Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys

RATIONALE: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent DA uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine. In a previous study using a fixed-ratio 10 schedule, two chloro-analogs (3'-Cl-BZT and 4'-Cl-BZT) maintained i.v. self-administration in monkeys but appeared to be weak positive reinforcers. OBJECTIVES: The present experiments were designed to test the hypothesis that 3'-Cl-BZT and 4'-Cl-BZT are relatively weak reinforcers by evaluating reinforcing effects under increased response requirements. To examine further the effect of this halogen substitution on self-administration, 3',4"-diCl-BZT was also evaluated for reinforcing effects. METHODS: Four rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under a fixed-ratio 25 (FR25) schedule until stable responding was established. Saline, various doses of cocaine (0.003-0.2 mg/kg per injection), the BZT analogs (0.012-0.2 mg/kg per injection), GBR 12909 (0.012-0.2 mg/kg per injection), and compounds with known reinforcing effects (d-amphetamine, morphine, pentobarbital, ketamine) were then made available for self-administration. Various doses (0.01-0.3 mg/kg per injection) of the compounds that maintained self-administration under the FR schedule were then substituted for cocaine (0.1 mg/kg per injection) under progressive-ratio (PR) schedules. RESULTS: Reinforcing effects were evident under the FR schedule for 3'-Cl-BZT, 4'-Cl-BZT, GBR 12909, and the control compounds, but not by 3',4"-diCl-BZT. Results with the PR suggested that the rank order of these compounds for their effectiveness as reinforcers was cocaine > GBR 12909 > 3'-Cl-BZT = 4'-Cl-BZT > 3',4"-diCl-BZT. CONCLUSIONS: This study confirms and extends previous results suggesting that compounds with high DAT affinity can have strong, moderate, weak, or no effectiveness as reinforcers. The mechanisms that may underlie this variation in reinforcing effectiveness of these DAT ligands remain to be established.     

A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule

The dopamine reuptake inhibitor GBR 12909 and the dopamine releaser phentermine may have potential for the treatment of cocaine abuse in humans. Pre-session treatment with either drug can decrease cocaine-maintained responding in rhesus monkeys while not affecting food-maintained responding. Both drugs are self-administered, but in some reports the patterns of responding they maintain differ from typical cocaine-reinforced responding. This study compared self-administration of cocaine (1--100 microg/kg/inj), GBR 12909 (3--100 microg/kg/inj), and phentermine (10--170 microg/kg/inj) in rhesus monkeys on a progressive-ratio schedule. Individual unit doses of each drug were available across several consecutive sessions. Cocaine self-administration was typical: the average number of ratios completed per session was a bitonic (increasing/decreasing) function of unit dose. Phentermine self-administration was variable across subjects (two of four monkeys self-administered reliably); one subject exhibited clear signs of behavioral toxicity. Self-administration of GBR 12909 was similarly variable across subjects. In the two subjects that self-administered GBR 12909 reliably, self-administration of small to mid-sized unit doses was enhanced following exposure to large unit doses. These data indicate that differences in self-administration of these drugs can be observed under progressive ratio procedures. Further, the data add to existing evidence suggesting that phentermine and GBR 12909 have at least moderate potential to be abused by humans.     

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.     

Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior

Previous studies found that GBR 12909 can decrease cocaine-maintained responding at doses that do not affect food-maintained responding. In this study, the effects of GBR 12909 (0.3-3.0 mg/kg) were further examined by varying the response requirement and unit dose of cocaine. Rhesus monkeys earned food or cocaine under a multiple fixed-ratio (FR) schedule. The FR for food was always 30, but the FR for cocaine was varied from 10-130 and the unit dose was varied from 5.6-56.0 microg/kg per injection. Doses of GBR 12909 were tested in an ascending order, for 5 consecutive sessions each. GBR 12909 selectively decreased cocaine-maintained responding in all monkeys in at least 1 condition. These effects were enhanced with large response requirements and/or small unit doses. The results demonstrate that environmental variables can influence the selectivity of GBR 12909's effects and contribute to a growing debate concerning the evaluation of potential pharmacotherapies for drug abuse.     

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.     

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).     

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.     

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.     

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.     

Escalation of intravenous cocaine self-administration,progressive-ratio performance,and reinstatement in rats selectively bred for high (HiS) and low (LoS) saccharin intake

Rationale Rats selectively bred for high saccharin (HiS) intake consume more alcohol and acquire intravenous (IV) cocaine self-administration more rapidly than their low saccharin (LoS) consuming counterparts.Objectives The purpose of the present study was to determine whether HiS and LoS rats also differ in the escalation, maintenance, and reinstatement of IV cocaine self-administration.Methods LoS and HiS female rats were allowed to self-administer cocaine [0.4 mg/kg; fixed ratio (FR) 1] under short (ShA, 2 h per day) or long (LgA, 12 h per day) access conditions for 21 days. Session lengths were subsequently equated (2 h) and (1) FR1-maintained cocaine (0.4 mg/kg) self-administration, (2) progressive ratio (PR)-maintained cocaine (0.2–1.6 mg/kg) self-administration, and (3) saline-induced and cocaine (10 mg/kg, IP)-induced reinstatement of drug-seeking behavior were examined.Results HiS LgA rats escalated their cocaine intake more rapidly and self-administered more cocaine (mg/kg) than LoS LgA rats; however, there was no LoS versus HiS phenotype difference in the number of infusions self-administered by Day 21. Post-escalation cocaine self-administration under an FR1 schedule did not differ as a function of phenotype (LoS versus HiS) or access condition (ShA versus LgA); however, LoS rats responded more for cocaine under the PR schedule than HiS rats, and they showed a greater reinstatement of cocaine-seeking behavior than HiS rats. In contrast, ShA versus LgA did not affect PR or reinstatement performance in the LoS and HiS groups.Conclusions These results suggest that LoS and HiS rats have distinct drug-seeking and drug-taking profiles that differ as a function of the experimental phase and access condition. The LoS and HiS rats differ along a wide range of behavioral dimensions and represent an important model to study the interactions of feeding, emotionality, and other factors related to vulnerability to drug abuse.An erratum to this article can be found at     

Sex differences in the acquisition of IV methamphetamine self-administration and subsequent maintenance under a progressive ratio schedule in rats

Rationale Previous work indicates that female rats initiate cocaine use sooner than male rats and reach significantly higher break points (BPs) for a single injection of cocaine under a progressive ratio (PR) schedule compared to male rats.Objectives The present study extends previous work examining sex differences to the acquisition of methamphetamine (METH) (0.02 mg/kg) and maintenance of METH-maintained responding under a PR schedule.Methods An automated priming procedure that has previously been shown to be sensitive to sex differences was used for the acquisition of drug self-administration. A PR schedule that has been shown to be sensitive in detecting sex differences in maintenance levels of cocaine-reinforced responding was used for the maintenance phase of the experiment.Results A greater percentage of female rats met the acquisition criterion for METH (0.02 mg/kg) self-administration compared to male rats (55.6% versus 11.1%, respectively), and they did so at a significantly faster rate. Under stable fixed-ratio 1 (FR1) conditions (after acquisition and 5 days before the PR schedule) female rats responded for significantly more METH (0.02 mg/kg) infusions compared to males. Dose-response curves obtained under the PR schedule during maintenance indicated that female rats self-administered significantly more METH infusions compared to male rats.Conclusions These data suggest that female rats are more vulnerable to the acquisition of METH self-administration, and they are more motivated to self-administer METH compared to male rats under a PR schedule during the maintenance phase.     

Progressive ratio and fixed ratio schedules of cocaine-maintained responding in baboons

Responding maintained under progressive ratio (PR) and fixed ratio (FR 160) schedules of IV saline or cocaine (0.01–4.0 mg/kg) injections was studied in baboons. Each injection was followed by a time-out period which was 3-h with the PR schedule and was either 3 or 12 h with the FR schedule. On the PR schedule the ratio requirement was systematically increased each day until reaching the breaking point at which self-injection performance fell below a criterion level (one or zero injections per day). Overall response rates on the PR schedule increased with progressive increases in the ratio until a maximum at which an abrupt reduction in responding occurred. With the 3-h time-out the dose-breaking point function on the PR schedule was similar to the dose-response rate function on the FR schedule. These dose-effect functions were inverted U-shaped curves characterized by a graded ascending limb (0.01–0.32 mg/kg) and a downturn at the highest doses (3.0–4.0 mg/kg). On the FR schedule the downturn in the dose-response rate function was attributable to a cumulative drug effect as revealed by manipulation of time-out duration and analysis of sequential interresponse time distributions and cumulative response records. PR and FR schedules provide similar information about the relative reinforcing efficacy of different cocaine doses.Portions of the results with the progressive-ratio schedule have been described previously (Griffiths et al., 1978a)     

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     

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.     

Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure

Frequency of drug access greatly affects the pattern and stability of cocaine self-administration. Previous research has shown that restricted drug availability produces remarkably consistent levels of daily cocaine intake, whereas increased or unlimited access produces more variable patterns of self-administration that may change over time. In the present study we used a discrete trials (DT) procedure to document how levels of access affect the pattern of cocaine intake. Rats that had been implanted with a chronically indwelling jugular cannula and trained to self-administer cocaine on an FR1 schedule were given access to cocaine during 10-min DT that were initiated throughout the day/night cycle for 21 days. Frequency of access (2, 3, 4 or 5 trials/h; 1.5 mg/kg/inj) and dose (1.0, 1.5, 2.0 and 2.5 mg/kg/inj, 3 trials/h) were investigated in separate groups of rats. When rats were presented with two or three trials an hour (1.5 mg/kg/inj), a highly regular and circadian pattern of intake was observed across weeks. Increasing the number of trials or increasing the unit dose resulted in a significant increase in average daily cocaine intake. Access to higher dose or higher frequency conditions produced a sustained drug-taking binge during the first few days on the schedule. Rats given access to five trials per hour typically responded at every opportunity for more than 48 h, then stabilized within a range of 80-100 mg/kg/day for the remainder of the experiment. To assess whether such high levels of cocaine intake had altered the motivation to respond, cocaine reinforced break-points were assessed on a progressive ratio schedule (0.32, 1.5 and 3.0 mg/kg/inj) in separate groups of animals before and 24 h after 5 days access on the DT procedure (5 trial/h). Sustained exposure to high levels of cocaine produced a shift in the dose-response curve to the right indicating tolerance to the reinforcing effects. This DT procedure provides a method to examine the behavioral and neurochemical effects of high cocaine intake over extended periods without toxicity.     

Modification of behavioral effects of cocaine by selective serotonin and dopamine uptake inhibitors in squirrel monkeys

Modification of the behavioral effects of cocaine by the selective serotonin (5-HT) uptake inhibitors citalopram and fluoxetine and the selective dopamine (DA) uptake inhibitor GBR 12909 was investigated in squirrel monkeys trained under a fixed-interval schedule of reinforcement or a two-lever cocaine-discrimination procedure. Under the fixed-interval schedule cocaine (0.03–1.78 mg/kg) produced dose-related increases in response rate, reaching an average maximum of 215% of control after a dose of 0.3 mg/kg. Similar rate-increasing effects were seen with GBR 12909 (3.0 or 10.0 mg/kg), but not citalopram (10.0 or 17.8 mg/kg) or fluoxetine (10.0 mg/kg). Pretreatment with citalopram or fluoxetine attenuated the rate-increasing effects of cocaine and produced an overall downward shift in the cocaine dose-response function. Pretreatment with GBR 12909, on the other hand, produced an overall leftward shift in the cocaine dose-response function. Under the drug-discrimination procedure cocaine (0.03–1.78 mg/kg) engendered dose-related increases in the percentage of cocaine-appropriate responses, as did GBR 12909 (1.0–17.8 mg/kg) but not citalopram (1.0–17.8 mg/kg). Pretreatment with citalopram attenuated the discriminative stimulus effects of cocaine and produced an overall rightward shift in the cocaine dose-response function, whereas pretreatment with GBR 12909 produced an overall leftward shift in the cocaine dose-response function. The results show that selective 5-HT and DA uptake inhibitors can modify the rate-altering and discriminative stimulus effects of cocaine in qualitatively different ways and suggest a modulatory role for 5-HT uptake inhibition in the behavioral effects of cocaine.     

Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in a D1 dopamine receptor dependent manner.

The effect of previous exposure to amphetamine (AMPH) in the ventral tegmental area (VTA) on the subsequent self-administration of cocaine was assessed. Rats in different groups were pre-exposed to three injections into the VTA of either saline (0.5 microl/side) or AMPH (2.5 microg/0.5 microl/side). Injections were given once every third day. Starting 7-10 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) under fixed ratio 1 and 2 (FR1 and FR2) schedules and then tested under a progressive ratio (PR) schedule of reinforcement for six consecutive days. No differences between groups were observed during self-administration training under the FR schedules of reinforcement. However, when tested under the PR schedule, VTA AMPH pre-exposed rats worked more and, as a result, obtained more infusions of cocaine than saline pre-exposed rats. Rats in a separate group pre-exposed to VTA AMPH but co-infused with the D(1)-like dopamine (DA) receptor antagonist SCH23390 (0.25 microg/0.5 microl/side) did not show enhanced cocaine self-administration. These rats, as well as others pre-exposed to VTA SCH23390 alone showed levels of cocaine self-administration similar to saline pre-exposed rats. Thus, in a manner paralleling the sensitization of AMPH-induced locomotion and nucleus accumbens DA overflow, previous exposure to AMPH in the VTA leads to enhanced intravenous self-administration of cocaine and activation of D(1) DA receptors in this site during pre-exposure is necessary for the production of this effect.     

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.     

Effects of estradiol on cocaine self-administration and cocaine discrimination by female rhesus monkeys.

The ovarian steroid hormone, estradiol, enhances the reinforcing and locomotor activating effects of cocaine in rodents under some conditions. The present study evaluated the acute effects of estradiol benzoate (E(2)beta) on cocaine self-administration and cocaine discrimination in female rhesus monkeys. Cocaine self-administration (0.10 mg/kg/inj., i.v.) was maintained on a fixed-ratio (FR) 30 schedule of reinforcement, and monkeys had access to cocaine during one 2-h session each day. E(2)beta in a cyclodextrin vehicle (0.00001-0.01 mg/kg, i.m.) was administered 30 min before test sessions conducted twice each week. Cocaine doses were administered in an irregular order during each dose-effect curve determination (0.001-0.3 mg/kg/inj.). Blood samples were collected after test sessions to determine 17beta-estradiol levels. Banana-flavored food pellets were available on an FR 30 schedule in three 1-h sessions each day. Five monkeys were trained to discriminate cocaine (0.18 mg/kg, i.m.) from saline in a two-key food-reinforced procedure, and the effects of pretreatment with E(2)beta in cyclodextrin and in sesame oil were studied. Acute administration of E(2)beta did not consistently alter the cocaine self-administration or drug discrimination dose-effect curves in comparison to saline control treatment. Females also did not self-administer E(2)beta (0.00001-0.10 mg/kg, i.v.) above saline levels. Finally, E(2)beta (0.0001-0.01 mg/kg, i.m.) did not substitute for cocaine in monkeys trained to discriminate cocaine from saline. Taken together, these data suggest that over the dose range studied, estradiol administration does not consistently alter the abuse-related effects of cocaine in female rhesus monkeys.     

Medication-related pharmacological manipulations of nicotine self-administration in the rat maintained on fixed- and progressive-ratio schedules of reinforcement

Rationale  The use of animal models to study existing medications for smoking cessation can elucidate the mechanism(s) of action of cessation agents and further validate the models for medication development. Objective  The objective of the study was to evaluate the response of nicotine self-administration (NSA) to pharmacological agents related to the smoking cessation medication bupropion and to nicotine dosing mimicking nicotine replacement on fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. Materials and methods  NSA was maintained at a nicotine dose of 30 μg/kg/infusion i.v. in rats trained on FR5 and PR40% schedules. Pharmacological manipulations related to bupropion were examined by treating animals with a dopamine reuptake inhibitor [GBR 12909 (GBR)], a norepinephrine reuptake inhibitor [nisoxetine (NIS)], and a nicotinic antagonist [dihydro-β-erythroidine (DHβE)]. The effect of nicotine replacement was examined on the PR schedule by chronic dosing with osmotic minipumps. Results  Significant treatment effects occurred with NIS and combinations of NIS–DHβE and with GBR on response rates. Chronic nicotine dosing reduced self-administration. The two schedules yielded different results with some treatments. Conclusions  Noradrenergic–nicotinic cholinergic interactions and enhanced responding consequent to dopamine reuptake inhibition may be part of the complex behavioral pharmacology of bupropion-like compounds. Observation of differential results with the two schedules has implication for the use of self-administration techniques to elaborate the mechanisms of dependence as well as drug discovery.