The effects of alcohol preexposure on cocaine, alcohol and cocaine/alcohol place conditioning

The present experiment examined the effects of alcohol preexposure on place conditioning with cocaine, alcohol or the cocaine/alcohol combination. Specifically, 91 male Sprague-Dawley rats were injected i.p. with 1.5 g/kg alcohol (n=46) or vehicle (n=45) every fourth day for 17 days prior to conditioning. On day 21, half of the animals from each preexposure condition were injected with 20 mg/kg cocaine, 1.5 g/kg alcohol or the cocaine/alcohol combination before being restricted for 30 min to a distinctive compartment of a place conditioning apparatus. The remaining subjects were injected with vehicle and restricted to the alternative side of the chamber. The following day, subjects previously given drug (or vehicle) were given vehicle (or drug) and placed in the alternative compartment of the chamber. Following four conditioning cycles, subjects were allowed 15-min access to the entire chamber. Both alcohol- and vehicle-preexposed animals conditioned with cocaine displayed a preference for the cocaine-paired compartment. Those conditioned with alcohol had an aversion to the alcohol-paired compartment. Consistent with our previous work, animals given the cocaine/alcohol combination displayed no compartment preference, indicating that concurrent alcohol affected the reinforcing effects of cocaine. Further, the attenuating effect of concurrent alcohol was unaffected by alcohol history. Under the present parameters, alcohol pretreatment has no effect on the rewarding (and possibly aversive) properties of cocaine alone or the cocaine/alcohol combination. Continued investigation of the conditions under which preexposure to alcohol might modulate the aversive/reinforcing properties of a cocaine/alcohol combination may be important for understanding vulnerability to the use and/or abuse of this drug combination.     

Reinstatement of morphine-conditioned reward is blocked by memantine.

Protection of abstinent individuals from relapse is the main goal of drug dependence treatment. Relapse is frequently precipitated by exposure to small doses of the drug of abuse or exposure to the environment that was previously associated with the drug. Mice exposed to morphine (10 mg/kg) in a unique test-box environment display a conditioned place preference for this environment. Such preference can be extinguished by subsequent pairing of physiological saline administration with the same environment. Once extinguished, the original place preference can be reinstated after a priming dose (1-2.5 mg/kg) of morphine is given. However, mice treated with 7.5 (but not 3.75) mg/kg of memantine (the glutamate/NMDA receptor antagonist) during the extinction phase were insensitive to morphine's ability to reinstate the place preference 2 days after extinction conditionings. Effect of memantine was also observed when priming dose of morphine was given 21 days after extinction conditionings. In contrast, morphine's ability to reinstate conditioned response was not affected by treatment with 10 mg/kg of chlordiazepoxide, 0.5 mg/kg of LSD-25, or 1 mg/kg of morphine given during extinction conditionings. A separate experiment demonstrated that memantine (7.5 mg/kg) treatment did not affect learning. We show for the first time that memantine treatment during extinction conditionings may abolish the ability of drug-related cues to evoke reinstatement, suggesting that this NMDA receptor antagonist can be useful in preventing relapse in opioid dependent individuals.     

Attenuation of cocaine-induced reinstatement of cocaine conditioned place preference by acamprosate

Acamprosate (calcium acetylhomotaurinate) is a glutamatergic neuromodulator efficacious at reducing relapse in alcoholic patients. The effect of acamprosate on relapse to other drugs of abuse has received little attention, however, and given increasing evidence that glutamatergic transmission mediates relapse to cocaine-seeking behavior, the purpose of this study was to assess the effects of acamprosate on the reinstatement of a conditioned place preference for cocaine. Mice were conditioned daily with cocaine (15 mg/kg), tested for the establishment of cocaine conditioned place preference, and then retested once weekly to monitor the extinction of the place preference. Following extinction of cocaine conditioned place preference, animals were treated daily with saline or acamprosate (30 or 100 mg/kg) for 3 days, followed by a single injection of cocaine (15 mg/kg) to reinstate conditioned place preference. In mice treated with saline or the low (30 mg/kg) dose of acamprosate, cocaine induced a significant reinstatement of the previously extinguished conditioned place preference; however, this reinstatement was not observed in mice treated with the high (100 mg/kg) dose of acamprosate. These results indicate that acamprosate can attenuate relapse-like behavior in mice and suggest that this compound may be potentially useful in the treatment for cocaine addiction.     

Effect of the kappa-opioid receptor agonist, U69593, on reinstatement of extinguished amphetamine self-administration behavior

Previous research has indicated that pretreatment with the kappa-opioid receptor agonist, U69593, decreased the ability of experimenter-administered cocaine to reinstate extinguished cocaine self-administration behavior. This effect was specific to cocaine-produced drug seeking since U69593 failed to attenuate the ability of experimenter-administered amphetamine to reinstate extinguished cocaine self-administration behavior. One possibility is that U69593 selectively attenuates the behavioral effects of the drug that was originally self-administered. In order to test this hypothesis, the present study examined the effect of U69593 (0.0 or 0.32 mg/kg) on the reinstatement of extinguished amphetamine self-administration behavior produced by experimenter-administered injections of cocaine and amphetamine. Following extinction of amphetamine self-administration (0.04 mg/kg/infusion) the ability of cocaine (0.0, 5.0, 10.0 or 20.0 mg/kg) or amphetamine (0.0, 0.3, 1.0 or 3.0 mg/kg) to reinstate extinguished self-administration behavior was measured. Both drugs reinstated extinguished responding and the reinstatement was attenuated by pretreatment with U69593. The data indicate that the ability of U69593 to decrease drug seeking is not restricted to subjects experienced with cocaine self-administration. Self-administration history does, however, determine the effect of U69593 on amphetamine-produced drug seeking.     

Cocaine-induced conditioned place preference in mice: induction, extinction and reinstatement by related psychostimulants.

Reinstatement of drug-seeking behavior in animals is relevant to drug relapse in humans. In the present study, we employed the conditioned place preference (CPP) paradigm to investigate the extinction and reinstatement of the place-conditioned response, a model that is consistent with drug-seeking behavior. Cocaine-induced CPP was rendered in Swiss Webster mice and then extinguished after repeated saline injections (8 days) in both the previously cocaine-paired compartment and the saline-paired compartment. Following the extinction phase, the reinstatement of CPP was investigated. Cocaine-experienced mice were challenged with one of the following psychostimulants, cocaine (15 mg/kg), methamphetamine (METH; 0.5 mg/kg), methylphenidate (MPD; 20 mg/kg) and phencyclidine (PCP; 5 mg/kg). The priming injection of cocaine, METH and MPD, unlike PCP, induced a marked preference for the previously cocaine-paired compartment. This finding suggests that all three psychostimulants reinstated the CPP response, and METH and MPD substituted for the reinforcing cue of cocaine. A challenge injection of cocaine administered two and four weeks after the reinstatement of CPP indicated that CPP was maintained up to two weeks. The finding that METH and MPD but not PCP reinstated and supported cocaine-induced CPP suggests that the CPP paradigm may be a useful tool for drug discrimination studies and the reinstatement of drug-seeking behavior.     

Influence of the dose and the number of drug-context pairings on the magnitude and the long-lasting retention of cocaine-induced conditioned place preference in C57BL/6J mice

Rationale The place conditioning procedure is increasingly used to study relapse in drug seeking in mice. However, the retention course of drug-induced place preference has not been systematically characterized.Methods The effects of cocaine doses and number of conditioning trials on both the magnitude and the persistence of cocaine-induced conditioned place preference (CPP) were investigated in C57BL/6J mice. Twelve groups of animals were injected with saline, 4, 8 or 12 mg/kg cocaine (i.p.) and submitted to an unbiased counterbalanced place conditioning protocol including one, two or four drug-pairing sessions. Subsequently, the animals were tested at various time intervals after the last conditioning session.Results One cocaine-pairing session was insufficient to induce a CPP. Two and four pairing sessions resulted in significant place preferences of similar magnitude for all tested doses of cocaine, the place preference induced by the greatest number of pairing sessions being the strongest. In the two-pairing groups, place preference lasted less than 14 days for any tested dose of cocaine. In contrast, all four-pairing groups still showed significant place preference 28 days after the last conditioning session. However, the magnitude of cocaine place preference slowly declined at a rate that was dependent upon cocaine dose. On the 35-day post-conditioning interval, only the 12-mg/kg cocaine group still displayed a significant place preference, whereas place preference was undetectable at 42 and 56 days post-conditioning for all groups.Conclusions The number of cocaine-pairing sessions, but not cocaine dose, affected the magnitude of cocaine place preference in mice when tested 1 day after the last conditioning session. In contrast, both cocaine doses and the number of pairing sessions affected the persistence of cocaine place preference. Overall, these results demonstrate that cocaine-induced place preference is a long lasting phenomenon that is strongly affected by the number of drug-pairing trials.     

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.     

A novel protocol for studying food or drug seeking in rhesus monkeys

The purpose of this study was to determine if multiple aspects of drug and food-reinforced behavior could be measured in a single study. Drug or food seeking can be observed under four conditions: 1) internal drug or food cues and external stimulus cues present; self-administration, 2) only internal cues present; priming, 3) no internal or external stimulus cues present; abstinence, and 4) no internal cues, but external stimulus cues present; extinction. Six adult rhesus monkeys lived in three-chambered enclosures: fluid (0.26, 0.52 mg/kg per delivery cocaine hydrochloride, sweetened-vehicle, or water)- related cues and oral fluid self-administration were specific to one end chamber, food pellet-related cues and food self-administration were specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10-h experimental day, monkeys experienced multiple food, fluid, and stimulus-cue test sessions. Adding cocaine to the vehicle initially increased fluid intake during training (condition 1), but vehicle intake did not return to baseline levels after cocaine was later removed (condition 4). Monkeys developed a location preference for the fluid chamber, even when fluid was not available, when responding was reinforced by cocaine, but not when responding was reinforced by vehicle (condition 3). Non-contingent food or fluid delivery did not increase responding in non-deprived animals (condition 2). The current protocol provides both self-administration and place-preference measures of the motivational effects of drugs. Given that human drug abusers spend much time thinking about and seeking drugs prior to actual self-administration, an animal model that uses multiple measures of drug seeking may be useful in the preclinical testing of pharmacological adjuncts for the treatment of drug abuse. Received: 9 September 1996 / Final version: 14 March 1997     

Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice

 Drug administration during test trials can increase the expression of place conditioning, offering an opportunity to determine the specificity of this enhanced response. Prior to training, Swiss-Webster mice spent similar durations in each of the distinctive compartments of a two-compartment box during three 900-s tests. During a 4-day conditioning period, daily injections of morphine (5–20 mg/kg, SC) or vehicle were differentially paired with one of two compartments of the box using an unbiased place conditioning procedure. Post-conditioning tests were conducted 2 and 3 days after the last conditioning day. Mice pre-treated during post-conditioning tests with vehicle did not show significant preference for the morphine-paired compartment when conditioned with morphine. Pretreatment with morphine (2.5–30 mg/kg, SC) led to a dose-dependent increase in time spent in the morphine-paired compartment. Post-conditioning tests in other groups of mice were conducted with heroin (0.1–3 mg/kg), fentanyl (0.01–0.3 mg/kg), cocaine (10–30 mg/kg) and pentobarbital (10–30 mg/kg), and results suggested that none of the tested drugs facilitated the expression of the morphine-conditioned place preference. In another experiment, naltrexone (0.1–10 mg/kg, SC) was administered as the conditioning drug. When tested with naltrexone (0.1–10 mg/kg), there was a dose-dependent avoidance of the naltrexone-paired compartment. Overall, the present data indicated that: (1) failure to exhibit place preference or place aversion when tested in a drug-free state does not imply the failure of conditioning procedure; and (2) effects of the morphine cue reinstatement during the post-conditioning tests appeared to be related to the unique pharmacological profile of the morphine stimulus. Received: 28 November 1997 / Final version: 23 July 1998     

Morphine,cocaine and antidepressant induced motivational activity and midbrain dopaminergic neurotransmission

Positive motivational properties of opioids, stimulants and serotonin selective reuptake inhibitors have been reported following place preference conditioning. The possibility that these effects are associated with changes in dopamine concentration in the nucleus accumbens or striatum was investigated. Male Wistar rats were place conditioned in a three compartment model to vehicle or drug (morphine 2.5 mg/kg, cocaine 5 mg/kg, sertraline 5 mg/kg or paroxetine 15 mg/kg) alternately for 8 days using a 30 min pre-treatment time. Control animals received saline only. Nucleus accumbens and striatal tissue were dissected 72 h after final drug dose, and the concentration of dopamine and its metabolites determined using high performance liquid chromatography (HPLC). Striatal dopamine D1-like receptor density was also determined through radioligand binding. Significant place preference (P<0.05) was observed with morphine, cocaine and sertraline. Morphine treated subjects showed a significant decrease (P<0.05) in striatal dopamine concentration, whilst cocaine and sertraline treatment resulted in a significant increase in striatal dopamine levels. Nucleus accumbens concentrations of dopamine, and striatal dopamine D1-like receptor density remained unchanged. The changes in striatal dopamine concentrations are consistent with withdrawal from opioid and stimulant compounds, and suggest that place preference conditioning may, in part, result from negative motivational or aversive effects.     

东莨菪碱对吗啡依赖大鼠条件位置性偏爱激活的抑制作用

目的:观察东莨菪碱(Scopolamine,Sco)对吗啡(Morphine,Mor)依赖大鼠条件位置性偏爱激活的抑制作用。方法:以剂量递增连续皮下(SC)给吗啡6天建立吗啡诱导大鼠条件位置性偏爱(CPP)模型,第7天用生理盐水替代吗啡训练大鼠10天,使形成的CPP逐渐消退,单次SC4mg/kg吗啡激发消退的CPP。部分大鼠在注射吗啡前30分钟分别腹腔注射(ip)Sco(1mg/kg、2mg/kg、3mg/kg)。观察东莨菪碱对吗啡依赖大鼠在伴药箱停留时间的变化。结果:与Mor依赖组相比在SC4mg/kgMor引燃刺激前30min应用Sco1mg/kg、2mg/kg、3mg/kg均可以使大鼠在伴药箱停留时间缩短(P<0.05)。结论:Sco一定程度上抑制Mor引燃的Mor依赖大鼠的条件位置性偏爱激活。     

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

INTRODUCTION: Prior activation of the kappa opioid system by repeated stress or agonist administration has been previously shown to potentiate the rewarding properties of subsequently administered cocaine. In the present study, intermittent and uncontrollable footshock, a single session of forced swim, or acute administration of the kappa agonist U50,488 (5 mg/kg) were found to reinstate place preference in mice previously conditioned with cocaine (15 mg/kg) and subsequently extinguished by repeated training sessions without drug. RESULTS AND DISCUSSION: Stress-induced reinstatement did not occur for mice pretreated with the kappa opioid receptor antagonist norbinaltorphimine (10 mg/kg) and did not occur in mice lacking either kappa opioid receptors (KOR -/-) or prodynorphin (Dyn -/-). In contrast, the initial cocaine conditioning and extinction rates were not significantly affected by disruption of the kappa opioid system. Cocaine-injection also reinstated conditioned place preference in extinguished mice; however, cocaine-primed reinstatement was not blocked by kappa opioid system disruption. CONCLUSION: The results suggest that stress-induced drug craving in mice may require activation of the dynorphin/kappa opioid system.     

D-serine facilitates the effectiveness of extinction to reduce drug-primed reinstatement of cocaine-induced conditioned place preference

Addiction is a disease that is characterized by compulsive drug-seeking and use despite negative health and social consequences. One obstacle in treating addiction is a high susceptibility for relapse which persists despite prolonged periods of abstinence. Relapse can be triggered by drug predictive stimuli such as environmental context and drug associated cues, as well as the addictive drug itself. The conditioned place preference (CPP) behavioral model is a useful paradigm for studying the ability of these drug predictive stimuli to reinstate drug-seeking behavior. The present study investigated the dose-dependent effects of D-serine (10?mg/kg, 30?mg/kg and 100?mg/kg) on extinction training and drug-primed reinstatement in cocaine-conditioned rats. In the first experiment, D-serine had no effect on the acquisition or development of cocaine-induced locomotor sensitization or CPP. In the second experiment, D-serine treatment resulted in significantly decreased time spent in the drug-paired compartment following completion of an extinction protocol. A cocaine-primed reinstatement test indicated that the combination of extinction training along with D-serine treatment resulted in a significant reduction of drug-seeking behavior. The third experiment assessed D-serine's long-term effects to diminish drug-primed reinstatement. D-serine treatment given during extinction was effective in reducing drug-seeking for more than four weeks of abstinence after the last cocaine exposure. These findings demonstrate that D-serine may be an effective adjunct therapeutic agent along with cognitive behavioral therapy for the treatment of cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'.     

Diazepam-induced place preference conditioning: Appetitive and antiaversive properties

The place conditioning paradigm was used to examine the reinforcing properties of diazepam. Rats were injeccted with diazepam (0.5–5.0 mg/kg, IP) and 30 min later were confined for 30 min to one side of a shuttle box, in which each of the two compartments had distinctive features. On alternate (control) days they received vehicle injections and were confined for 30 min to the opposite side. At almost all doses tested, diazepam produced place preference for the distinctive compartment that had been previously associated with the drug. Preference for the drug side developed regardless of whether diazepam was paired or unpaired with the least-preferred side, and regardless of whether testing was carried out in the undrugged or in the drugged state. The rats preferred the drug side over a novel compartment, but they did not change their initial preference for the side when diazepam was given after removal from the training box.Animals injected with meprobamate (70 mg/kg, PO), a non-benzodiazepine anxiolytic, also developed conditioned preference for the drug side, comparable to that seen following cocaine hydrochloride (10 mg/kg, IP).The diazepam (2.5 mg/kg)-induced place preference was antagonized by CGS 8216 (3 mg/kg, IP), picrotoxin (2 mg/kg, IP) and naloxone (0.8 mg/kg, SC), injected 3 min before and 15 and 20 min after diazepam respectively. Sodium valproate (200 mg/kg, IP) did not influence diazepam (1 mg/kg)-induced place preference. Sodium valproate by itself had marginal effects on place conditioning. Picrotoxin and naloxone, but not CGS 8816, produced place aversion which, in the case of picrotoxin, was due to state dependent learning. The results provide a clear indication that the place preference paradigm is valid as a test for evaluating appetitive properties of minor tranquilizers. They suggest that the rewarding effects of diazepam are mediated through central benzodiazepine receptors. Wheter GABA and/or endogenous opioid peptides are involved in the reinforcing properties of diazepam remains an open question.A preliminary report of this research was made at the 14 C.I.N.P. Congress (Florence 1984)     

Gamma-hydroxybutyric acid affects the acquisition and reinstatement of cocaine-induced conditioned place preference in mice

Cocaine addicts very often use different combinations of cocaine and other drugs of abuse such as gamma-hydroxybutyric acid. The objective of the present work was to evaluate the impact of gamma-hydroxybutyric acid administration on the rewarding actions of cocaine, using the conditioned place preference procedure. Cocaine-induced conditioned place preference (50 mg/kg) was studied after pairing this drug with different gamma-hydroxybutyric acid doses (6.25, 12.5, 25, 50 and 100 mg/kg) during either the acquisition or the expression phase of the procedure. After conditioned place preference had been established, and the preference was extinguished, a reinstatement was induced by a dose of cocaine half of that used to produce conditioning, or by gamma-hydroxybutyric acid alone or by both drugs together. The doses of 12.5 and 100 mg/kg of gamma-hydroxybutyric acid blocked the acquisition of cocaine-induced conditioned place preference, and no dose affected the expression of this conditioning. Reinstatement was abolished only with the dose of 25 mg/kg gamma-hydroxybutyric acid, which did not reinstate the preference by itself. This is the first study evaluating the effects of gamma-hydroxybutyric acid on the rewarding properties of cocaine using the conditioned place preference procedure. The principal conclusion of the study is that gamma-hydroxybutyric acid does not enhance the rewarding effect of cocaine, and within a narrow margin of effective doses, blocks the acquisition and reinstatement of cocaine-induced preference.     

Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months

Rationale and objectives We previously found time dependent increases, or incubation, of cocaine seeking induced by re-exposure to cocaine cues over withdrawal periods of up to 3 months. Here, we studied cocaine seeking induced by re-exposure to cocaine cues or cocaine itself over an extended withdrawal period of 6 months.Methods Rats were trained to self-administer intravenous cocaine for 6 h/day for 10 days. Cocaine seeking induced by re-exposure to cocaine cues or cocaine itself, as measured in extinction or drug-induced reinstatement tests, respectively, was then assessed 1 day, or 1, 3 or 6 months after withdrawal. Rats were first given six 1-h extinction sessions wherein lever presses resulted in contingent presentations of cues previously paired with cocaine infusions. Subsequently, reinstatement of drug seeking induced by cocaine injections (expt 1: 0, 5, and 15 mg/kg, IP; expt 2: 0, 2.5, and 5 mg/kg) was assessed during three 1-h sessions.Results Profound time dependent changes in responsiveness to cocaine cues in the extinction tests were observed, with low responding after 1 day, high responding after 1 and 3 months, and intermediate responding after 6 months of withdrawal. In contrast, no significant time dependent changes in cocaine-induced drug seeking were found; acute re-exposure to cocaine effectively reinstated responding at all withdrawal periods.Conclusions Results indicate that the withdrawal period is a critical modulator of drug seeking provoked by re-exposure to cocaine cues, but not cocaine itself. Results also indicate that while the incubation of responsiveness to cocaine cues is a long lasting phenomenon, it is not permanent.     

Classically conditioned motor effects do not occur with cocaine in an unbiased conditioned place preferences procedure

Classical conditioning and behavioural sensitisation of motor activity induced with cocaine (10mg/kg, i.p.) were examined using an unbiased two-compartment conditioned place preference (CPP) procedure. Habituation of the rats to the testing environment prior to training was varied (i.e. either the rats were habituated to the environment for three 30min sessions or they were not) in order to examine a possible influence of latent inhibition on conditioned locomotion or behavioural sensitisation. Furthermore, rats were either trained with an explicit CS+ (cocaine-paired compartment) and CS- (vehicle-paired compartment), or else they were trained with no barrier between the compartments (effectively a single-compartment procedure with no explicit CS-) in order to examine a possible influence of stimulus change (training rats while confined to one compartment, but testing with no barrier between compartments). On a drug-free test day with free access to both compartments, rats previously exposed to cocaine in one compartment (CS+) and vehicle in the second compartment (CS-) spent more time in the CS+ compartment (conditioned place preference). However, under no circumstance was the rate of motor activity higher in the CS+ compartment than in the CS- compartment, as would be expected if cocaine-induced motor activity was classically conditioned to contextual cues. Whether or not increased activity extinguished with repeated drug-free exposures to previously drug-paired contexts depended on habituation experience. In addition, both habituation and current access to compartments (free or restricted) determined the presence of post-extinction sensitisation to a challenge dose of cocaine (7.5mg/kg). Classical conditioning and non-associative sensitisation, independently or together, cannot account for this pattern of results.     

Determination of the place conditioning and locomotor effects of amperozide in rats: a comparison with cocaine

Amperozide promotes social interactions in rats (Rattus norvegicus) and reduces craving for cocaine and alcohol without producing adverse side effects. Amperozide administration produced a place preference in the dose range from 3.0 to 10.0 mg/kg. Locomotor behavior tended to be suppressed on the days of amperozide pairings, elevated on the days of vehicle pairings, and elevated on test days. Administration of 20.0 mg/kg but neither 2.0 nor 0.2 mg/kg cocaine produced place preference. Rats exhibited a greater place preference for the chamber paired with 2.0 mg/kg and 20.0 mg/kg but not 0.2 mg/kg cocaine compared to the chamber paired with 5.0 mg/kg amperozide. The results indicate that amperozide is appetitive. The most appetitive dose of amperozide (5.0 mg/kg) is less appetitive than the most appetitive dose of cocaine (20.0 mg/kg). More research is needed before conclusions regarding the degree of abuse potential for amperozide can be made.     

Genetic liability increases propensity to prime-induced reinstatement of conditioned place preference in mice exposed to low cocaine

Rationale Relapse to drug use after periods of forced or self-imposed abstinence is a central problem in the treatment of addiction; therefore, identification of factors modulating the risk to relapse is a relevant goal of preclinical research. Objectives These experiments evaluated the influence of the amount of drug experienced, the duration of drug withdrawal, and individual liability on the propensity to cocaine-induced reinstatement of conditioned place preference (CPP). Materials and methods Mice from the inbred strains C57BL/6J and DBA/2J were trained for CPP with a high (20 mg/kg) or low (5 mg/kg) effective dose of cocaine. After CPP testing, all groups underwent extinction. Twenty-four hours after the extinction test, mice were challenged with saline, a cocaine dose unable to induce CPP (2.5 mg/kg) or an intermediate effective dose (10 mg/kg), and tested for CPP reinstatement. Additional groups of mice trained with the low cocaine dose were left undisturbed for 8 days after extinction test (long withdrawal), retested for extinction, and evaluated for prime-induced reinstatement (0, 2.5, 10 mg/kg of cocaine). Results Mice trained with the high cocaine dose, but not with the low one, showed prime-induced reinstatement 24 h after the extinction test; DBA/2J mice trained with the low dose showed reinstatement after long withdrawal. Conclusions These results indicate that reinstatement of CPP by cocaine prime depends on the amount of drug experienced and on an interaction between individual liability and duration of drug abstinence and suggest that the risk to relapse into drug seeking is not prevented by moderated drug consumption.     

Stress and relapse to drug seeking in rats: studies on the generality of the effect

RATIONALE: Intermittent footshock reinstates drug-taking behavior in rats, but not behaviors previously maintained by food reinforcers. Here we tested further the generality of this phenomenon by determining whether restraint and food deprivation stressors would reinstate heroin seeking, whether the environment in which footshock is given modulates footshock-induced reinstatement, and whether footshock would reinstate operant responding previously maintained by brain stimulation reward (BSR). METHODS: Groups of rats were trained to self-administer for 10 days either heroin (0.05-0.1 mg/kg/infusion, IV, three 3-h sessions/day) or brain stimulation into the septal area (trains of monopolar cathodal pulses of 100 micros for 500 ms, one 60-min session/day). After extinction of the heroin-reinforced behavior (10-13 days), the rats were tested for reinstatement after exposure to food deprivation (1 and 21 h), restraint given outside the self-administration environment (5, 15 and 30 min), or intermittent footshock (0.8 mA, 15 min) given in the self-administration environment or in a novel (non-drug) environment. For BSR-trained rats, the effect of footshock on reinstatement after extinction (6-10 days) was compared with that induced by noncontingent brain stimulation (three or six discrete stimulations at the start of the test sessions). RESULTS: Food deprivation reinstated heroin seeking. Footshock reliably reinstated heroin seeking when given in the drug environment, but not when given in a non-drug environment. Similarly, restraint given outside the self-administration environment failed to reinstate heroin seeking. In addition, footshock was as effective as priming brain stimulation in reinstating operant responding previously maintained by BSR. CONCLUSIONS: The effect of footshock on reinstatement of heroin seeking generalizes to food deprivation, and appears to be dependent on the environment in which the stressor is given. The data with BSR indicate that the phenomenon of footshock-induced reinstatement is not selective for drug reinforcers.