated specifically with escalating cocaine intake during prior self-administration. These animals also developed locomotor sensitization to amphetamine following cocaine self-administration (post-test vs. pre-test), but the capacity to develop locomotor sensitization was not sufficient to determine a propensity for cocaine-seeking behavior. The findings suggest that the relationship between locomotor responses to novelty, amphetamine and behavioral sensitization a,nd the propensity for cocaine-seeking behavior during abstinence is complex, while the level of drug intake during prior self-administration is a primary determinant of this behavior.     

Drug self-administration methods to the study of drug craving (drug seeking behavior)

The drug self-administration procedure is necessary for the study of addiction in terms of two similarities with human. One similarity is drug taking pattern, and the other is reinstatement of drug-seeking responses after the withdrawal. This procedure consists of two phase, called as the acquisition of drug taking behavior and the extinction. The drug taking behavior is formed on the base of reinforcing effects of drug under a fixed ratio schedule. On the other hands, a progressive ratio schedule is a useful procedure to estimate the potency of reinforcing/rewarding effect. Clinically, drug craving can be triggered by taking the other drug which has the effects similar to abused drug, by stimuli previously associated with drug-taking, or by exposure to stressors. In preclinical study, these three initiating factors also reinstate drug-seeking. From the studies that clarify the responsible brain regions, the importance of the nucleus accumbens, prefrontal cortex and hippocampus is clarified. The brain regions associated with drug craving are identified using a PET and fMRI technologies. In the future study, it is expected to integrate/reconstruct between the identified brain regions that provoke drug craving in humans and responsible brain regions that induce reinstatement of drug-seeking in animal model of drug dependence.     

Nicotine enhances responding with conditioned reinforcement

Rationale The mesolimbic dopamine system has been implicated in the primary reinforcing properties of drugs of abuse as well as in enhanced responding with conditioned reinforcement produced by psychomotor stimulant drugs. Despite clinical observations that nicotine self-administration (i.e. smoking) depends strongly upon conditioned reinforcement (i.e. cues support smoking behavior), little is known about whether nicotine directly affects motivational processes.Objective In these experiments, we investigated whether acute nicotine would influence responding with conditioned reinforcement and the degree to which pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine would modify any nicotine-induced behavioral effects.Methods After subjects had been trained to associate an initially neutral stimulus with water reward, they received acute nicotine (43,25–350 µg/kg SC; –5 min) or saline injections and were tested on the acquisition of a new response for conditioned reinforcement paradigm. In separate experiments, the effect of pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine (300 or 1000 µg/kg SC; –20 min) alone, or in combination with nicotine (350 µg/kg SC; –5 min), on conditioned reinforcement was also examined.Results Acute nicotine injection produced a selective enhancement of responding with conditioned reinforcement (i.e. on the CR lever), without producing non-selective increases in overall responding. The effect of nicotine (350 µg/kg SC; –5 min) was selectively blocked by mecamylamine (300 µg/kg).Conclusions These findings demonstrate that acute exposure to nicotine augments the control over behavior by a conditioned reinforcer, suggesting that nicotine may enhance motivational processes.     

Neural substrates of cocaine-cue associations that trigger relapse

Learned associations that occur during the process of repeated drug use in addiction can later manifest as trigger factors in relapse to renewed drug-seeking and drug-taking behavior. The process of conditioned-cued relapse of drug-seeking behavior has been successfully modeled in animals using the reinstatement procedure, in which chronic drug self-administration can be extinguished or withheld, and then reinstated using conditioned stimuli previously paired with the drug. Our laboratory has extensively studied the neural circuitry underlying conditioned-cued drug-seeking during the expression of reinstatement. In order to study the learning process of drug-cue pairings, we further developed a procedure whereby discrete cocaine-cue pairings can be conducted in a single pavlovian training session in animals previously trained to self-administer cocaine. Presentation of these cues during later reinstatement trials produces robust responding over extinction levels at levels similar to those seen when animals experience the cues on a daily basis. In a series of experiments, we have shown that reversible pharmacological inactivation of the basolateral complex of the amygdala just prior to acquisition of cocaine-cue associations blocks the ability of cocaine-paired stimuli to elicit conditioned-cued reinstatement. This learning process is mediated in part by muscarinic acetylcholine and dopaminergic inputs to the basolateral complex of the amygdala, as intra-amygdala infusion of selective receptor antagonists at the time of acquisition significantly affects reinstatement. We have also recently found that disruption of neural activity within the basolateral complex of the amygdala at the time of consolidation (just after cocaine-cue pairings) will disrupt reinstatement. Taken together, these results reveal the importance of the amygdala in the acquisition, consolidation, and expression of drug-stimulus learning that drives relapse to drug-seeking behavior.     

Stimulus conditioned to foot-shock stress reinstates alcohol-seeking behavior in an animal model of relapse

Rationale. Stress and conditioned responses to drug cues have been implicated as critical factors in relapse to drug use. In the animal literature, both the conditioned effects of drug-related stimuli and the unconditioned effects of foot-shock stress have been well documented to reinstate extinguished drug-seeking behavior. What has remained largely unexplored, however, is the significance of stimuli conditioned to foot-shock stress for the resumption of drug seeking. Additionally, although relapse is often the result of several risk factors acting in combination, the possibility that interactions among risk factors such as conditioned stress and drug cues may intensify drug-seeking behavior has received little experimental attention. Objectives. The purpose of this study was to examine the individual and interactive effects of a stimulus conditioned to foot-shock stress (STRESS CS) and a stimulus conditioned to ethanol reward (EtOH CS) on the reinstatement of ethanol-seeking behavior following extinction. Methods. Male Wistar rats were trained to orally self-administer 10% ethanol on a fixed-ratio 3 schedule of reinforcement. The EtOH CS was established by response-contingently pairing 0.5 s illumination of a white cue light with each reinforced response. The STRESS CS was established by pairing a continuous white noise (70 dB) with intermittent foot shock (10 min; 0.5 mA; 0.5 s on; mean off period of 40 s). Ethanol dependence was induced by an ethanol vapor-inhalation procedure. After ethanol-maintained instrumental responding was extinguished by withholding ethanol and the EtOH CS, reinstatement tests were conducted. Results. Both exposure to the STRESS CS and response-contingent presentation of the EtOH CS reinstated extinguished responding at the previously active, ethanol-paired lever without further ethanol availability. When response-contingent availability of the EtOH CS was preceded by exposure to the STRESS CS, interactive effects of these stimuli on responding were observed. However, both the individual and interactive effects of the STRESS CS and the EtOH CS reached statistical significance only in rats with a history of ethanol dependence but not in ethanol-nondependent rats. Conclusions. The results confirm that both conditioned stress and ethanol cues elicit ethanol-seeking behavior and, more importantly, that these stimuli produce interactive effects resulting in an increased ethanol-seeking response. The findings also indicate that susceptibility to ethanol seeking induced by conditioned stress and alcohol cues depends significantly on the history of prior alcohol exposure.     

Repeated nicotine exposure enhances responding with conditioned reinforcement

Rationale Stimuli associated with a reinforcer (e.g., an addictive drug) can acquire conditioned reinforcing effects. Clinical observations indicate that smoking depends strongly upon conditioned reinforcement (i.e., cues support smoking behavior); however, little is known about the effects of repeated nicotine exposure on these processes.Objective This study investigated the consequences of prior repeated nicotine exposure on responding with conditioned reinforcement and on the potentiation of conditioned reinforcement by intra-NAc amphetamine infusion.Methods Rats received repeated saline or nicotine injections (0.35 mg/kg; 15 days) and were, following 3 days of withdrawal, trained to associate a tone + light stimulus with water reinforcement for 10 days. Animals were subsequently tested on acquisition of a new instrumental response with conditioned reinforcement (i.e., 14 days after the final nicotine injection). In additional experiments, animals received an infusion of amphetamine (10 µg per side) prior to the conditioned reinforcement test.Results Prior repeated nicotine exposure produced a behaviorally specific enhancement of responding with conditioned reinforcement. Furthermore, repeated nicotine pretreatment also augmented the potentiation of conditioned reinforcement by intra-NAc amphetamine.Conclusions These findings demonstrate that prior repeated nicotine exposure augments the control over behavior by a conditioned reinforcer. Such long-lasting alterations in incentive motivational processes produced by repeated nicotine exposure may depend on drug-induced neuroadaptations in dopamine-regulated signaling within limbic-striatal brain regions that could underly persistent and compulsive aspects of addiction.     

Acamprosate attenuates cue-induced reinstatement of nicotine-seeking behavior in rats

Acamprosate is used in the treatment of alcoholism; however, there is little information on its effects on nicotine addiction. The objective of this study was to determine whether acamprosate inhibits cue-induced relapse to nicotine self-administration in the rat. Rats were trained to press a lever to obtain intravenous infusions of nicotine (0.03 mg/kg/infusion) that were associated with the illumination of a cue light. After 29 days of nicotine self-administration sessions, extinction sessions were run during which responses on the active lever did not result in the infusion of nicotine or the illumination of the cue light. After 14 days of extinction sessions the rats received twice-daily injections of saline or acamprosate (50, 100, or 200 mg/kg/intraperitoneally). Seven days later the response to the previously conditioned cue was tested, but only saline infusions were delivered. Pretreatment with all doses of acamprosate reduced responding to a cue previously associated with nicotine. The lowest dose of acamprosate (50 mg/kg) reduced responding for the cue previously associated with nicotine infusions, but had no effect on food-rewarded behavior. These results show that acamprosate reduced cue-induced nicotine-seeking behavior and suggest that acamprosate might be efficacious in treating nicotine addiction in humans.