Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose

Rationale The motivational effects of nicotine-associated cues have been demonstrated in animal studies. However, it is unknown whether the effectiveness of nicotine cues in reinstating nicotine-seeking varies with the extent of prior nicotine self-administration. In addition, the issue of whether bupropion (an FDA-approved smoking cessation medication) interferes with the conditioned incentive of nicotine cues remains to be addressed. Objective This study determined the relationship of cue-reinstated nicotine-seeking and the levels of prior self-administration and examined the effect of bupropion on cue-induced reinstatement of nicotine-seeking in comparison with that on self-administration. Materials and methods Male Sprague–Dawley rats were trained in daily 1-h sessions to intravenously self-administer nicotine at different doses (0, 0.015, 0.03, 0.06 mg/kg/infusion) and to associate an auditory/visual cue with each nicotine delivery. After extinction, three reinstatement tests at 15 day intervals were conducted with re-presentation of the cue without nicotine delivery. In separate groups of rats trained with 0.03 mg/kg/infusion nicotine, bupropion (0, 10, 20, 40 mg/kg) was intraperitoneally administered to different groups before the reinstatement and in a within-subject design before the self-administration tests. Results Cue-induced reinstatement of active lever responses was observed at all nicotine doses in the first reinstatement test, but at only the two highest doses during the second and third tests. The magnitude of reinstatement was positively correlated with level of prior responding for nicotine. Bupropion pretreatment decreased nicotine self-administration but enhanced cue-reinstated nicotine-seeking. Conclusions These results demonstrate the positive correlation of cue-reinstated nicotine-seeking with prior responding for nicotine self-administration and the persistence of the cue effect after taking higher doses of nicotine. The results of pharmacological tests suggest that although it is able to help achieve smoking cessation, bupropion may have little clinical benefit for the prevention of relapse associated with exposure to environmental smoking cues.     

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.     

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.     

Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats

Rationale Sex differences have been reported in physiological and behavioral responses to cocaine, but it is unclear whether sex differences exist in conditioned-cued relapse to cocaine seeking after prolonged abstinence. Furthermore, the role of estrous cyclicity in conditioned-cued relapse has not been investigated.Objective We assessed the influence of sex and estrous cyclicity on conditioned-cued reinstatement of drug-seeking behavior in Sprague–Dawley rats.Methods Rats were trained to self-administer intravenous cocaine (unconditioned stimulus, US; 0.25, 0.4, 0.5, 0.6, or 1.0 mg/kg per infusion) paired with light+tone conditioned stimuli (CSs) and were subsequently tested for the ability of the CSs to reinstate extinguished cocaine seeking (i.e., nonreinforced lever responding).Results Females exhibited more responding on the cocaine-paired lever during self-administration and extinction than males. Subsequently, males exhibited equally robust conditioned-cued reinstatement of extinguished drug-seeking behavior independent of cocaine training dose. Males and females trained on 0.4–0.6 mg/kg cocaine reinstated to a similar extent. However, females trained on the lowest dose (0.25 mg/kg) exhibited less reinstatement than males, and the source of this effect was the absence of reinstatement in estrous females. In addition, independent of estrous state, females trained on the highest dose (1.0 mg/kg) exhibited less reinstatement than males.Conclusions While males and females are equally responsive to cocaine-paired CSs when the conditions for CS–US association are optimal, females appear to attribute less motivational significance to the CS when it presumably acquires weaker motivational salience because of (a) a low cocaine dose or (b) weaker CS–US contiguity due to the prolonged effects of a high cocaine dose.     

The cannabinoid antagonist AM251 attenuates nicotine self-administration and nicotine-seeking behaviour in rats

The cannabinoid receptor subtype (CB1) antagonist rimonabant (SR141716) has been shown to decrease nicotine self-administration and attenuate nicotine-evoked dopamine release in the nucleus accumbens; effects that support recent findings on its clinical efficacy as a smoking cessation aid. The present experiments aim to advance our understanding on the role of CB1 receptors in rodent models of nicotine dependence. AM251, a selective antagonist at CB1 receptors dose-dependently (1, 3 and 10mg/kg IP) suppressed intravenous nicotine (0.03mg/kg per infusion) self-administration in rats during three successive days of pre-treatment. This reduction was short lasting since behaviour was reinstated by suspending AM251 pre-treatment. This was relatively specific to nicotine self-administration since the profile of these reductions produced by AM251 was significantly different from the responses maintained by food pellets. In a model of nicotine-seeking behaviour, rats that had been extinguished by removal of nicotine and associated cues, and presented with a priming dose of nicotine (0.2mg/kg SC) with the cues, showed robustly reinstated responses to nicotine-seeking behaviour. Acute pre-treatment with AM251 (1-10mg/kg IP) dose-dependently attenuated the reinstatement effects produced by nicotine and the contingently presented cues. These preclinical findings support the use of rimonabant as a smoking cessation aid and highlight the CB1 receptor as a viable target to control intake of nicotine and prevent relapse.     

Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats

Background

Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse.

Methods

Rats lever pressed for nicotine (0.03 and 0.05 mg/kg/infusion, IV) during 15 daily 2-h sessions, followed by extinction of lever responding. Once responding was extinguished, we examined the ability of previously nicotine-paired cues (tone + light), the anxiogenic drug yohimbine (2.5 mg/kg, IP), a priming injection of nicotine (0.3 mg/kg, SC), or combinations of drug + cues to reinstate nicotine-seeking.

Results

Both males and females readily acquired nicotine self-administration and displayed comparable levels of responding and intake at both nicotine doses. Following extinction, exposure to the previously nicotine-paired cues or yohimbine, but not the nicotine-prime alone, reinstated nicotine-seeking in males and females. Moreover, when combined with nicotine-paired cues, both yohimbine and nicotine enhanced reinstatement. No significant sex differences or estrous cycle dependent changes were noted across reinstatement tests.

Conclusions

These results demonstrate the ability to reinstate nicotine-seeking with multiple modalities and that exposure to nicotine-associated cues during periods of a stressful state or nicotine can increase nicotine-seeking.     

Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat.

Clinical observations suggest that stimuli associated with the availability or consumption of ethanol can evoke subjective feelings of craving and trigger episodes of relapse in abstinent alcoholics. To study the motivational significance of alcohol-related environmental cues experimentally, the effects of discriminative stimuli previously predictive of alcohol availability on the reinstatement of ethanol-seeking behavior were examined. Wistar rats were trained to lever-press for 10% (w/v) ethanol or water in the presence of distinct auditory cues. The rats were then subjected to an extinction phase where lever presses had no scheduled consequences. After extinction, the animals were exposed to the respective auditory cues without the availability of ethanol or water. Neither the ethanol (SA+) nor water-associated (SA-) auditory cue increased responding over extinction levels. In contrast, subsequent presentation of an olfactory cue associated with ethanol (SO+), but not a water-associated (SO-) cue significantly reinstated lever pressing behavior in the absence of the primary reinforcer. Moreover, responding elicited by the concurrent presentation of the SO+ and SA+ was selectively attenuated by the opiate antagonist naltrexone (0.25 mg/kg; s.c.). The results suggest that ethanol-associated cues can reinstate extinguished ethanol-seeking behavior in rats, but that the efficacy of these stimuli may be modality-specific. In addition, the present procedures may be useful for studying neurobiological mechanisms of alcohol-seeking behavior and relapse.     

Nicotine increases alcohol self-administration and reinstates alcohol seeking in rats

Rationale and objective Alcohol and tobacco are often co-abused in humans and previous studies found that nicotine increases alcohol consumption in rats. Here, we studied whether nicotine would reinstate alcohol-taking behavior in drug-free rats and whether this effect would be enhanced by prior exposure to nicotine during alcohol self-administration training. Methods Rats were trained to press a lever for alcohol (12% w/v, 1 h/day), and following stable alcohol intake groups of rats (n=11–12) were given daily vehicle or nicotine (0.2, 0.4 or 0.8 mg/kg, SC) injections just prior to the self-administration sessions for 10 days. Rats were then given 6 days of alcohol self-administration in the absence of nicotine and an additional 5–10 drug-free days during which lever presses were not reinforced (extinction). Subsequently, rats were tested for reinstatement of alcohol seeking following exposure to priming injections of vehicle or nicotine (0.4 mg/kg, SC). Results Nicotine increased alcohol self-administration in a dose- and time-dependent manner over the 10-day period. Nicotine also reinstated alcohol seeking after extinction of the alcohol-reinforced behavior, and this effect was strongly enhanced by prior nicotine exposure. Conclusions The present data extend previous studies on the effect of nicotine on alcohol self-administration, and further indicate that nicotine is an effective stimulus for reinstatement of alcohol seeking during drug-free periods.     

Cocaine-seeking behavior after extended cocaine-free periods in rats: role of conditioned stimuli

Rationale. Cocaine abstinence symptoms and conditioned stimuli (CSs) previously associated with cocaine administration are postulated to contribute to relapse to drug taking in humans. Objective. The present study assessed the role of both non-contingent CS presentation and experimenter-imposed extended cocaine-free periods on cocaine-seeking behavior in rats. Methods. A fixed interval (FI) second-order schedule of intravenous cocaine (0.5 mg/infusion) reinforcement of the type FI 15 min (fixed ratio 8:S) was used. Results. Non-contingent CS presentation before exposure to a cocaine binge had no effect on responding under the second-order schedule of reinforcement for cocaine after 23 h of no access to cocaine. By contrast, six non-contingent presentations of the CS during a 1-min period before the test session increased the number of responses in both no-binge (daily 2-h sessions, five infusions) and binge (two 12-h overnight sessions; maximum 48 infusions) exposed rats on day 7 of the cocaine-free period compared to no-binge- and binge-exposed rats that were not presented with the CSs. On day 30 of the cocaine-free period, only binge-exposed rats presented with the CSs exhibited a tendency for increased level of responding. Conclusions. The results indicated that non-contingent CS presentation had no effect after 23 h of no access to cocaine, increased drug-seeking behavior on day 7 of the cocaine-free period independent of binge exposure, and a strong tendency to increase drug-seeking behavior only in binge-exposed rats, on day 30 of the cocaine-free period, illustrating the interactive effects of conditioned stimuli with the extended cocaine-free period.     

Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats

RATIONALE: Clinical studies examining the efficacy of the selective serotonin reuptake inhibitor, fluoxetine, in decreasing craving and cocaine use have been inconsistent. OBJECTIVE: To understand better the effects of fluoxetine treatment on incentive motivation for cocaine, the present study assessed the effects of chronic fluoxetine treatment on cocaine-seeking behavior in rats following exposure to a cocaine self-administration environment or a cocaine priming injection. METHODS: Rats were trained to press a lever for a cocaine reinforcer (0.5 mg/kg per 0.1 ml, i.v.) or received yoked administration of saline. They were then withdrawn from this regimen and given 20 daily injections of saline or fluoxetine (3.0 mg/kg, i.p.). Twenty-four hours after the last injection, the rats were placed in the self-administration environment and cocaine-seeking behavior (i.e., non-reinforced lever pressing) was measured for 90 min. Reinstatement of extinguished cocaine-seeking behavior was then measured for 60 min following a saline injection and for 90 min following a cocaine priming injection (15 mg/kg, i.p.). RESULTS: Chronic fluoxetine treatment attenuated cocaine-seeking behavior following exposure to the self-administration environment in most rats (n = 16), but enhanced cocaine-seeking behavior in two rats. Furthermore, the treatment failed to alter cocaine-seeking behavior following a cocaine priming injection. Interestingly, the amount of cocaine intake during self-administration training correlated with cocaine-seeking behavior following the cocaine priming injection. In fact, the priming injection reinstated cocaine-seeking behavior only in rats with high, but not low, cocaine intake based on a median split. CONCLUSIONS: These results suggest that chronic fluoxetine treatment decreases motivation for cocaine when animals are in a cocaine-free state. Furthermore, individual differences in cocaine use are related to individual differences in sensitivity to the incentive motivational effects of cocaine priming.     

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.     

The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats

Rationale Recent studies have implicated an important role for the dorsal striatum during craving for cocaine and in cocaine-seeking after abstinence in rats. Objectives We compared the effects of pharmacological inactivation of mesencephalic dopamine (DA) cell body regions and dorsal vs ventral striatal terminal fields in an animal model of relapse after chronic cocaine self-administration. Materials and methods Rats self-administered cocaine for 2 h/day for ten sessions, followed by 2 weeks of abstinence (i.e., no extinction training). Immediately before being returned to the self-administration chamber, we assessed the effects of gamma-aminobutyric acid agonist inhibition of midbrain DA regions (substantia nigra [SN] and ventral tegmental area [VTA]) and striatum (dorsolateral caudate–putamen, nucleus accumbens core, and nucleus accumbens shell) on relapse to cocaine-seeking in the absence of reinforcement. Further testing examined daily extinction responding subsequent to the initial relapse test. Results Inactivation of the dorsal caudate–putamen and midbrain regions attenuated cocaine seeking, while inactivation of the ventral striatum had no such effects. However, subsequent sessions under extinction conditions revealed a rebound in cocaine seeking in animals that had undergone inactivation in all regions except the dorsolateral caudate–putamen. Conclusions The dorsal but not ventral striatum plays a critical role in cocaine seeking immediately after abstinence. These data support the theory that chronic cocaine may shift activity from the ventral to dorsal striatum during drug seeking under certain conditions. While not necessary at the time of relapse, the ventral striatum appears to be involved in processing critical information of the relapse event. An erratum to this article can be found at     

Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats

Rationale The nucleus accumbens (NAC) is theorized to be a critical element of the neural circuitry that mediates relapse to cocaine seeking. Evidence suggests that the NAC is a functionally heterogeneous structure, and the core (NACc) and shell (NACs) regions of the NAC may play a differential role in stimulus-induced motivated behavior. Thus, determination of the involvement of NAC subregions in conditioned cue-induced reinstatement of cocaine seeking is warranted.Objectives The present study compared the effects of GABA agonist-induced inactivation of the NACc versus NACs on conditioned cue-induced reinstatement of cocaine seeking behavior.Methods Rats were trained to lever press for cocaine infusions (0.20 mg/infusion, IV) paired with presentations of a light-tone stimulus complex. Responding was then allowed to extinguish prior to reinstatement testing. Reinstatement of cocaine seeking (i.e. responses on the previously cocaine-paired lever) was measured in the presence of response-contingent presentation of the light-tone stimulus complex following microinfusion of muscimol+baclofen (Mus+Bac, 0.1/1.0 mM, respectively, 0.3 l/side) or vehicle into the NACc or NACs. The effects of these manipulations on locomotor activity were also examined.Results Mus+Bac-induced inactivation of the NACc abolished, whereas inactivation of the NACs failed to alter, conditioned cue-induced reinstatement of operant responding relative to vehicle pretreatment. Time course analyses of the effects of these manipulations on locomotion versus operant responding confirmed that the effects of Mus+Bac on reinstatement were not due to suppression of general activity.Conclusions The functional integrity of the NACc, but not the NACs, is necessary for conditioned cue-induced reinstatement of cocaine seeking behavior.     

Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: effects of naltrexone

Rationale A positive relationship exists between chronic ethanol intoxication experiences and the severity of neural hyperactivity and withdrawal seizures. An important possibility is that withdrawal reactions also influence the motivation to obtain and consume ethanol. Objectives To test this hypothesis, the effects of ethanol-cues on the recovery of extinguished ethanol-seeking and the reversal of this effect by naltrexone, were determined in non-dependent rats and in rats subjected to single versus repeated ethanol intoxications. Methods Rats were trained to self-administer and discriminate between 10% ethanol and water. Instrumental responding then was extinguished and the effects of exposure to ethanol and water cues were determined. Subsequently, rats were divided into three groups and exposed to control vapor (CTRL), to 12-day ethanol vapor prior to withdrawal (SW), or to three cycles of 3-day intoxication experiences (MW), respectively. Following intoxication, reacquisition and breaking point for ethanol self-administration and cues-induced reinstatement of drug-seeking were investigated. Results Ethanol cues significantly reinstated responding in the pre- and post-dependence test, but no significant differences between groups was observed. However, the ability of naltrexone to attenuate the response-reinstatement was significantly reduced in MW rats. Moreover, in the progressive ratio schedule, the breaking points for ethanol were significantly increased in the MW animals. Conclusions The results suggest that repeated intoxication did not enhance cue-induced reinstatement of ethanol-seeking. However, naltrexone effects on cues-induced "relapse" appear to be attenuated in MW rats.     

Effects of fluoxetine and d-fenfluramine on cocaine-seeking behavior in rats

Rationale. Serotonin (5-HT) systems may play a role in modulating cocaine-seeking behavior. Objectives. The present study examined the effects of acute administration of the 5-HT reuptake inhibitor (SRI) fluoxetine, and the SRI/releaser d-fenfluramine, on reinstatement of extinguished cocaine-seeking behavior elicited by either response-contingent presentations of cocaine-paired cues or cocaine priming. Methods. Separate groups of rats that had been trained to press a lever for a cocaine reinforcer (0.75 mg/kg per 0.1 ml, IV) with a light/tone stimulus complex paired with each infusion underwent daily extinction sessions during which responding had no scheduled consequences (i.e. neither cocaine nor the stimulus complex was available). Subsequently, the effects of fluoxetine (0–10.0 mg/kg, IP) on extinction and cue reinstatement of extinguished cocaine-seeking behavior were examined, as well as the effects of d-fenfluramine (0–3.0 mg/kg, IP) on cue reinstatement. Additionally, dose-dependent effects of fluoxetine (0–10.0 mg/kg, IP) and d-fenfluramine (0–1.0 mg/kg, IP) on cocaine-primed (0–15.0 mg/kg, IP) reinstatement of extinguished cocaine-seeking behavior were examined. Results. Fluoxetine dose-dependently attenuated cocaine-seeking behavior during extinction. Both fluoxetine and d-fenfluramine dose-dependently attenuated cue-reinstated cocaine-seeking behavior. In contrast, neither drug reliably altered cocaine-seeking behavior reinstated by cocaine priming. Conclusions. These findings suggest that 5-HT indirect agonists effectively attenuate cocaine-seeking behavior elicited by cocaine-associated stimuli, but are much less effective in attenuating cocaine-seeking behavior elicited by cocaine priming.     

Reinstatement of cocaine seeking in 129X1/SvJ mice: effects of cocaine priming,cocaine cues and food deprivation

RATIONALE AND OBJECTIVES: The mechanisms underlying relapse to cocaine seeking induced by exposure to priming cocaine injections, cues associated with cocaine self-administration and environmental stressors have been studied in rats. Here we describe a reinstatement method for studying relapse to cocaine seeking in mice, a suitable species for studying the effect of genetic manipulations such as gene knockout or gene over-expression on compulsive drug use.METHODS: Male mice of the 129X1/SvJ strain were trained for 14-16 days to self-administer cocaine (0.75 mg/kg/infusion; 4 h/day; fixed-ratio-1 schedule of reinforcement; infusions were paired with a light-tone compound cue). Next, the lever-pressing behavior was extinguished by removing the cocaine syringes in the presence (Exps. 1 and 3) or absence (Exp. 2) of the cocaine cue. Subsequently, tests for reinstatement were conducted after exposure to priming injections of cocaine (0, 1.5, 3.0 and 6.0 mg/kg, IV; Exp. 1), response-contingent presentations of the cocaine-associated cue (Exp. 2), or food deprivation stress (1 and 22 h; Exp. 3).RESULTS: The effect of cocaine priming on reinstatement was modest and was only observed at the highest dose tested. On the other hand, reinstatement of cocaine seeking was observed following exposure to the cocaine-associated cue and food deprivation stress.CONCLUSIONS: The present data suggest that factors contributing to relapse to drugs can be studied in the reinstatement model using the common 129X1/SvJ mouse inbred strain.     

The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats

Rationale Evidence from preclinical and clinical studies indicates an important role for the mesocorticolimbic dopamine system in cocaine craving and relapse.Objectives To investigate the relative involvement of prefrontal cortex D1-like and D2-like dopamine receptors in cocaine-primed, drug-seeking behavior.Methods Rats were trained to press a lever to self-administer cocaine (i.v., 0.25 mg per infusion) in daily 2-h sessions. Responding was reinforced, contingent on a modified fixed-ratio 5 schedule. Reinstatement tests began after lever-pressing behavior was extinguished in the absence of cocaine and conditioned cues (light and tone). Before each reinstatement test, rats received bilateral microinfusions of different doses of selective D1-like and D2-like antagonists, SCH 23390, and eticlopride, respectively, followed by intraperitoneal administration of 10 mg/kg cocaine; 3 min later the session started. Responding in the reinstatement test was reinforced only by the conditioned cues contingent on a fixed-ratio 5 schedule.Results Both drugs dose dependently decreased cocaine-primed reinstatement without affecting operant behavior maintained by food. Eticlopride, but not SCH 23390, increased cocaine self-administration and decreased food-primed reinstatement at the dose found to decrease cocaine-primed reinstatement.Conclusions These data suggest that, although both D1-like and D2-like receptors in the prefrontal cortex are involved in cocaine-primed drug-seeking behavior, they may modulate different aspects of this process.     

Nicotine elicits methamphetamine-seeking in rats previously administered nicotine

Research has indicated a high correlation between psychostimulant use and tobacco cigarette smoking in human substance abusers. The objective of the current study was to examine the effects of acute and repeated nicotine administration on responding for intravenous methamphetamine (0.03 mg/kg/infusion) in a rodent model of self-administration, as well as the potential of nicotine to induce reinstatement of previously extinguished drug-taking behavior in male Sprague–Dawley rats. In addition, it was assessed whether nicotine-induced reinstatement of methamphetamine-seeking behavior and nicotine-induced locomotor sensitization require that nicotine be temporally paired with the methamphetamine self-administration session or the locomotor activity chamber. Nicotine acutely decreased methamphetamine self-administration, but did not persistently alter responding during the maintenance of methamphetamine self-administration. However, following extinction of methamphetamine self-administration, nicotine administration reinstated methamphetamine-seeking behavior only in rats that had previously been administered nicotine. Nicotine-induced reinstatement and expression of locomotor sensitization were not dependent on a temporal pairing of nicotine with either the methamphetamine self-administration session or the locomotor activity chamber, respectively. These results indicate that nicotine may be acting, at least in part, through a non-associative mechanism to reinstate methamphetamine-seeking behavior.     

Reinstatement of heroin self-administration habits: morphine prompts and naltrexone discourages renewed responding after extinction

The effects of morphine, naltrexone, and nalorphine were studied in rats trained to lever-press for intravenous heroin and then tested under conditions of non-reinforcement. Animals were reinforced for lever-pressing on a continuous reinforcement schedule (100 µg/kg per infusion) for 2–3 h each day following which reinforcement was terminated and animals were studied under extinction conditions for the remainder of the session. Each day following the termination of responding under extinction conditions, animals were given a single injection of saline, morphine, nalorphine, or naltrexone; lever-pressing under the extinction conditions was then observed for several hours. When animals adapted to this regimen, very low levels of responding were seen following saline injections; morphine (2 or 10 mg/kg) reinstated vigorous responding that lasted 1–4 h. Naltrexone (2 mg/kg) suppressed responding below the levels seen after saline, and nalorphine (10 mg/kg) had the same effect as saline. These observations support the view that opioid-seeking behavior is primed by the proponent or opioid-like actions of opioids and not by the opponent or drug-opposite effects associated with opioid withdrawal.     

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

Rationale Although considerable progress has been made, we do not yet fully understand the behavioral and neurobiological basis of nicotine reinforcement, and without this knowledge, treatment strategies aimed at reducing smoking remain deficient. Objectives This review describes an original perspective on nicotine reinforcement, which arises from substantial evidence of complex interactions between nicotine and nonpharmacological stimuli. We hypothesize that nicotine reinforcement derives from at least two sources: (1) primary reinforcement, an action that requires response-dependent drug administration and is capable of conveying secondary reinforcing effects on associated stimuli, and (2) the reinforcement-enhancing effect of nicotine, which directly enhances behavior maintained by salient nonnicotine stimuli and does not require a contingent relationship between drug administration and reinforced operant responding. Although novel for nicotine, this hypothesis has origins in an extensive literature on the reinforcing effects of psychostimulants. Empirical support for this hypothesis, based largely on animal models of reinforcement, will be presented. Conclusions Animal models of drug reinforcement have evolved to reflect our growing awareness of the multidimensional nature of drug dependence in humans. Investigating the interaction between nicotine and nonpharmacological stimuli within the context of the drug self-administration paradigm in rats has generated new insights into the paradox of how nicotine, an apparently weak primary reinforcer, can sustain the robust behavior observed in self-administration and in smoking. The hypothesis presented in this paper—that nicotine acts as both a primary reinforcer and an enhancer of other nonnicotine reinforcers—provides important direction for future investigations into the neurobiology of nicotine reinforcement and treatments for smoking cessation.