Blockade of the serotonin 5-ht2a receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model.

The serotonin 5-HT2A receptor (5-HT2AR) may play a role in reinstatement of drug-seeking. This study investigated the ability of a selective 5-HT2AR antagonist to suppress reinstatement evoked by exposure to cues conditioned to cocaine self-administration. Cocaine self-administration (0.75 mg/kg/0.1 mL/6 s infusion; FR 4) was trained in na?ve, free-fed rats to allow interpretation of results independent from changes related to food deprivation stress. Pretreatment with the selective 5-HT2AR antagonist M100907 (volinanserin) failed to reduce rates of operant responding for cocaine infusions. On the other hand, M100907 (0.001–0.8 mg/kg ip) significantly suppressed the cue-induced reinstatement of cocaine-seeking behavior following extinction; effective M100907 doses did not alter operant responding for cues previously associated with sucrose self-administration. Importantly, a greater magnitude of active lever presses on the initial extinction session (high extinction responders) predicted the maximal susceptibility to M100907-induced suppression of cue-evoked reinstatement. The findings indicate that blockade of the 5-HT2AR attenuates the incentive-motivational effects of cocaine-paired cues, particularly in high extinction responders, and suggests that M100907 may afford a therapeutic advance in suppression of cue-evoked craving and/or relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats.

Estradiol benzoate (EB) facilitates the acquisition and reinstatement of cocaine-seeking behavior when administered to ovariectomized (OVX) rats. In contrast, progesterone (P) decreases acquisition of cocaine self-administration, but the effects of P on the reinstatement of drug seeking are not known. The purpose of the present study was to compare the effects of EB and P on the reinstatement of cocaine-seeking behavior in female rats. Rats received either OVX or sham surgery (SH) and were trained to lever press for intravenous cocaine infusions (0.4 mg/kg) under a fixed ratio 1, 20-s time-out schedule during daily 2-hr sessions. After 14 days of stable responding, saline replaced cocaine, and a 21-day extinction period began. After extinction, rats were separated into 5 treatment groups (OVX+EB, OVX+EB+P, OVX+vehicle [VEH], SH+P, or SH+VEH), and VEH, EB, or EB+P was administered 30 min prior to each session for 5 days. After 3 days of hormone treatment, rats received a saline or cocaine (10 mg/kg) injection, and reinstatement of lever responding was assessed. Reinstatement responding in the OVX+EB group was greater relative to the OVX+EB+P, SH+P, and OVX+VEH groups, which had low levels of cocaine-primed responding. The SH+VEH and OVX+EB groups displayed similar high levels of cocaine-elicited reinstatement. The suppression of cocaine-induced reinstatement following P treatment suggests a role for P in the prevention of relapse to cocaine self-administration in female cocaine users. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fine structure of the pecten oculi of the barred owl (Strix varia)

Relapse prevention in abstinent cocaine addicts remains a major focus of drug addiction therapy. We used a rat model of cocaine addiction that focused on cocaine-seeking behavior elicited interoceptively and by conditioned stimuli. Each of 18 rats could self-administer a maximum of 20 intravenous cocaine injections (1.5 mg/kg) per session per day. To prevent initiation of responding by cocaine itself priming injections were never administered. Although cocaine was available beginning every session the rats displayed a self-imposed period of abstinence followed by a period of rapid consumption. The abstinence period was variable among rats but consistent for individual rats. In experiment 1 we studied the contribution of a CS+ (stimulus light and lever retraction) to the motivation to initiate and maintain a cocaine self-administration episode. We compared the number of responses the rats emitted to receive the first and subsequent injections of the day between a group responding on a fixed-ratio (FR) schedule (n = 6) and a group responding on a second-order (SO) schedule (n = 5) of reinforcement. For all rats the number of responses per injection was raised daily until a rat failed to consume more than four injections. The SO group was able to emit approximately four times as many responses as the FR group to obtain their first and subsequent injections. In experiment 2 (n = 7) responses during extinction were counted with and without the CS+. Responding was greater in the presence of the CS+ than in its absence. The present model demonstrates that the motivation to self-administer cocaine is variable and greatly enhanced by conditioned stimuli.     

Effects of ethanol on encoding, consolidation, and expression of extinction following contextual fear conditioning.

Studies of contextual fear conditioning have found that ethanol administered prior to a conditioning session impairs the conditioned freezing response during a test session the next day. The present experiments examined the effects of ethanol on extinction, the loss of conditioned responding that occurs as the animal learns that a previously conditioned context no longer signals shock. Ethanol (1.5 g/kg) administered prior to single (Experiment 1) or multiple (Experiment 2) extinction sessions impaired extinction. Ethanol administered prior to a test session disrupted the expression of freezing after extinction (Experiments 3-5). There was some evidence that ethanol served as an internal stimulus signaling the operation of conditioning or extinction contingencies (Experiments 4-5). In Experiment 6, postsession injections of 1.5 g/kg ethanol had no effect on extinction with brief (3 min) or long (24 min) exposures to the context, but injections of 3 g/kg after long exposures impaired extinction. Together, these results indicate that ethanol affects extinction by acting on multiple learning and performance processes, including attention, memory encoding, and memory expression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Human methadone self-administration: Effects of diazepam pretreatment.

The effect of diazepam on methadone self-administration was examined. Five methadone maintained patients with a history of benzodiazepine abuse were recruited, Patients were stabilized on 80 mg of methadone per day. After stabilization patients participated in methadone self-administration sessions. During each session, 128 presses (fixed ratio 128) of 1 button delivered 10 ml of 0.054 mg/ml methadone solution. The same number of button presses on a 2nd button delivered 10 ml of vehicle. Forty-five min prior to the self-administration session, 0 (placebo), 5, 10, or 20 mg per 70 kg body weight diazepam was administered. Ratings of drug liking, goodness, strength, and high were collected 5, 30, 60, 90, and 150 min after the end of the self-administration session. Diazepam pretreatment significantly decreased the amount of methadone consumed. The 10- and 20-mg diazepam doses significantly increased reports of good, like, strong, and high. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of acquisition training schedule on extinction and reinstatement of cocaine self-administration in male rats.

Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.     

Binge cocaine self-administration by humans: smoked cocaine

Tolerance develops to the cardiovascular and subjective effects of intravenous cocaine during single self-administration sessions, but diminishes within 3 h after the session ends. To examine whether a similar pattern of tolerance occurs to smoked cocaine, seven adult 'crack' cocaine users completed a protocol investigating changes in behavior during the repeated self-administration of smoked cocaine. During sessions, participants could self-administer up to 6 doses of smoked cocaine (50 mg per dose), one every 14 min. Both two- and three-day binge conditions were tested. During the two-day binge, a 2.5 h cocaine self-administration session began at 1200 h and again at 1600 h on two consecutive days, while during the three-day binge, self-administration sessions occurred at 1200 h and 1600 h on three consecutive days. The first one or two cocaine doses in each session increased cardiovascular and subjective effects ratings; subsequent cocaine inhalations during the session did not increase these measures further, suggesting the development of acute tolerance to these effects. Ratings of 'I want cocaine' decreased slightly across three days of repeated smoked cocaine self-administration, while anxiety scores increased slightly across three days, suggesting that some effects of smoked cocaine may persist beyond a binge.     

A history of postponing shock does not appear to alter the discriminative stimulus effects of cocaine

Previous research has shown that the rate of punished lever pressing of monkeys is typically decreased by cocaine administration. However, cocaine increases punished responding in monkeys with a history of responding maintained by the postponement of shock presentation. This raises the question of whether other behavioral effects of cocaine differ following a history of postponing shock. The present experiment examined whether a history of postponing shock alters the discriminative stimulus effects of cocaine. Three squirrel monkeys were trained to discriminate cocaine (0.56 mg/kg, intramuscular) from saline. Presses on the left lever produced food following saline injections whereas presses on the right lever were reinforced following administration of cocaine. Occasional test sessions were conducted in which cocaine (0.1-0.56 mg/kg), midazolam (0.03-0.56 mg/kg) or pentobarbital (0.3-5.6 mg/kg) was injected prior to the session and responding on either lever was reinforced. Discrimination training was discontinued during a second experimental phase in which responding was maintained by shock postponement. Pulling a chain postponed mild shocks for 25 s, whereas shocks occurred every 5 s in the absence of responding. Next, the drug discrimination dose-response curves were redetermined. The dose-response curves for all drugs before and after the shock postponement history were similar. This outcome suggests that the influence of a history of shock postponement is specific to punished responding.     

A role for α?-adrenergic receptors in extinction of conditioned fear and cocaine conditioned place preference.

Previous work has demonstrated an important role for adrenergic receptors in memory processes in fear and drug conditioning paradigms. Recent studies have also demonstrated alterations in extinction in these paradigms using drug treatments targeting β- and α2-adrenergic receptors, but little is known about the role of α?-adrenergic receptors in extinction. The current study examined whether antagonism of α?-adrenergic receptors would impair the consolidation of extinction in fear and cocaine conditioned place preference paradigms. After contextual fear conditioning, injections of the α?-adrenergic receptor antagonist prazosin (1.0 or 3.0 mg/kg) following nonreinforced context exposures slowed the loss of conditioned freezing over the course of 5 extinction sessions (Experiment 1). After cocaine place conditioning, prazosin had no effect on the rate of extinction over 8 nonreinforced test sessions. Following postextinction reconditioning, however, prazosin-treated mice showed a robust place preference, but vehicle-treated mice did not, suggesting that prazosin reduced the persistent effects of extinction (Experiment 2). These results confirm the involvement of the α?-adrenergic receptor in extinction processes in both appetitive and aversive preparations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impulsive choice as a predictor of acquisition of IV cocaine self- administration and reinstatement of cocaine-seeking behavior in male and female rats.

Drug abuse and impulsive choice are related in humans. In female rats, impulsive choice predicted the rate of acquisition of IV cocaine self-administration. The objectives of the present experiments were to: (a) compare impulsive choice in males and females, (b) extend previous research on impulsive choice and acquisition of cocaine self-administration to males, and (c) compare males and females during maintenance, extinction, and reinstatement of cocaine-seeking behavior. Male and female rats were trained on an adjusting delay task in which a response on one of two levers yielded one food pellet immediately, and a response on the other resulted in three pellets after an adjusting delay that decreased after responses on the immediate lever and increased after responses on the delay lever. A mean adjusted delay (MAD) was used as the quantitative measure of impulsivity. In Experiment 1, MADs were analyzed for sex differences. In Experiment 2, acquisition of cocaine self-administration was examined in rats selected for high (HiI; MADs ≤9 seconds) or low (LoI; MADs ≥13 seconds) impulsivity. In Experiment 3, HiI and LoI groups were compared on maintenance and extinction of cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior. There were no sex differences in impulsive choice; however, HiI male and female rats acquired cocaine self-administration faster than their LoI counterparts. LoI females responded more on a cocaine-associated lever during maintenance and extinction than HiI females, but HiI females showed greater reinstatement of cocaine-seeking behavior than all other groups at the highest dose tested (15 mg/kg). Thus, individual differences in impulsive choice were associated with differences in cocaine-seeking behavior. Impulsive choice and sex may be additive vulnerability factors in certain phases of drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuron discharges in the rat auditory cortex during electrical intracortical stimulation

Cocaine and cocaine-associated cues elicit craving in addicts and reinstate cocaine-seeking behavior in rats. Craving and cocaine-seeking behavior may be mediated by withdrawal-induced changes in dopamine (DA) neurotransmission in the amygdala. To examine whether there are concomittant changes in cocaine-seeking behavior and extracellular DA levels during withdrawal, experimental rats were trained to self-administer cocaine (0.75 mg/kg i.v.). After 14 daily 3-hour training sessions, animals underwent either a 1-day, 1-week, or 1-month withdrawal period. Extracellular DA levels were assessed during baseline, extinction, cue reinstatement, and cocaine (15 mg/kg i.p.) reinstatement of cocaine-seeking behavior (i.e., defined as the difference in nonreinforced lever presses on an active minus inactive lever). Cocaine-seeking behavior became more intense during the course of cocaine withdrawal. Additionally, basal and cocaine-induced extracellular DA levels were enhanced after the 1-month withdrawal period. We suggest that the former may reflect a persistent elevation in tonic extracellular DA levels in the amygdala, whereas the latter may reflect a persistent elevation in phasic extracellular DA levels.     

Antithrombotic agents in unstable angina. Review of clinical trials

The purpose of this experiment was to investigate the regulation of drug intake in rats (n = 20) self-administering heroin or cocaine during daily 5-hr sessions. Operant chambers were equipped with 2 levers and associated stimulus lights. A response on the lever with stimuli signaling an increase in dose size increased the infusion duration by 3 s, and a response on the lever with stimuli signaling a decrease in dose size decreased the infusion duration by 3 s. Results showed that daily and hourly drug intake for cocaine and heroin groups were relatively constant. Significant correlation coefficients were obtained for heroin and cocaine groups for the relationship between interdose interval (IDI) and infusion duration (dose size). These findings indicate that subjects regulated their drug intake by adjusting IDI throughout drug self-administration sessions.     

AMPA receptors and motivation for drug: effect of the selective antagonist NBQX on behavioural sensitization and on self-administration in mice

A series of experiments was carried out in which the potency of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (10-100 mg/kg) on locomotor activity was investigated, in mice. NBQX reduced all forms of activity studied, but its potency to do so varied according to the conditions of the experiment. The smallest dose of NBQX significantly reducing spontaneous or cocaine-induced activity was 100 mg/kg. Mice that had been repeatedly treated with 16 mg/kg cocaine once per week, for 7 weeks, showed a sensitized locomotor response to a challenge dose of cocaine (16 mg/kg). NBQX reversed the sensitized response at 30 and 100 mg/kg. The pattern of results obtained leaves open the role that AMPA-receptors may have in the expression of behavioural sensitization. In two further experiments, mice were trained to self-administer cocaine (30 micrograms per reinforcer) via intravenous catheters, using an operant lever pressing technique. When the amount of cocaine per reinforcer was doubled (to 60 micrograms) or halved (to 15 micrograms) the mice adapted lever pressing rates to maintain some constancy of self-dosing (but not at 7.5 micrograms per reinforcer) and when saline was substituted for cocaine, response rates increased considerably (extinction bursting). NBQX (10 and 30 mg/kg) reduced the self-administration of 30 micrograms reinforcers of cocaine, but only during the first 30 min of the test session. There was no evidence that NBQX specifically antagonized the reinforcing effect of cocaine, as responding was similarly reduced on both the reinforced and the non-reinforced lever, nor did the response to NBQX mimic behaviour seen following changes in the concentration of the reinforcer. The results of the locomotor experiments and the self-administration experiments are discussed together, in terms of current hypotheses about glutamatergic mechanisms involved in motivation for drug.     

Locomotor Activity Predicts Acquisition of Self-Administration Behavior but Not Cocaine Intake.

The current study investigates locomotor activity in a novel environment and correlates these activity levels with cocaine self-administration in rats that were either trained or untrained on a lever-pressing task prior to cocaine self-administration. The authors report that it is the rate of learning the lever-pressing task, not cocaine self-administration, that correlates with locomotor activity. The results suggest that a correlation between locomotor activity and cocaine self-administration is secondary to a link between locomotor activity and rate of learning to lever press for a reward. The authors conclude that locomotor activity is not necessarily an indicator of propensity to self-administer cocaine and demonstrate that environmental novelty and rate of learning an operant task are important considerations when designing experiments on drug-seeking behaviors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A novel paradigm to investigate regulation of drug intake in rats self-administering cocaine or heroin intravenously.

The purpose of this experiment was to investigate the regulation of drug intake in rats (n?=?20) self-administering heroin or cocaine during daily 5-hr sessions. Operant chambers were equipped with 2 levers and associated stimulus lights. A response on the lever with stimuli signaling an increase in dose size increased the infusion duration by 3 s, and a response on the lever with stimuli signaling a decrease in dose size decreased the infusion duration by 3 s. Results showed that daily and hourly drug intake for cocaine and heroin groups were relatively constant. Significant correlation coefficients were obtained for heroin and cocaine groups for the relationship between interdose interval (IDI) and infusion duration (dose size). These findings indicate that subjects regulated their drug intake by adjusting IDI throughout drug self-administration sessions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of a context shift and multiple context extinction on reactivity to alcohol cues.

Cue exposure treatment (CET) attempts to reduce the influence of conditioned substance cues on addictive behavior via extinction, but has received only modest empirical support in clinical trials. This may be because extinction learning appears to be context dependent and a change in context may result in a return of conditioned responding (i.e., renewal), although this has received only limited empirical examination. The current study used a 4-session laboratory analogue of CET to examine whether a change in context following 3 sessions of alcohol cue exposure with response prevention would result in renewal of conditioned responding. In addition, this study examined whether conducting extinction in multiple contexts would attenuate renewal of conditioned responding. In one-way between-subjects design, 73 heavy drinkers (71% men) were randomized to 3 conditions: (a) single context extinction (extinction to alcohol cues in the same context for 3 sessions followed by a context shift at the fourth session), (b) multiple context extinction (extinction to alcohol cues in different contexts each day for all 4 sessions), and (c) pseudoextinction control condition (exposure to neutral cues in the same context for 3 sessions followed by exposure to alcohol cues at the fourth session). The results revealed the predicted cue reactivity and extinction effects, but the hypotheses that a context shift would generate renewed cue reactivity and that multiple contexts would enhance extinction were not supported. Methodological aspects of the study and the need for parametric data on the context dependency of extinction to alcohol cues are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Extracellular serotonin is decreased in the nucleus accumbens during withdrawal from cocaine self-administration

Many of the withdrawal symptoms reported by human cocaine users are thought to be correlated with serotonergic dysfunction. To explore the neurochemical basis for this hypothesis, we used in vivo microdialysis to monitor extracellular serotonin (5-HT) in the nucleus accumbens of the rat both during and for several hours after unlimited-access intravenous cocaine self-administration. Self-administration of cocaine produced an increase of approx. 340% of baseline in the dialysate concentration of 5-HT that persisted for the entire 12 h session. During the first 6 h after self-administration, dialysate 5-HT levels were significantly decreased to 41% of pre-session levels and 25% of the levels in drug-naive control animals. The effects of cocaine exposure on basal extracellular 5-HT concentrations were also examined using a quantitative microdialysis method (Difference Method). Rats withdrawing from extended-access cocaine self-administration displayed significantly lower extracellular 5-HT levels (0.6 +/- 0.3 nM) than either drug-naive control animals (2.0 +/- 0.5 nM) or animals which received daily 3-h self-administration training sessions only (limited-access; 1.4 +/- 0.2 nM). Together these results indicate that extracellular 5-HT is significantly decreased in the nucleus accumbens during withdrawal from cocaine self-administration. The severity of this decrease is contingent on the length of time cocaine is self-administered.     

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.     

Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats.

The powerful, long-lasting association between the rewarding effects of a drug and contextual cues associated with drug administration can be studied using conditioned place preference (CPP). The GABAB receptor agonist baclofen facilitates the extinction of morphine-induced CPP in mice. The current study extended this work by determining if baclofen could enhance the extinction of methamphetamine (Meth) CPP. CPP was established using a six-day conditioning protocol wherein Meth-pairings were alternated with saline-pairings. Rats were subsequently administered baclofen (2 mg/kg i.p. or vehicle) immediately after each daily forced extinction session, which consisted of a saline injection immediately prior to being placed into the previously Meth- or saline-paired chamber. One extinction training cycle, consisted of six once-daily forced extinction sessions, mimicking the alternating procedure established during conditioning, followed by a test for preference (Ext test). CPP persisted for at least four extinction cycles in vehicle-treated rats. In contrast, CPP was inhibited following a single extinction training cycle. These data indicate that Meth-induced CPP was resistant to extinction, but extinction training was rendered effective when the training was combined with baclofen. These findings converge with the prior demonstration of baclofen facilitating the extinction of morphine-induced CPP indicating that GABAB receptor actions are independent of the primary (unconditioned) stimulus (i.e., the opiate or the stimulant) and likely reflect mechanisms engaged by extinction learning processes per se. Thus, baclofen administered in conjunction with extinction training may be of value for addiction therapy regardless of the class of drug being abused. (PsycINFO Database Record (c) 2011 APA, all rights reserved)