Effects on cocaine and food self-administration of (+)-HA-966, a partial agonist at the glycine/NMDA modulatory site, in rats

Rationale (+)-HA-966, a partial agonist at the glycine/NMDA modulatory site, significantly reduced IV cocaine self-administration in a fixed-ratio (FR) schedule. Since this effect was observed studying only one dose of cocaine and considering the characteristic bell-shaped curve generated by cocaine in self-administration studies under FR schedules, the precise nature of the effect is not clear.Objective To identify the nature of the effect of (+)-HA-966 on cocaine self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement.Methods Rats were prepared with IV catheters and trained to self-administer cocaine. In the first experiment three doses of (+)-HA-966 (10, 30 and 100 µg/5 µl ICV) were evaluated for their effects on 0.25 mg/0.1 ml per infusion cocaine self-administration on FR1 with 20-s time-out (TO). Next, 30 µg/5 µl ICV (+)-HA-966 was evaluated as pretreatment on a complete dose-response for cocaine self-administration. In a third experiment the effect of the same dose was evaluated on cocaine or food self-administered on the PR schedule.Results (+)-HA-966 at doses of 10 or 30 µg reduced cocaine self-administration in an FR1 schedule during the first hour interval of the 2-h session. This partial agonist at the glycine/NMDA modulatory site also reduced the number of injections of cocaine earned during the first hour of the session but not the final ratio reached under a PR schedule. However, under this schedule (+)-HA-966 also reduced operant responding for food reinforcement.Conclusions (+)-HA-966 reduced responding maintained by cocaine or food. Whether (+)-HA-966 induces a general motivational rather than a performance deficit, leading to reduced responding for either cocaine and food, is unclear.     

Exposure to mild stress enhances the reinforcing efficacy of intravenous heroin self-administration in rats

The effect of a mild footshock on intravenous heroin self-administration was examined in male rats. Animals in the stress condition were exposed to 10 min of intermittent footshock (0.5 mA; 0.5 s on, with a mean off period of 40 s) before each of four daily self-administration sessions. Animals in the control group were not exposed to footshock. Following acquisition of heroin-reinforced behavior (100 µg/kg per infusion), during which no group differences emerged, animals were placed on a progressive ratio schedule of reinforcement and were subsequently tested under a decreasing series of doses. Animals exposed to footshock before each drug session had higher rates of lever pressing for heroin and achieved higher final ratios on the progressive ratio schedule than animals in the control group at the higher doses of heroin. Thus, under the conditions of this experiment, exposture to mild intermittent stress appeared to enhance the reinforcing efficacy of heroin. The parameters of footshock used in the present study, and its relation to drug availability may characterize conditions under which stress leads to increased opioid abuse.     

A new progressive ratio schedule for support of morphine self-administration in opiate dependent rats

Rationale and objectives In preliminary studies, we observed that opiate dependent rats self-administered only a small number of morphine injections under a PR (progressive ratio) schedule developed to study psychostimulant self-administration. Therefore, a new schedule was developed to support morphine self-administration by incrementing response requirements in a relatively gradual manner. The present study compared morphine self-administration under a commonly used PR schedule to self-administration maintained by our modified PR schedule. Methods After pretreatment with non-contingent morphine, rats acquired self-administration under fixed-ratio (FR) schedules of intravenous morphine delivery. Morphine-maintained behavior was evaluated under a standard PR schedule (termed "PR3–4", because the third response requirement was four lever presses), and our modified PR schedule (termed "PR9–4", because the ninth response requirement was four lever presses). The PR9–4 schedule was also evaluated for self-administration of morphine doses of 0.001–3.2 mg/kg per injection. Results The number of ratios completed for morphine self-administration on the PR9–4 schedule, but not the PR3–4 schedule, exceeded values obtained during extinction. Dose-related increases in completed ratios occurred for morphine self-administration on the PR9–4 schedule, with stable patterns emerging after three sessions. A relatively flat dose-response relationship was observed, which did not increase monotonically with morphine dose. Morphine self-administration on the PR9–4 schedule decreased mean inter-injection interval and prolonged the duration of responding during 6-h sessions. Conclusions In the present study, a schedule that incremented response requirement gradually (PR9–4) supported reliable self-administration across a range of morphine doses.     

Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats

Rationale Recently, we provided evidence for a cannabinoid mechanism in relapse to cocaine seeking in rats. There is also increasing evidence for functional cross-talk between cannabinoid and opioid systems in several physiological processes. Objectives This study was designed to evaluate whether the cannabinoid system plays a role in mediating the reinforcing and motivational effects of heroin and heroin-paired stimuli. Methods Male Wistar rats were trained to self-administer heroin (50 μg/kg per infusion) on fixed (FR5) or progressive ratio schedules of reinforcement in the presence of a discriminative and discrete heroin-associated cue. The selective cannabinoid CB1 antagonist SR141716A was given 30 min before the session to determine its effect on responding for heroin. Separate groups of rats were subjected to extinction training during which heroin-associated cues were absent and no heroin was delivered. During subsequent reinstatement tests, the effects of the cannabinoid agonist HU210 and the antagonist SR141716A on reinstatement of heroin seeking were evaluated. Results The cannabinoid antagonist dose-dependently reduced responding for heroin on the FR5 schedule and to a greater extent on the progressive ratio schedule. HU210 (20 μg/kg) reinstated heroin seeking behaviour following a 2-week extinction period, whereas SR141716A dose-dependently attenuated heroin seeking that was provoked by a priming injection of heroin (0.25 mg/kg) and heroin seeking that was triggered by re-exposure to heroin paired stimuli. Conclusions The results show that the reinforcing and motivational effects of heroin and heroin-paired stimuli are mediated, at least in part, by activation of cannabinoid CB1 receptors. Therefore, the present study provides a rationale for the use of cannabinoid antagonists in the treatment of opiate addiction.     

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.     

Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin

The effect of intracerebral injections of 5,7-dihydroxy-tryptamine (5,7-DHT) on cocaine self-administration behavior was assessed. Rats were tested on a progressive ratio (PR) schedule for cocaine reinforcement. The first response on the lever each day produced an IV infusion of cocaine (0.6 mg/injection) after which the requirements of the schedule escalated with each reinforcement until the behavior extinguished. The final ratio completed was defined as the breaking point. Bilateral injections of 5,7-DHT into either the medial forebrain bundle (MFB) or amygdala (AMY) significantly increased the breaking points on the PR schedule compared to vehicle-injected control animals. We interpret these data to indicate that depletion of forebrain serotonin increases the incentive value of cocaine.     

Self administration of heroin and cocaine in morphine-dependent and morphine-withdrawn rhesus monkeys

Rationale  Dependence can develop during chronic opioid use, and the emergence of withdrawal might promote drug taking. Objective  This study examined how chronic morphine administration or withdrawal modified self administration of heroin or cocaine. Methods  Four monkeys responded under a fixed ratio 10 schedule to receive i.v. infusions of heroin (0.56–560 μg/kg/infusion) or cocaine (1–100 μg/kg/infusion). Monkeys received morphine twice daily; the final dose was 10 mg/kg/12 h. Dose–effect curves for heroin or cocaine were determined in 150-min sessions throughout morphine administration and during temporary suspension when withdrawal signs were also monitored. Heroin dose–effect curves and withdrawal signs were determined daily following termination of morphine administration. Results  Before monkeys received morphine, heroin, and cocaine maintained responding with unit doses of 1.78 μg/kg of heroin and 10 μg/kg/injection of cocaine resulting in, on average, 13.4 and 20.8 infusions, respectively. When monkeys received morphine daily, self administration of heroin and cocaine decreased to, on average, 3.1 and 11.3 infusions, respectively. Responding for heroin or cocaine recovered following temporary (17–53 h) suspension of morphine administration. The number of heroin infusions and total withdrawal signs increased when morphine administration was terminated. Withdrawal signs peaked 3–4 days after morphine; however, the number of infusions remained elevated for 8 weeks. Conclusions  Changes in self administration responding did not precisely covary with signs of withdrawal and responding for small doses of heroin persisted long after discontinuation of morphine, suggesting that non-pharmacologic (e.g., conditioned reinforcing) effects might contribute to the maintenance of lever pressing under these conditions. This work was supported by United States Public Health Service Grant DA05018 and Senior Scientist Award K05 DA17918 (CPF).     

Self-administration of cocaine and heroin combinations by rhesus monkeys responding under a progressive-ratio schedule

 The present study examined the reinforcing effects of cocaine and heroin, alone and combined, in rhesus monkeys (n=4) responding under a progressive-ratio (PR) schedule. The PR schedule consisted of five components, each made up of four trials (i.e., 20 trials total), with each trial in a component having the same response requirement. The initial response requirement was fixed-ratio (FR) 120, which doubled across components to a maximum of FR1920. A trial ended with an injection or the expiration of a 15-min limited hold and the inter-trial interval was 30 min. Cocaine dose-response functions (13–400 μg/kg per injection) for injections/session were monophasic, i.e., increased with dose until responding reached an asymptote or a peak. Heroin dose-response functions (1.6–100 μg/kg per injection) for injections/session were biphasic functions, i.e., increased to a peak and then decreased, whereas heroin dose-response functions for response rate were monophasic and reached an asymptote. When cocaine (1.6–200 μg/kg per injection) was combined with heroin (0.4–6.4 μg/kg per injection), low doses of cocaine (3.2–25 μg/kg per injection) and heroin (0.4–1.6 μg/kg per injection) that did not maintain behavior when tested alone did so when tested in combination. Combination with heroin resulted in a leftward shift in the cocaine dose-response functions, indicating that heroin increased the potency of cocaine as a reinforcer. This heroin-induced increase in cocaine′s reinforcing potency may be a contributing factor to abuse of cocaine and heroin combinations (i.e., ”speedballs”) in humans. However, maximum injections/session for cocaine combined with heroin were not different from cocaine alone, suggesting that the reinforcing efficacy of combinations of cocaine and heroin were not higher than that of cocaine alone. Received: 14 January 1997 / Final version: 25 March 1997     

Dopamine D(1) antagonist SCH23390 attenuates self-administration of both cocaine and fentanyl in rats

To investigate the role of dopamine D(1) receptors in the reinforcing effects of cocaine and fentanyl, the effect of the D(1) antagonist SCH23390 on intravenous self-administration of these drugs was investigated in rats using a progressive ratio (PR) reinforcement schedule, during which the rats received the first three injections under an FR1 schedule. Then the number of lever presses required to deliver an injection (lever press ratio) increased by three after every three further injections. The last lever press ratio completed by each rat during each 6 h session was designated the breaking point. Breaking point values increased dose-dependently during both cocaine (0.125-1.00 mg/kg per injection) and fentanyl (0.25-2.00 μg/kg per injection) self-administration. Pretreatment with SCH23390 (0.01 mg/kg, s.c.) decreased breaking point values for both cocaine and fentanyl, reflecting a decrease in the reinforcing efficacy of the drugs. To determine whether the effect of SCH23390 was due to general suppression of the lever pressing response, the effect of SCH23390 (0.01 mg/kg, s.c.) on the performance of rats maintained by water-reinforcement was examined. SCH23390 suppressed performance only transiently, therefore general suppression appears to have little or no effect on the breaking point. These results suggest that dopamine D(1) receptors are involved in mediating the reinforcing effects of both the psychostimulant cocaine and the opiate fentanyl.     

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

AIM: To characterize the patterns of resumption of drug-seeking induced by drug-related cues and the extent to drug-seeking controlled by these cues in rats after withdrawal. METHODS: Nosepoke responding by male rats was reinforced with intravenous heroin (0.05 mg/kg per infusion, 4 h session daily) under a PR schedule of reinforcement for 14 d. A green light in active nosepoke served as discriminative cue (DS). Each earned heroin injection was also paired with 5 s red light and a house light, the     

Comparison of the reinforcing effects of cocaine and cocaine/heroin combinations under progressive ratio and choice schedules in rats.

The co-use of cocaine and heroin is relatively common, with a growing clinical and preclinical literature dedicated to investigating the factors underlying the phenomenon. Specifically, several studies have compared the reinforcing effects of the coadministration of cocaine and heroin, referred to commonly as 'speedball', to either drug alone. The present study assessed whether addition of heroin to a wide range of cocaine doses produces reinforcing effects greater than cocaine alone using both a progressive ratio (PR) schedule and a choice procedure. Patterns of coadministration of cocaine and heroin offered simultaneously were also assessed using double-lumen cannulas. Under the PR schedule, speedball combinations across a range of doses (0.38-3.0 mg/kg/inf cocaine+1.5-48 microg/kg/inf heroin) did not support higher break points than cocaine alone. When cocaine and heroin were made available concurrently (ie on two separate levers), rats self-administered cocaine exclusively. Using a choice procedure, however, a preference was demonstrated for some speedball combinations (eg 0.18 mg/kg/inf cocaine+50 microg/kg/inf heroin; 0.38 mg/kg/inf cocaine+50 microg/kg/inf heroin) over cocaine alone (0.75 mg/kg/inf). So while results obtained using the PR schedule do not support the hypothesis that speedball combinations are more reinforcing than cocaine alone, data from the choice procedure do support this hypothesis. These apparently discrepant results demonstrate that these models are measuring different aspects of drug reinforcement, and suggest that choice procedures in rats provide a useful tool to study speedball self-administration.     

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     

The dopamine D2 partial agonist and antagonist terguride decreases heroin self-administration on fixed- and progressive-ratio schedules

Dopamine partial agonists have been suggested to be potential therapeutic candidates for pharmacological intervention in drug addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are hypothesized to behave as functional antagonists in conditions of high dopaminergic tone. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the dopamine D₂ receptor, on intravenous heroin self-administration on fixed- and progressive-ratio schedules of reinforcement. The effects of terguride on oral sweet solution (4% sucrose) self-administration on a fixed-ratio schedule were also tested. Terguride dose-dependently decreased heroin self-administration on the fixed-ratio schedule and decreased the maximum number of responses for heroin self-administration on a progressive-ratio schedule. In contrast, terguride did not significantly affect oral sucrose self-administration. These data suggest that terguride may represent a novel pharmacological strategy for the treatment of opiate addiction.     

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

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

The GABAB receptor agonist baclofen prevents heroin-induced reinstatement of heroin-seeking behavior in rats

Opiate addiction is a chronic relapsing disorder characterized by high rates of relapse. The gamma-aminobutyric acid GABA(B) receptor agonist baclofen is known to affect the reinforcing effects of several drugs of abuse, including heroin, as well as to decrease cue-maintained responding for heroin, cocaine and nicotine and suppress alcohol deprivation effect in rats. Here we studied the effect of baclofen on the reinstatement of extinguished heroin-seeking behavior triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin (30 microg/kg per infusion) under a continuous reinforcement schedule. Following extinction, the effect of non-contingent non-reinforced primings with heroin, baclofen or heroin/baclofen combination on the resumption of responding was evaluated. Results indicate that heroin priming (0.25mg/kg) promptly reinitiated heroin-seeking behavior, an effect dose-dependently reduced by baclofen at doses (0.625 and 1.25mg/kg) not affecting responding per sè. Importantly, baclofen did not affect locomotion either alone or in combination with heroin, dispelling any doubt as to the eliciting of possible non-specific (motor) effects. The present results show that GABA(B) receptor activation may reduce the propensity to resume drug-induced heroin-seeking behavior thus offering a possible approach in maintaining opiate abstinence.     

Opiate antagonists reduce cocaine but not nicotine self-administration

Rats were trained to self-administer cocaine in 1-h sessions on a fixed ratio 5 (FR5) schedule of reinforcement. Acquisition was carried out at a unit dose of 0.3 mg/kg and responding was then stabilized at cocaine doses of 0.1, 0.3, and 1.0 mg/kg/infusion. Pretreatments with naltrexone (0.1-10 mg/kg, SC) 20 min prior to the start of self-administration sessions resulted in decreases in cocaine self-administration at doses of 0.1 and 0.3 mg/kg/infusion, but not at 1.0 mg/kg/infusion. Decreases depended on the dose of naltrexone used, with greater decreases in self-administration occurring at higher antagonist doses. In addition, treatment with the opiate antagonist naloxone also reduced cocaine self-administration at a unit dose of 0.3 mg/kg. A group of rats trained to self-administer nicotine at a dose of 0.03 mg/kg/infusion on the same schedule of reinforcement was unaffected by naltrexone treatment. These results may indicate that an endogenous opiate system plays a role in cocaine reinforcement.     

Beta-funaltrexamine affects cocaine self-administration in rats responding on a progressive ratio schedule of reinforcement

Many studies have shown interactions between mu-opiates and the mesolimbic dopamine (DA) system. Mu-opiate receptor antagonists have been reported to either increase or decrease the rate of cocaine self-administration, and the interpretation of these data has been difficult. In an attempt to further characterize and localize the effect of opiate receptor blockade on the reinforcing effects of cocaine, the mu-opiate irreversible antagonist beta-funaltrexamine (betaFNA) was administered locally to different regions of the mesocorticolimbic system. Microinjection of betaFNA into the ventral tegmental area (VTA) or the nucleus accumbens (NAcc) had no effect on cocaine self-administration under a fixed ratio (FR) schedule of reinforcement. However, blockade of opiate receptors in both brain regions did attenuate responding for cocaine maintained by a progressive ratio (PR) schedule. Administration of betaFNA in the dorsal striatum had no effect under either schedule condition. The present findings suggest that endogenous opiate systems within the mesolimbic DA system modulate the reinforcing effects of cocaine; however, this modulation seems to be schedule dependent.     

Effects of drug history on the acquisition of responding maintained by GBR 12909 in rhesus monkeys

The reinforcing effects of cocaine have been associated with its actions at the dopamine reuptake site. Previous studies have shown that selective dopamine reuptake inhibitors can attenuate cocaine self-administration in animals, suggesting that they may serve as pharmacotherapeutic agents. In order to assess the potential reinforcing effects of one of these agents, the acquisition and maintenance of GBR 12909 self-administration were studied in different groups of rhesus monkeys (Macaca mulatta) that were either experimentally naive or experienced with respect to the self-administration of cocaine or GBR 12909. Lever-pressing was maintained under a multiple FR30 schedule with alternating components of either food or drug presentation. Experimentally naive monkeys failed to self-administer low doses of GBR 12909 (3–30 µg/kg per injection). However, after a history of cocaine self-administration, GBR 12909 (56 µg/kg per injection and then 30 µg/kg per injection) maintained numbers of drug deliveries similar to those maintained by cocaine. When another group of experimentally-naive monkeys was initially exposed to GBR 12909 self-administration, 56 µg/kg per injection failed to maintain responding. However, subsequent exposure to 100 µg/kg per injection established GBR 12909 self-administration, and high levels of responding were sustained later when the unit dose was decreased to 30 µg/kg per injection. In monkeys with prior experience with cocaine self-administration (75 sessions) unit doses of either 30 µg/kg per injection or 56 µg/kg per injection GBR 12909 maintained responding. In another group of monkeys with a more extensive history of cocaine self-administration (320 sessions), unit doses of either 10 µg/kg per injection or 30 µg/kg per injection GBR 12909 maintained responding. These results show that drug-maintained responding can be established with higher unit doses of GBR 12909. After exposure to these higher, more effective doses of GBR 12909, or effective doses of cocaine, lower doses of GBR 12909 are more likely to support drug-maintained responding.     

Chronic opiate treatment enhances both cocaine-reinforced and cocaine-seeking behaviors following opiate withdrawal

After chronic exposure to psychostimulants or opiates, self-administration or conditioned place preference with either class is increased (sensitized). Cross-sensitization of conditioned place preference, i.e., enhancement of psychostimulant-induced preferences after exposure to opiates, has also been described, but increases in cocaine self-administration after morphine pretreatment have not been reported. The present study evaluated effects of chronic morphine treatment on cocaine reinforcement. Opiate dependence was established in Wistar rats by administration of morphine as a constant infusion that was gradually increased to a dose of 50mg/kg per day over a 1-week period. Immediately after discontinuation of chronic morphine treatment, animals were allowed to acquire cocaine self-administration under a simple fixed-ratio schedule (FR-1), and were subsequently advanced to a progressive ratio schedule. Acquisition of cocaine self-administration under the FR-1 did not differ in saline- and morphine-pretreated animals. For cocaine self-administration under a progressive ratio schedule measured at 5 or more days after the onset of opiate withdrawal, chronic pretreatment with morphine increased the number of ratios completed, augmented final response requirements, and produced a more stable pattern of cocaine self-administration. Responding was also increased in morphine-pretreated animals during an initial extinction session. These results show that chronic opiate treatment can enhance both cocaine-reinforced and cocaine-seeking behaviors following opiate withdrawal. A similar effect may occur in human patients who discontinue methadone or other forms of replacement therapy for opiate abuse, and may contribute to relapse involving use of cocaine or other psychostimulants.     

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.