Neonatal isolation enhances maintenance but not reinstatement of cocaine self-administration in adult male rats

Rationale Previously, we demonstrated that neonatal isolation increases acquisition of cocaine self-administration in adult male rats.Objective Now we examine whether neonatal isolation enhances maintenance and cocaine-induced reinstatement of extinguished self-administration behavior. To test the specificity of the effect, a separate study examined maintenance of food responding.Methods Litters were subjected to neonatal isolation (individual isolation; 1 h/day; postnatal days 2–9) or were non-handled. In experiment 1, adult male rats trained to self-administer cocaine (0.5 mg/kg per infusion; fixed-ratio 3 or FR3) were tested under fixed and progressive ratio (PR) schedules with different cocaine doses (0.125–1.0 mg/kg per infusion). After cocaine self-administration was extinguished, cocaine (0.5 or 2 mg/kg)-induced reinstatement of responding was assessed. In experiment 2, responding for food under an FR15 and two PR schedules were assessed in separate groups of neonatally isolated and non-handled male rats.Results Neonatally isolated rats responded for low cocaine doses at higher rates and infused more cocaine relative to non-handled rats under both FR and PR schedules. However, there are no group differences in cocaine-induced reinstatement or in responding for food under the PR schedules. However, neonatally isolated rats lever pressed for food at lower rates under the FR schedule.Conclusions Together with our previous studies, the results of the present study suggest that the early life stress of neonatal isolation enhances cocaine-taking (acquisition and maintenance) at lower doses but does not alter drug-induced cocaine-seeking (reinstatement) behavior.     

The discriminative stimulus properties of (+)-HA-966, an antagonist at the glycine/N-methyl-D-aspartate receptor

Using a two-lever operant drug discrimination paradigm, rats have been trained to discriminate between the administration of saline and R-(+)-HA-966 (R-(+)-3-amino-1-hydroxypyrrolid-2-one, 30 mg/kg i.p.) an antagonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex. Drug-appropriate responding was not induced in stimulus generalisation experiments when the non-competitive NMDA receptor antagonist, phencyclidine (PCP, 1-8 mg/kg i.p.) was substituted for (+)-HA-966. Similarly, (+)-HA-966 (6-50 mg/kg i.p.) did not induce drug-appropriate responding in animals trained to discriminate PCP (3 mg/kg i.p.) from saline. The results suggest that the behavioural profile of compounds attenuating the actions of NMDA via blockade of the glycine modulatory site may be substantially different from those acting at the ion channel of the NMDA receptor complex.     

Increases in the reinforcing efficacy of cocaine after particular histories of reinforcement

In humans, the progression to cocaine addiction presumably involves increases in the effectiveness of cocaine to function as a reinforcer. Here we use breakpoints assessed using the progressive ratio (PR) schedule as an index of the efficacy of cocaine as a reinforcer. To date, no preclinical studies have demonstrated an increase in breakpoint as a consequence of self-administration history. In the current study, baseline performances on fixed ratio (FR) and PR schedules were determined. Rats were then exposed to different self-administration histories and deprivation periods, and responding under FR and PR schedules was reassessed. Exposure to a discrete-trials procedure (access to cocaine 4 times/hour, 24 hours/day; DT4) for 7 or 10 days, coupled with a deprivation period of 7 days, resulted in increases in breakpoint on a PR schedule, with no change in FR1 schedule responding. Exposure to an FR1 schedule for 72 consecutive hours followed by 7 days of deprivation, failed to change breakpoints, but increased rates of intake assessed with an FR1 schedule. Thus, the type of self-administration history and the length of deprivation experienced contribute to changes in the reinforcing efficacy of cocaine as measured by a PR schedule.     

Heightened cocaine and food self-administration in female rats with neonatal isolation experience.

Previously, we demonstrated that the early life stress of neonatal isolation facilitates acquisition of cocaine and food self-administration in adult female rats. We now test whether it enhances responding for these reinforcers after operant performance is established. Adult female rats were derived from litters that were either subjected to neonatal isolation (1 h/day isolation; postnatal days 2-9) or were nonhandled and assigned to one of two experiments. In Experiment 1, female rats well trained to self-administer cocaine were tested under a fixed-ratio 3 (FR3) schedule with several cocaine doses (0.0625-1.0 mg/kg/infusion) and under a progressive-ratio (PR) schedule (0, 0.5, and 1.0 mg/kg/infusion cocaine). In Experiment 2, female rats well trained to respond for food reinforcers under an FR15 schedule were tested under two PR schedules. Results show that neonatal isolation enhanced responding for cocaine under both schedules of reinforcement and increased responding for food under a PR schedule of reinforcement. These data extend our previous acquisition study in female rats to show that neonatal isolation enhances responding under maintenance conditions. These enduring behavioral changes may relate to the ability of neonatal isolation to increase striatal dopamine responses to psychostimulants, effects we showed previously in infant and juvenile rats.Neuropsychopharmacology (2006) 31, 70-76. doi:10.1038/sj.npp.1300779; published online 1 June 2005.     

Effects of ibogaine on responding maintained by food,cocaine and heroin reinforcement in rats

The effects of ibogaine (40 and 80 mg/kg, IP), an indole alkaloid proposed for the treatment of drug abuse, were determined in three different groups of rats responding under an FR10 schedule of food, cocaine or heroin reinforcement. Ibogaine (80 mg/kg, IP) given 60 min before the start of the session resulted in a 97% decrease in the number of ratios completed under the food reinforcement schedule and resulted in a decrease in responding the following day. Neither 40 mg/kg ibogaine given 60 min prior to the session nor 80 mg/kg given 24 h before the session suppressed responding maintained by cocaine infusions (0.33 mg/infusion). Pretreatment with 80 mg/kg ibogaine either 60 or 90 min prior to the session suppressed cocaine self-administration on the day it was administered and the longer pretreatment continued to suppress responding for 48 h. Responding maintained by heroin (18 µg/infusion) was the most sensitive to the effects of ibogaine. Both 40 and 80 mg/kg ibogaine resulted in an almost complete suppression of responding following a 60-min pretreatment period. Responding maintained by heroin returned to control levels the day following the administration of ibogaine.     

Pharmacological effects of naltrexone and intravenous alcohol on craving for cigarettes among light smokers: a pilot study

Rationale Although reinstatement of extinguished cocaine self-administration is widely used as an animal model of relapse, it is unclear which behavioral effects of the drug stimulus (i.e., unconditioned, discriminative or reinforcing) mediate the increases in responding after extinction. Objective To examine the influence of experience with cocaine as a reinforcer on the ability of response-independent cocaine injections to increase extinguished responding. Materials and methods Effects of noncontingent injections of cocaine (0.01–1.0 mg/kg, i.v.) were assessed in two groups of cynomolgus monkeys, those with extensive histories of cocaine self-administration when responding was maintained under a concurrent fixed ratio (FR) 50 schedule of saline and food presentation (n = 8) and cocaine-naive monkeys (n = 5) responding under an FR 50 schedule of food presentation. In the latter group, the effects of noncontingent cocaine and food (one or five pellets) were examined before and after a brief history of cocaine (0.03 mg/kg/inj) self-administration under an FR 50 schedule. Results In the cocaine-experienced subjects responding under a concurrent schedule of saline and food availability, noncontingent cocaine dose-dependently increased injection-lever responding. In the initially cocaine-naive subjects, no dose of cocaine increased extinguished food-maintained responding before or after a brief exposure to cocaine self-administration. In contrast, noncontingent delivery of five food pellets significantly increased extinguished food-maintained responding after cocaine self-administration. Conclusions These results support the view that, under self-administration conditions, the discriminative stimulus effects of cocaine play a prominent role in the ability of cocaine to increase extinguished responding.     

Intravenous cocaine self-administration: individual differences in male and female C57BL/6J mice

This study examined individual differences in male and female C57BL/6J (C57) mice responding for intravenous cocaine reinforcement. The experiment used 4 groups of mice, distinguished by sex and cocaine unit dose (0.3 or 1 mg/kg/infusion). Mice trained to lever respond for IV cocaine were given the drug initially on an FR2 schedule and then on a Progressive Ratio 2(PR2) schedule. Hierarchical linear modeling (HLM) techniques were used to examine data generated across four FR2 and four PR2 sessions, as well as within session data when cocaine was delivered on the PR2 schedule. HLM techniques, although uncommon in the animal literature, characterize individual differences in human studies and are likely to be useful in more complex preclinical studies. Analysis established distinct patterns of self-administration both across and within sessions. Responses for cocaine delivered on the FR2 schedule was dose-dependent, but did not differ according to sex. Response output was greater when either dose of cocaine was delivered on the PR2 than the FR2 schedule. Although response output for the more rewarding 1 mg/kg unit dose was similar for the two sexes, males responded more and had greater cocaine intake than females when the less reinforcing 0.3 mg/kg dose was delivered at the more behaviorally challenging PR2 schedule. HLM analysis of response patterns and cocaine intake within the PR2 sessions corroborated this sex difference and also indicated that trajectories differed for individual mice after accounting for the sex and dose factors. The reduced response output by females for cocaine in the present experiment is consistent with previous reports that sex differences in the rewarding effects of either alcohol or food reinforcement were revealed for C57 mice only when delivered on more behaviorally demanding schedules (e.g. PR2 or FR100).     

Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ratio (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or FR 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013–0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.     

Previous exposure to cocaine enhances cocaine self-administration in an alpha 1-adrenergic receptor dependent manner.

Noradrenergic transmission is implicated in the biochemical and behavioral effects of cocaine. Recently, we demonstrated that the alpha 1-adrenergic receptor antagonist prazosin attenuates cocaine-induced reinstatement of drug-seeking behavior. We now assessed whether prazosin could counter the effect of previous exposure to cocaine to enhance subsequent self-administration behavior. Rats were pre-exposed to systemic injections of either saline, prazosin (0.3 mg/kg), saline+cocaine (10 mg/kg), or prazosin+cocaine for 5 days. Starting 15-18 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.5 mg/kg/infusion) under a fixed ratio 3 (FR3) schedule of reinforcement. Several tests were conducted. First, responding for cocaine under an FR3 schedule was assessed across several doses (0.125-1.0 mg/kg/infusion). Second, responding for cocaine (0.5 mg/kg/infusion) under a progressive-ratio (PR) schedule was examined for 6 consecutive days. Finally, responding for cocaine (0, 0.5, and 1.0 mg/kg/infusion) was determined under the PR schedule of reinforcement. Results showed that cocaine pre-exposed rats self-administer more cocaine compared to saline pre-exposed rats when tested under both the FR and PR schedules. Rats pre-exposed to cocaine plus prazosin did not show enhanced cocaine self-administration. These rats, as well those pre-exposed to prazosin alone, showed levels of cocaine self-administration similar to saline pre-exposed rats. Thus, previous exposure to cocaine enhanced cocaine self-administration, an effect that appears to involve activation of alpha 1-adrenergic receptors. These data, along with several recent studies, show further support for the contribution of noradrenergic transmission in the behavioral effects of cocaine.     

Continuous intracerebroventricular infusion of the competitive NMDA receptor antagonist, LY235959, facilitates escalation of cocaine self-administration and increases break point for cocaine in Sprague-Dawley rats

Although escalation of consumption is an important characteristic of cocaine dependence, the neurobiological mechanisms that mediate this phenomenon have not been fully described. In this study, we used male, Sprague-Dawley rats to measure the effects of acute and continuous intracerebroventricular (ICV) administration of the competitive NMDA receptor antagonist, LY235959, on cocaine self-administration behavior under various schedules of reinforcement and access conditions. Single ICV infusions of LY235959 (0.03-0.3 microg/5 microl) produced dose-dependent and statistically significant decreases in the number of cocaine infusions earned under a progressive ratio schedule of reinforcement. In a second experiment, vehicle or LY235959 (0.2-0.3 microg/day) was continuously administered ICV to rats via surgically-implanted subcutaneous osmotic minipump/intracranial cannula assemblies. Both vehicle- and LY235959-treated rats significantly escalated cocaine self-administration over the 10 long access sessions; however, rats treated with LY235959 escalated cocaine self-administration faster and to a greater degree than vehicle-treated rats. There was a statistically significant increase in cocaine infusions earned under the PR schedule in LY235959-treated rats, but not vehicle-treated rats, after 10 long access cocaine self-administration sessions. These data support the hypothesis that escalation of cocaine consumption is mediated by hypo-glutamatergic tone in the central nervous system and this facilitation of escalation is associated with an increase in motivation to respond for cocaine.     

Impulsivity predicts the escalation of cocaine self-administration in rats

Impulsivity, as measured by the delay-discounting task, predicts the acquisition of cocaine self-administration and reinstatement of cocaine seeking in rats. The purpose of this study was to extend these results to the escalation phase of drug self-administration. Female rats were initially screened for high (HiI) or low (LoI) impulsivity for food reinforcement using a delay-discounting procedure. They were then implanted with i.v. catheters and trained to lever press for cocaine infusions (0.8 mg/kg). Once cocaine intake stabilized, rats were allowed to self-administer cocaine (0.4 mg/kg) under a fixed-ratio 1 (FR 1) schedule during three, 2 h short-access sessions. Subsequently, performance was briefly assessed under a progressive ratio (PR) schedule for 3 doses of cocaine (0.2, 0.8, and 3.2 mg/kg). Following PR testing, the cocaine dose was then changed to 0.4 mg/kg. Session length was then extended to 6 h for 21 days (extended access), and 0.4 mg/kg cocaine was available under a FR 1 schedule. After the 21-day extended access phase, responses and infusions under the short access FR and PR dose-response conditions were reassessed. The results indicated that HiI rats escalated cocaine-reinforced responding during the extended access condition, but LoI rats did not. HiI rats also earned significantly more infusions than LoI rats under the post-escalation short access FR condition. However, HiI and LoI rats did not differ under the pre- and post-extended access PR conditions. This study suggests that individual differences in impulsivity predict escalation of cocaine self-administration in female rats, which may have implications in the prediction of binge-like patterns of cocaine intake in women.     

Pretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose-effect function to the left under different schedules in the rat

This study tested the hypothesis that administration of the dopamine agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) shifts the cocaine self-administration dose-effect function to the left, rather than producing nonspecific effects or exclusively enhancing the rate-decreasing effects of high doses of cocaine. Under fixed-ratio or progressive-ratio schedules, rats were allowed to intravenously self-administer cocaine, 7-OH-DPAT, or a combination of cocaine and 7-OH-DPAT. In additional tests under fixed-ratio schedules, cocaine self-administration followed subcutaneous pretreatment with 7-OH-DPAT. Cocaine dose-effect functions were obtained by varying the unit dose of cocaine either between test sessions or within a single session. Intravenous 7-OH-DPAT (1-4μg) decreased self-administration of the training dose of cocaine (0.25mg) under a fixed-ratio schedule, but failed to shift the entire cocaine self-administration dose-effect function to the left under fixed-ratio or progressive-ratio schedules. 7-OH-DPAT alone maintained i.v. self-administration under these schedules, but produced a shallow self-administration dose-effect function, relative to cocaine, under the progressive-ratio schedule. In contrast to intravenous 7-OH-DPAT, s.c. pretreatment with 7-OH-DPAT (0.1-0.4mg/kg) not only decreased self-administration of the training dose of cocaine but also lowered the minimum effective dose of cocaine under fixed-ratio schedules, producing a shift to the left of the cocaine self-administration dose-effect function; these effects were independent of whether the dose of cocaine was varied between sessions or within a single session. Likewise under a multiple schedule, in which responding was maintained by cocaine and food in alternate components, s.c. pretreatment with 7-OH-DPAT increased self-administration of the dose of cocaine on the ascending limb of the dose-effect function and decreased self-administration of doses of cocaine on the descending limb, while uniformly decreasing responding for food. These observations suggest that pretreatment with 7-OH-DPAT enhances the reinforcing properties of cocaine rather than producing nonspecific effects or enhancing exclusively the rate-decreasing effects of high doses of self-administered cocaine.     

Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules

Rationale: Recent reports have indicated that the γ-aminobutyric acid (GABA)_B agonist baclofen attenuates the reinforcing effects of cocaine. Objectives: To further evaluate the effect of baclofen on cocaine self-administration under a fixed ratio (FR) and progressive ratio (PR) schedule of reinforcement. Methods: In the first series of experiments, three dose–response curves were generated that examined the effect of three doses of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) against four unit-injection doses of cocaine (0.19, 0.38, 0.75, and 1.5 mg/kg per injection) reinforced under a FR1 schedule. For comparison, an additional group of rats was pretreated with haloperidol (32, 56, or 100 μg/kg, i.p.). A separate experiment examined the effect of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) on responding for concurrently available cocaine or food reinforcement. Results: Under the FR1 schedule, baclofen suppressed intake of low but not high unit injection doses of cocaine. In contrast to haloperidol, baclofen had no effect on the distribution of inter-injection intervals and, instead, produced long pauses in cocaine self-administration. Baclofen dose dependently reduced cocaine- reinforced responding on a PR schedule; concurrent access to a food-reinforced lever demonstrated that the animals retained the capacity to respond at high rates. Conclusion: The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule. Received: 22 July 1999 / Final version: 23 September 1999     

Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats

Dopamine D3-preferring agonists are commonly used to treat Parkinson's disease and restless leg syndrome; however, laboratory animal studies suggest that they may possess a moderate abuse potential. These studies aimed to compare the highly selective, full D3 agonist PF-592,379 to the less selective D3 agonist 7-OH-DPAT, and the indirect dopamine agonist cocaine in drug self-administration and discrimination assays. Although rats readily acquired high rates of fixed ratio (FR)1 responding for cocaine, experimentally naive rats failed to acquire responding when 7-OH-DPAT or PF-592,379 was made available during an 18-session acquisition period. Cocaine also maintained dose-dependent levels of responding when available under a FR5 or a progressive ratio (PR) schedule of reinforcement. Although 7-OH-DPAT maintained modest levels of responding when substituted under a FR5, it failed to maintain significant levels of PR responding. PF-592,379 maintained saline-like rates of responding when substituted under FR5 or PR schedules of reinforcement. Similar behavioral profiles were observed in cocaine discrimination assays, with 7-OH-DPAT partially substituting for cocaine, and PF-592,379 producing saline-like effects over a wide range of doses. Together, the results of these studies predict that highly selective D3 agonists, such as PF-592,379, will have low abuse potential in humans.     

Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats

Rationale Previous studies have strongly implicated a role for GABA_B receptors in modulating the reinforcing effects of cocaine.Objective The purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABA_B receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement.Methods Rats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined.Results On a PR schedule, CGP7930 markedly decreased break points maintained by 1.5 mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5 mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30 mg/kg CGP7930, 3.0 mg/kg GS39783 and 2.5 mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs.Conclusions These findings suggest that positive allosteric modulators of the GABA_B receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.     

Effects of different food-reinforcement histories on cocaine self-administration by rhesus monkeys

The purpose of the present study was to examine whether a history of responding under food reinforcement schedules that generated either high or low response rates would influence the acquisition and maintenance of cocaine self-administration. Eight experimentally naive rhesus monkeys were initially trained to respond on the right lever under either a fixed-ratio (FR) 50 or interresponse times (IRT) > 30-s schedule of food reinforcement. After 65 sessions of food-maintained responding, monkeys were surgically prepared with indwelling intravenous catheters and cocaine 0.03 mg/kg per injection (IV) was available on the left lever under a fixed-interval (FI) 5-min schedule. After at least 60 consecutive sessions at this dose, a cocaine dose-response curve (saline, 0.01–0.3 mg/kg per injection) was determined. The FR 50 schedule generated high rates of food-maintained responding (90.1±6.2 responses/min), while response rates under the IRT >30-s schedule were low (1.9±0.1 responses/min). Across the 60 consecutive sessions under the FI 5-min schedule, linear changes in response rates and cocaine intake were significantly different between FR- and IRT-history monkeys. FR-history monkeys responded at higher rates than IRT-history subjects, while cocaine intake during the first 15 sessions was lower in FR- compared to IRT-history monkeys. Rates of cocaine-maintained responding after food-reinforcement histories were compared to response rates of monkeys initially trained to self-administer cocaine under an FI 5-min schedule (Nader and Reboussin 1994). Response rates were higher in this latter group compared to rates generated by either group of monkeys after food-reinforcement histories. Furthermore, a significant interaction between behavioral history and cocaine dose on response rates was observed. Results from the present study indicate that a history of responding maintained by a nondrug reinforcer can have significant and long-lasting effects on response rates and total cocaine intake under an FI schedule. Furthermore, these results indicate that prior experiences may produce different effects on acquisition and maintenance of cocaine self-administration.     

Disruption of learning by excitatory amino acid receptor antagonists

Compounds that act as competitive or uncompetitive N-methyl-D-aspartate (NMDA) antagonists, glycine/NMDA-site antagonists, or alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxalzolepropionic acid (AMPA)-receptor antagonists were evaluated for effects on a repeated acquisition of behavioral chains schedule by rats. Responding by rats was maintained by food presentation under a repeated acquisition or a performance procedure. Under the repeated acquisition procedure, subjects acquired a different three-response chain each daily session. Thus, each day a new learning curve could be generated for each animal thereby providing a repeated measure of learning. Food was presented under a second-order fixed-ratio three (FR3) schedule. Under the performance schedule rats responded under the same second-order FR3 schedule of food presentation: however, instead of a new sequence being presented each day, the same sequence of responding was required for each daily session. Both the competitive (CGS 19755) and uncompetitive (dizocilpine) NMDA antagonists distrupted repeated acquisition at doses that did not disrupt performance. In contrast, the glycine/NMDA antagonist MDL 104,653 or the competitive AMPA receptor antagonist LY 293558 did not disrupt acquisition or performance up to doses that suppressed responding. These results suggest there are different roles for various excitatory amino acid receptors, or sites on the NMDA receptor, in the neural bases of learning and that the disruption of acquisition by glutamate antagonists is dependent upon the particular receptor at which they have activity as well as the particular modulatory site of action.     

The GABA<Subscript>B</Subscript> antagonist CGP56433A attenuates the effect of baclofen on cocaine but not heroin self-administration in the rat

RATIONALE: Several reports have demonstrated that the gamma-aminobutyric acid (GABA)(B) agonist baclofen attenuates the reinforcing effects of cocaine in rats, and recent evidence indicates that it might have a similar effect on heroin self-administration. OBJECTIVES: The specific GABA(B) receptor antagonist CGP56433A was used to further evaluate the involvement of GABA(B) receptors in the baclofen-induced suppression of cocaine and heroin self-administration. METHODS: In the first series of experiments, dose-response curves were generated to examine the effect of CGP56433A (0.6, 1.0, or 1.8 mg/kg, i.p.) on cocaine (1.5 mg/kg per injection) and heroin (25 microg/kg per injection) self-administration reinforced under a fixed-ratio (FR1) or progressive ratio (PR) schedule. Separate sets of experiments then examined the effect of the co-administration of CGP56433A and baclofen on responding for cocaine or heroin under both schedules. RESULTS: Pretreatment with CGP56433A had no effect on cocaine or heroin self-administration, while baclofen dose dependently reduced responding for both cocaine and heroin under both the FR1 and PR schedule. CGP56433A (1.8 mg/kg) blocked the effect of baclofen on cocaine but not on heroin self-administration. CONCLUSION: The specific GABA(B) antagonist CGP56433A attenuated the effect of baclofen on cocaine self-administration, suggesting that GABA(B) receptors are critical in mediating the anti-cocaine effect of baclofen. In combination with other studies, the data demonstrate that the susceptibility of baclofen and other GABA(B) agonists to receptor blockade depends on the behavioral response being studied. Whether this indicates different receptor mechanisms are involved (e.g., pre- versus post-synaptic effects or differential receptor reserve) remains to be determined.     

The effects of behavioral history on cocaine self-administration by rhesus monkeys

The purpose of the present study was to examine whether a history of responding under schedules that generate either high or low response rates could modify previously established cocaine self-administration. Eight experimentally naive rhesus monkeys were trained to respond on one of two levers under a fixed-interval (FI) 5-min schedule of intravenous cocaine (0.03 mg/kg per injection) presentation. When responding was stable a cocaine dose-response curve (saline, 0.01–0.3 mg/kg per injection) was determined. Following completion of the dose-response curves, the monkeys were randomly assigned to one of two groups (n=4/group) and trained to respond on the other lever under either a fixed-ratio (FR) 50 or inter-response times (IRT) > 30-s schedule of cocaine (0.03 mg/kg per injection) presentation. After 65 sessions responding was again maintained under the FI5-min schedule of 0.03 mg/kg per injection cocaine for 60 sessions, followed by redetermination of the cocaine dose-response curve. During the initial exposure to the FI schedule, the mean rate of responding was 4.02 (± 0.33) responses/min and the cocaine dose-response curve was characterized as an inverted-U shape function of dose, with peak responding at 0.03 mg/kg per injection. The FR50 schedule generated high rates (66.80 ± 5.6 responses/min), while response rates under the IRT > 30-s schedule were low (2.62 ± 0.2 responses/min). Following different behavioral histories, response rates under the FI5-min schedule were significantly higher for 60 sessions in FR-history monkeys compared to IRT-history subjects. Compared to the initial FI baselines, cocaine intake (mg/kg per session) was significantly higher following an FR-history and significantly lower following training under an IRT schedule, for 60 consecutive sessions. In addition, there was a significant effect of behavioral history on the cocaine dose-response curve, such that descending limb was shifted farther to the right in FR-history subjects compared to IRT-history monkeys. Results from the present study indicate that previously established drug-seeking behavior can be modified by training under different reinforcement schedules. Knowledge of such historical variables may be important in understanding the determinants of drug self-administration.     

Effects of (+)-HA-966 and 7-chlorokynurenic acid on the kinetics of N-methyl-D-aspartate receptor agonist responses in rat cultured cortical neurons.

It has been suggested that one of the effects of glycine at the N-methyl-D-aspartate (NMDA) receptor complex is to reduce the amount of apparent receptor desensitization. Thus, blockade with a glycine site antagonist results in NMDA responses that show an increased amount of fade. In agreement with this, we found that antagonism of NMDA-evoked whole-cell currents by 7-chlorokynurenic acid (7-Cl-KYNA) indeed resulted in NMDA responses that displayed an increased amount of fade. However, those responses that were antagonized by (+)-HA-966 showed the opposite, i.e., less tendency to fade. On examination of these responses, it appeared that those produced in the presence of (+)-HA-966 were slower in onset and faster in offset than control responses recorded in the presence of glycine alone. Kinetic analysis of the on- and off-rates of NMDA- and glutamate-evoked NMDA receptor-mediated responses revealed that these were markedly affected by (+)-HA-966 but only slightly by 7-Cl-KYNA. The decrease of the glutamate response decay time constant and the increase of the response rise time constant produced by (+)-HA-966 indicated that it reduced the affinity of glutamate for its recognition site on the NMDA receptor by 5-fold. These results suggest that binding of (+)-HA-966 to the glycine site on the NMDA receptor complex produces an allosteric reduction in the affinity of agonists for the glutamate recognition site, whereas 7-Cl-KYNA has relatively little effect and, thus, acts more as a pure antagonist at the glycine site.