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.     

CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats

We have found that peptide antagonists of corticotropin-releasing factor (CRF) receptors attenuate reinstatement of heroin and cocaine seeking induced by footshock. Here we examined the effect of a non-peptide, selective CRF₁ receptor antagonist, CP-154,526, on reinstatement of heroin and cocaine seeking induced by footshock. Rats were trained to self-administer heroin or cocaine (0.1 and 1.0 mg/kg per infusion, IV, respectively) for 9–12 days. Extinction sessions were given for up to 14 days, during which saline was substituted for the drugs. Tests for reinstatement were then conducted after exposure to intermittent footshock (10 or 15 min, 0.5 mA). The footshock stressor reliably reinstated extinguished cocaine- and heroin-taking behavior. Pretreatment with CP-154,526 (15 and 30 mg/kg, SC) significantly attenuated the reinstatement effect of the stressor in both heroin- and cocaine-trained rats. CP-154,526, administered in the absence of the footshock stressor, did not affect extinguished drug seeking. In addition, in a separate experiment, CP-154,526 was shown not to alter high rates of lever pressing for a 10% sucrose solution, suggesting that the suppression of lever pressing in stress-induced reinstatement is not caused by a performance deficit. These results extend previous reports on the role of CRF in reinstatement of drug seeking induced by stressors. The present data also suggest that, to the extent that exposure to environmental stressors provoke relapse to drug use in humans, systemically effective CRF receptor antagonists may be of use in the treatment of relapse to drug use. Received: 12 July 1997/Final version: 20 October 1997     

Stress reinstates nicotine seeking but not sucrose solution seeking in rats

  Rationale: Intermittent footshock stress effectively reinstates extinguished heroin-, cocaine- and alcohol-taking behaviors, but not behaviors previously maintained by food reinforcers. Here we tested further the generality of the phenomenon of stress-induced reinstatement by determining the effect of footshock on reinstatement of operant responding previously maintained by nicotine or palatable sucrose solutions. Methods: Groups of rats were trained to self-administer either nicotine (0.03 mg/kg per infusion, 14 days) or sucrose (10 or 30% w/v, 14–20 days). After extinction of the nicotine- or the sucrose-reinforced behaviors for 5–15 days, the rats were exposed to intermittent footshock stress (5 and 15 min, 0.8 mA) during tests for reinstatement. Results: Footshock reliably reinstated nicotine seeking after extinction of the drug-reinforced behavior. In contrast, the same parameters of footshock stress did not consistently reinstate operant responding previously maintained by sucrose solutions. Conclusions: These and previous data suggest that stressors may be more effective stimuli for reinstatement of behaviors previously maintained by drug reinforcers as compared with non-drug reinforcers. Received: 15 October 1998 / Final version: 10 December 1998     

Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats

The effects of blockade of opioid and dopamine receptors on relapse to heroin-seeking induced by footshock stress and re-exposure to heroin were examined in a reinstatement procedure. Male rats were trained to self-administer heroin (100 µg/kg per infusion, IV; four 3-h sessions/day for 8–11 consecutive days). Extinction sessions were given for 5–7 days during which saline was substituted for heroin. In nine groups, the effects on relapse induced by footshock (10 min, 0.5 mA, 0.5 s on with a mean off period of 40 s), heroin priming (0.25 mg/kg), and saline priming were studied after pretreatment with either naltrexone (1 or 10 mg/kg, SC), the D₁-like receptor antagonist SCH 23390 (0.05 or 0.1 mg/kg, IP), the D₂-like receptor antagonist raclopride (0.25 or 0.5 mg/kg, IP), the mixed dopamine antagonist flupenthixol decanoate (3 or 6 mg/kg, IM), or IP injection of saline (control condition). Naltrexone, flupenthixol, raclopride, and the highest dose of SCH 23390 attenuated heroin-induced relapse: only the mixed DA receptor antagonist, flupenthixol, attenuated footshock-induced relapse. These results, and those from microdialysis showing that heroin elicits greater locomotor activity and DA release in the nucleus accumbens than footshock, suggest that the neurochemical events underlying stress- and heroin-induced relapse are not identical.     

The role of corticosterone in food deprivation-induced reinstatement of cocaine seeking in the rat

Rational and objectives. Acute 1-day food deprivation stress reinstates heroin seeking in rats, but the generality of this effect to other drugs, and its underlying mechanisms, are largely unknown. Here we studied whether food deprivation would reinstate cocaine seeking and whether the stress hormone, corticosterone, is involved in this effect. Methods. Rats were trained to press a lever for cocaine for 10–12 days (0.5–1.0 mg/kg per infusion, IV, 4 h/day) and were then divided into four groups that underwent different manipulations of plasma corticosterone levels: (1) bilateral adrenalectomy (ADX) surgery, (2) ADX surgery+50-mg corticosterone pellets (ADX+P), (3) ADX surgery+50-mg corticosterone pellets+4-h access (0800–1200 hours) to corticosterone (50 μg/ml) dissolved in a drinking solution (ADX+P/W), or (4) sham surgery. Next, rats were given 7–12 days of extinction training (during which lever presses were not reinforced with cocaine), and after reaching an extinction criterion they were tested for reinstatement of cocaine seeking following exposure to 21 h of food deprivation. Results. Food deprivation was found to reinstate cocaine seeking in sham-operated rats, but not in rats in which circulating corticosterone was removed (ADX group). In addition, the effect of food deprivation on reinstatement of cocaine seeking was significantly attenuated in rats maintained on basal diurnal levels of corticosterone (ADX+P group). However, food deprivation reinstated cocaine seeking in rats with limited daily access to additional corticosterone in the drinking water (ADX+P/W group). In this group, corticosterone levels were twice as high as the ADX+P group but were significantly lower than those of sham rats. Conclusions. The present data, together with previous work on footshock-induced reinstatement of drug seeking, suggest that corticosterone plays a permissive role in stress-induced reinstatement of cocaine seeking, yet its effects are not associated with the stressor-induced increases in plasma corticosterone levels.     

A role for corticotropin-releasing factor, but not corticosterone, in acute food-deprivation-induced reinstatement of heroin seeking in rats

Rationale Acute 1-day food deprivation reinstates heroin seeking in rats via a leptin-dependent mechanism. However, leptin has no effect on footshock- or heroin-priming-induced reinstatement of drug seeking. These data may indicate that the neuronal systems underlying food-deprivation-induced reinstatement are dissociable from those involved in reinstatement induced by footshock stress.Objectives We used the reinstatement procedure to examine the roles of the adrenal stress hormone, corticosterone, and brain corticotropin-releasing factor (CRF) in acute food-deprivation-induced reinstatement of extinguished heroin seeking in rats.Materials and methods The rats were trained to press a lever for heroin (0.05−0.1 mg/kg/infusion, i.v.) for 10 days. Experiment 1: After heroin self-administration training, the rats were divided into two groups, which received either bilateral adrenalectomy surgery or sham surgery. Next, the rats were given 7–10 days of extinction training (during which lever presses were not reinforced with heroin). The rats were subsequently tested for reinstatement after acute (21 h) food deprivation. Experiment 2: After heroin self-administration and extinction training, the rats were tested for reinstatement induced by acute food deprivation. Before the test session, the rats were given intracerebroventricular injections of the CRF receptor antagonist α-helical CRF (0, 3, or 10 μg/rat).Results Adrenalectomy had no effect on the extinction behavior or acute food-deprivation-induced reinstatement of heroin seeking. The CRF receptor antagonist, α-helical CRF, dose-dependently blocked food-deprivation-induced reinstatement.Conclusions The present data suggest that, as demonstrated for footshock-induced reinstatement of drug seeking, brain CRF, but not corticosterone, plays a critical role in acute food-deprivation-induced reinstatement of heroin seeking.     

The reinstatement model of drug relapse: history,methodology and major findings

Rational and objectives. The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. Conclusions. The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.     

Acamprosate suppresses the expression of morphine-induced sensitization in rats but does not affect heroin self-administration or relapse induced by heroin or stress

Acamprosate (calcium-acetyl homotaurinate) is a new compound used in the treatment of alcohol abuse. Because of the putative link between alcoholism and the endogenous opioid systems in both humans and laboratory animals, we tested in rats the effects of acamprosate on behavioral and neurochemical effects of opioid drugs related to their abuse potential. These included sensitization to the behavioral effects of morphine, morphine-induced dopamine (DA) release in the nucleus accumbens (NAS), intravenous (IV) heroin self-administration and relapse to heroin seeking in drug-free rats. In experiment 1, rats were injected daily with either morphine (10 mg/kg, SC) or saline for 14 days. Three days later in a test for the expression of sensitization, an injection of morphine (10 mg/kg) resulted in increased locomotor activity and enhanced DA release in the NAS in rats previously exposed to morphine. Acamprosate (two injections of 200 mg/kg; 12 h apart; IP) suppressed the expression of the sensitized responses, but did not alter the effects of morphine in drug-naive control rats. In experiment 2, it was found that acamprosate (two injections of 50–200 mg/ kg; IP) had no consistent effects on IV heroin self-administration (50–100 μg/kg per infusion) and, in experiment 3, that acamprosate (100–200 mg/ kg, IP) did not alter reinstatement of drug seeking induced by priming injections of heroin (0.25 mg/kg, SC) or a footshock stressor (15 min; 0.5 mA) after a 5- to 8-day period of extinction. Thus, although acamprosate attenuated the expression of sensitized locomotor activity and DA release in the NAS, it did not have any consistent effect on either the intake of heroin during the maintenance phase or the relapse to heroin seeking in a drug-free state. Thus, to the extent that the self-administration and the reinstatement procedures provide valid preclinical models for drug use and relapse in humans, our data suggest that acamprosate may not be effective in altering drug-taking behavior in heroin users. Received: 4 November 1997/Final version: 25 January 1998     

The dissociation of heroin-seeking patterns induced by contextual,discriminative, or discrete conditioned cues in a model of relapse to heroin in rats

Rationale The role of heroin-related stimuli in motivating the resumption of heroin use is not fully understood. Objectives The objective was to characterize the relative importance of drug-related contextual stimuli, discriminative stimuli (DS), or discrete conditioned stimuli (CSs) on drug seeking when rats were reintroduced into the operant context after withdrawal. Methods Nose-poke responding by male rats was reinforced with intravenous heroin (0.05 mg/kg per infusion, 4-h session daily) under a progressive ratio schedule of reinforcement for 14 days. Each session began with the illumination of a green light in the active hole that served as DS. Each earned heroin injection was paired with a 5-s compound cue light and the sound of the infusion pump that served as the discrete CSs. Results Response rates of heroin seeking induced by the contextual stimuli were comparable to the average rates of responding during self-administration training, but rates induced by either DS or CSs were greater than those induced by the contextual stimuli alone (P<0.05). The responding induced by contingent presentations of CSs was higher than that of DS after extinction of instrumental behavior. The drug seeking induced by CSs can be maintained after 3 days extinction with DS in the original context, although the responding elicited by DS cannot be recovered after 3 days of extinction with CSs. Conclusions The relapse to drug seeking can be elicited separately by environmental cues, heroin-predictive DS, or discrete CSs in the same rat after withdrawal.     

Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats

Rationale and objectives We and others have shown that a stressor commonly used in laboratory studies, intermittent footshock, reinstates alcohol seeking in a rat relapse model. The effects of more ethologically relevant stressors on reinstatement have not been examined. Here, we characterized the effects of social defeat (a naturalistic stressor) or a cue associated with the defeat experience on reinstatement of alcohol seeking. We also examined the effect of unconditioned and conditioned social defeat on alcohol self-administration.Methods Rats were trained to self-administer alcohol (12% w/v, 1 h day⁻¹), and after stable responding, one group of animals received five exposures to social defeat paired with peppermint odor prior to daily self-administration sessions. After three more self-administration sessions, these rats were tested for the effects of the peppermint odor cue on self-administration. In another group of rats, the effects of three daily exposures to social defeat paired with peppermint odor on extinction of responding were examined. After further extinction sessions, the effect of the odor cue on reinstatement was tested in these animals. The acute effect of social defeat on reinstatement was examined in another group of animals.Results Acute exposure to social defeat decreased alcohol self-administration, reduced rates of responding during extinction, and did not reinstate alcohol seeking. Exposure to a discrete odor cue previously paired with social defeat decreased alcohol self-administration but induced modest reinstatement of alcohol seeking.Conclusions Results provide the first demonstration of reinstatement of alcohol seeking by a cue paired with social defeat and are also in agreement with previous findings on the suppressive effect of social defeat stress on alcohol self-administration.     

Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus

Rationale Gender differences exist in the patterns of drug taking in cocaine addiction, suggesting that the propensity to relapse varies between men and women. Previous reports have shown sex differences in both cocaine-primed and conditioned-cued reinstatement of cocaine-seeking behavior, including recent evidence that the estrous cycle influences the level of conditioned-cued reinstatement. However, the influence of the estrous cycle on cocaine-primed reinstatement has not been examined. Objective Accordingly, we assessed the influence of sex and estrous cycle status on cocaine-primed reinstatement of drug-seeking behavior in Sprague–Dawley rats. Methods Intact male and female rats were trained to lever press to self-administer intravenous cocaine (0.5 mg/kg every infusion; fixed ratio 1, 20-s time-out following each infusion), followed by prolonged extinction training, and subsequently tested for the ability of a cocaine-priming injection (0, 5, or 10 mg/kg i.p.) to reinstate extinguished cocaine seeking (i.e., nonreinforced lever responding). Results Despite no differences in cocaine intake between male and female rats, females responded more on the cocaine-paired lever during self-administration and extinction relative to males. Subsequently, both males and females exhibited a dose-dependent cocaine-primed reinstatement of extinguished drug-seeking behavior. Moreover, females in estrus exhibited significantly higher reinstatement than either males or non-estrus females, following a high-dose (10 mg/kg) cocaine prime. Conclusions Estrus females display heightened sensitivity to the motivational and/or stimulant effects of cocaine, suggesting that hormonal state modulates drug craving and propensity for drug relapse in cocaine addicts.     

Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats

RATIONALE AND OBJECTIVES: Footshock stress reliably reinstates heroin seeking in rats, but the time course of the development of this effect following drug withdrawal is not known. Here we studied the effect of intermittent footshock stress on reinstatement of heroin seeking following different withdrawal periods (1-66 days). We also studied whether changes in corticotropin-releasing factor (CRF) mRNA in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) are correlated with this reinstatement after 1 day and 6 days of heroin withdrawal. METHODS: Rats were trained to self-administer heroin (9 h/day; 0.1 mg/kg per infusion) for 10 days. Tests for extinction behavior and footshock-induced reinstatement of heroin seeking were then conducted after 1, 6, 12, 25, or 66 days of heroin withdrawal. On the test day, rats were given five to ten 60-min extinction sessions until they reached the extinction criterion of less than 15 responses per 60 min on the lever previously associated with heroin. Rats were then exposed to intermittent foot-shock (0.8 mA; 10 min), and lever-pressing behavior was recorded for 120 min. RESULTS: Reinstatement of lever-pressing behavior by footshock followed an inverted U-shaped curve with maximal responding after 6 days and 12 days of heroin withdrawal. Surprisingly, foot-shock did not reinstate lever-pressing behavior on day 1 of withdrawal. Lever pressing during extinction, prior to exposure to footshock, also followed an inverted U-shaped curve, with higher responding after 6, 12, and 25 days of heroin withdrawal. Finally, compared with control groups not exposed to shock, CRF mRNA levels in response to footshock were increased in the CeA (day 1 of withdrawal) and the dorsal BNST (day 1 and day 6), but not in the ventral BNST. CONCLUSIONS: The duration of the heroin withdrawal period is an important factor in the manifestation of (1) footshock stress-induced reinstatement of heroin seeking and (2) extinction of the heroin-reinforced behavior. Finally, the time-dependent changes in footshock stress-induced reinstatement following withdrawal from heroin were not correlated with alterations in CRF mRNA in the CeA and BNST.     

Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats

Rationale and objectives Alpha-2 adrenoceptors are known to be involved in stress-induced reinstatement of heroin and cocaine seeking in laboratory animals. Here, we studied the involvement of these receptors in stress-induced reinstatement of alcohol seeking by using an agonist (lofexidine) and an antagonist (yohimbine) of these receptors, which inhibit and activate, respectively, noradrenaline transmission. We also tested the effect of lofexidine and yohimbine on alcohol self-administration. Lofexidine is used clinically for treating opiate withdrawal symptoms and yohimbine induces stress-like responses in humans and non-humans.Methods Rats were trained to self-administer alcohol (12% w/v, 1 h/day) and after extinction of the alcohol-reinforced behavior, they were tested for the effect of lofexidine (0, 0.05 and 0.1 mg/kg, IP) on reinstatement of alcohol seeking induced by intermittent footshock stress (10 min, 0.8 mA) or for the effect of yohimbine (0, 1.25 and 2.5 mg/kg, IP) on reinstatement of alcohol seeking. Other rats were trained to self-administer alcohol, and after stable responding, the effects of lofexidine and yohimbine on alcohol self-administration were determined.Results Pretreatment with lofexidine (0.05 mg/kg and 0.1 mg/kg) attenuated stress-induced reinstatement of alcohol seeking and also decreased alcohol self-administration. In contrast, yohimbine pretreatment potently reinstated alcohol seeking after extinction and also induced a profound increase in alcohol self-administration.Conclusions Results indicate that activation of alpha-2 adrencoceptors is involved in both stress-induced reinstatement of alcohol seeking and alcohol self-administration. To the degree that the present results are relevant to human alcoholism, alpha-2 adrencoceptor agonists should be considered in the treatment of alcohol dependence.     

Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats

Rationale Recent evidence suggests that prolonged cocaine self-administration produces escalation in drug-seeking behavior in rats analogous to the increased intake patterns observed in cocaine-dependent individuals. However, the contributions of prolonged access to cocaine taking vs the pharmacologic effects of the consequent increased cocaine exposure on escalation of drug-seeking behaviors have not been investigated.Objective The present study assessed the effects of these two factors on maintenance of cocaine self-administration and reinstatement of cocaine seeking.Methods Male, Sprague–Dawley rats were trained to self-administer cocaine (0.2 mg/i.v. infusion; FR1) for 1 h per day for 10 sessions followed by short access (1 h/day), contingent long access (6 h/day), or noncontingent long access (1 h contingent + 5 h of yoked cocaine infusions/day; i.e., short access + yoked) to cocaine for 14 daily sessions. All rats underwent extinction training and were subsequently tested for the ability of cocaine-paired cues or a cocaine-priming injection (7.5 mg/kg i.p.) to reinstate extinguished cocaine seeking.Results Rats in all groups maintained stable responding for cocaine reinforcement and subsequently showed significant reinstatement of cocaine-seeking behavior. Conditioned-cued reinstatement was enhanced after the contingent long access and short access + yoked cocaine exposure relative to short access cocaine exposure. Conversely, cocaine-primed reinstatement was enhanced after contingent long-access cocaine exposure relative to the other two conditions.Conclusions Enhanced drug seeking produced by prolonged daily cocaine self-administration is due to a combination of behavioral and pharmacological factors. Specifically, conditioned-cued reinstatement is enhanced by increased cocaine intake and cocaine-primed reinstatement is enhanced by increased cocaine taking.     

Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats

 Previous studies using a reinstatement procedure have found that acute reexposure to the self-administered drug and exposure to footshock stress reinstate heroin and cocaine seeking after prolonged drug-free periods. Here we tested whether these findings generalize to alcohol-taking behavior. Male rats were initially allowed to consume alcohol in a two-bottle choice procedure (water versus alcohol) for 30 min/day for 36 days. Rats were then trained for 60 min/day in operant chambers to press a lever for the drug (0.13 ml of 12% w/v of an alcohol solution) for up to 55 days. After stable drug-taking on a fixed-ratio-3 schedule of reinforcement was obtained, lever pressing for alcohol was extinguished by terminating drug delivery for 4–9 days. Reinstatement of drug seeking was then determined after non-contingent priming injections of alcohol (0.24 and 0.48 g/kg; given IP and orally) or exposure to intermittent footshock stress (5 and 15 min; 0.8 mA). Priming injections of alcohol produced a modest dose-dependent reinstatement of drug seeking, whereas footshock stress potently reinstated extinguished alcohol seeking. In contrast, similar parameters of footshock failed to reinstate extinguished sucrose-taking behavior in rats previously trained to lever press for sucrose pellets. These findings extend previous reports on reinstatement of cocaine and heroin seeking by a footshock stressor and by priming drug injections. It also appears that the reinstatement procedure provides an appropriate methodology to study relapse to alcohol-taking behavior in the drug-free state. Received: 9 April 1997 / Final version: 1 August 1997     

Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats

RATIONALE: Methamphetamine is a highly addictive psychostimulant, and chronic methamphetamine users show high rates of relapse. Furthermore, prolonged methamphetamine abuse can lead to psychiatric symptoms and has been associated with various cognitive dysfunctions. However, the impact of self-administered methamphetamine on cognitive dysfunction and relapse has not been concurrently examined in an animal model. OBJECTIVES: The present study determined the effects of short- vs. long-access contingent methamphetamine on self-administration, extinction responding, reinstatement of methamphetamine seeking, and cognitive performance on an object exploration task. MATERIALS AND METHODS: Long-Evans rats self-administered methamphetamine i.v. (0.02 mg/infusion) or received saline during daily sessions (1 or 2 h) for 10 days, followed by either maintained short- (1 or 2 h) or long-access (6 h) self-administration for 14 days. Lever responding was extinguished prior to reinstatement, which consisted of presentation of drug-paired cues or a priming injection of methamphetamine (1.0 mg/kg). Animals were also tested on an object exploration task prior to self-administration and at 10-12 days after cessation of self-administration, thus providing a comparison of pre-methamphetamine exposure with post-methamphetamine exposure. RESULTS: Long-access methamphetamine self-administration resulted in escalation of daily intake. Furthermore, animals in both short- and long-access groups showed robust conditioned-cued and drug-primed reinstatement, with long access resulting in enhanced methamphetamine-primed reinstatement. Methamphetamine self-administration also led to access-dependent impairments on novel object recognition but failed to impair recognition of spatial reconfiguration. CONCLUSIONS: Extended methamphetamine self-administration enhances drug-primed reinstatement and decreases novel object recognition, indicating that prolonged contingent methamphetamine increases motivation for drug seeking following withdrawal while increasing cognitive deficits.     

Reconditioning of drug-related cues: a potential contributor to relapse after drug reexposure

To investigate the process of relapse to drug seeking caused by reexposure to drugs, we studied the consequences of recurring instances of stimuli–drug associations using heroin conditioned place preference (CPP) in rats. After original conditioning and extinction, rats received either a single compartment–heroin pairing (reconditioning) or were primed with heroin and tested for reinstatement of CPP. It was found that the session of reconditioning, but not the session of reinstatement, caused the reappearance of a preference for the heroin-paired compartment on a test given 24 h later, in drug-free conditions. The effect of reconditioning was found to be dependent on heroin doses, and was not seen when heroin injections were given outside the conditioning environment. Furthermore, a single session of reconditioning elevated heroin seeking even on a test given 96 h later. Finally, heroin seeking was found to be significantly elevated on a test given 28 days after the last extinction session whether animals received 1 or 3 reconditioning sessions. These results suggest that the motivational value of cues associated with heroin is not eliminated by extinction and, importantly, that these cues can rapidly regain their ability to promote drug seeking behavior if they are re-associated with the effect of heroin.     

Stress reinstates heroin-seeking in drug-free animals: An effect mimicking heroin,not withdrawal

Exposure to 10 min of footshock stress (1 mA; 0.5 s on, with a mean off period of 40 s) reinstated heroin-seeking behavior in heroin-experienced, drug-free rats after many sessions of extinction and up to 6 weeks after last exposure to heroin. In reinstating the behavior, the footshock mimicked the effect of a non-contingent priming infusion of heroin (50 µg/kg). By contrast, the aversive state of acute opioid withdrawal induced by injection of the opioid receptor antagonist naltrexone (5 mg/kg, SC), following an acute injection of morphine (10 mg/kg, SC), had no effect on heroin-seeking behavior. In a second experiment it was shown in drug naive animals that these parameters of footshock increased dopamine overflow in the nucleus accumbens, a terminal region of the mesolimbic dopamine system implicated in the reinforcing effects of drugs. Similarly, dopamine overflow was increased by an injection of 10 mg/kg morphine, SC, an effect that was reversed by an injection of 5 mg/kg naltrexone given 40 min after to induce the withdrawal condition. A possible interpretation of the present results is that stressors can reinstate drug-taking behavior by activating neural systems in common with those activated by heroin.     

Role of dopamine D1-family receptors in dorsolateral striatum in context-induced reinstatement of heroin seeking in rats

Rationale  In humans, exposure to environmental contexts previously associated with heroin intake can provoke relapse to drug use. In rats, exposure to heroin-associated contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by blockade of D₁-family receptors in lateral or medial accumbens shell, but not accumbens core. Objectives  In this study, we further characterized the role of striatal D₁-family receptors in context-induced reinstatement by assessing the effect of dorsolateral or dorsomedial injections of the D₁-family receptor antagonist SCH 23390 on this reinstatement. Materials and methods  Rats were trained to self-administer heroin (0.05–0.10 mg/kg per infusion) for 12 days; drug infusions were paired with a discrete tone–light cue. Subsequently, heroin-reinforced lever pressing was extinguished in the presence of the discrete cue in a nondrug context. During reinstatement tests under extinction conditions, the D₁-family receptor antagonist SCH 23390 (0.3–1.0 μg per side) was injected into the dorsolateral or dorsomedial striatum prior to exposure to heroin self-administration context or the nondrug (extinction) context. We then used a disconnection procedure to examine whether D₁-family receptors in the dorsolateral striatum and lateral accumbens shell jointly or independently support context-induced reinstatement. Results  Dorsolateral but not dorsomedial SCH 23390 injections attenuated context-induced reinstatement of heroin seeking. SCH 23390 injections into the dorsolateral striatum of one hemisphere and lateral accumbens shell of the other hemisphere were ineffective. Conclusions  Results indicate that dorsolateral striatum D₁-family dopamine receptors are critical for context-induced reinstatement of heroin seeking. Results also suggest that D₁-receptor-mediated dopamine transmission in the dorsolateral striatum and lateral accumbens shell independently support this reinstatement.     

The contribution of drug history and time since termination of drug taking to footshock stress-induced cocaine seeking in rats

Rationale There is reason to think that footshock stress-induced reinstatement of cocaine may be affected by the history of drug use and time since termination of drug taking.Objectives Here, we assessed the contribution of daily access (hours per day) and duration (number of days) of cocaine self-administration to propensity to reinstate drug seeking following footshock stress at three time points following cocaine self-administration.Methods Rats were trained to self-administer cocaine (0.5 mg kg⁻¹ infusion⁻¹) on a fixed ratio 1 schedule in one of four training combinations of hours per day and number of days [2/7, 2/21, 12/7, and 12/21 (h/day)]. Rats were then tested for the first time under extinction conditions at either day 1, 10, or 60 after termination of cocaine availability. Once extinction criterion was met (<15 lever presses in 1 h), rats were then tested for stress-induced reinstatement after 15 min of intermittent, inescapable footshock (0.8 mA, 0.5 s/shock, mean off period of 40 s).Results Rats that were given 12-h access to cocaine during training responded less in tests of extinction than those rats given 2-h access. Rats in all groups tested in extinction at days 10 and 60 showed higher responding than at day 1, suggesting an incubation of responding. In footshock stress-induced reinstatement tests, rats with greater exposure to cocaine showed a similar suppression of responding at day 1 and enhanced responding at day 60. As expected, rats that were given 12-h/21-day access to cocaine had the greatest intake of cocaine across the training phase with a slow escalation of hourly intake.Conclusion Greater access to cocaine results in suppression of cocaine seeking following footshock stress at early time points and a progressive increase over time.