Chlordiazepoxide alters intravenous cocaine self-administration in rats

This investigation was designed to examine the effects of benzodiazepines on intravenous cocaine self-administration in rats. Pretreatment with low doses of the benzodiazepine receptor agonist, chlordiazepoxide (0.3 to 1.0 mg/kg, IP), resulted in small but nonsignificant increases in drug intake with 0.5 mg/kg cocaine, while higher doses (10 mg/kg, IP) significantly decreased drug intake in all rats tested. The effects of chlordiazepoxide on self-administration were attenuated when the concentration of cocaine was increased to 1.0 mg/kg, suggesting that chlordiazepoxide was opposing rather than augmenting the pharmacological actions of cocaine. Pretreatment with the benzodiazepine receptor antagonist, Ro 15-1788 (1.0 to 10 mg/kg, IP), had no effect on self-administration, suggesting that the reinforcing properties of cocaine do not result from direct interactions with benzodiazepine receptors. The result of this investigation demonstrate that chlordiazepoxide alters intravenous cocaine self-administration in rats. Although additional research will be necessary to confirm these data, the results of this investigation suggest that chlordiazepoxide may decrease the reinforcing efficacy of cocaine through indirect actions on dopaminergic neuronal activity potentially mediated through GABAergic mechanisms via benzodiazepine receptor activation.     

Effects of memantine, haloperidol, and cocaine on primary and conditioned reinforcement associated with cocaine in rhesus monkeys

Rationale The N-methyl-d-aspartate (NMDA) receptor has been implicated in mediating the reinforcing effects of abused drugs. Some reports indicate the uncompetitive NMDA antagonist, memantine, modulates the conditioned and unconditioned effects of stimulants in rats. Objective The objective of this study was to evaluate the effects of memantine on the primary and conditioned reinforcing effects of cocaine in the rhesus monkey. Methods Rhesus monkeys were trained to press levers reinforced with either cocaine-associated stimuli (brief stimuli, BS) or 30-μg/kg cocaine infusion during daily, 75-min experimental sessions in which the reinforcers were independently available in separate components according to identical progressive ratio (PR) schedules. Memantine (0.3–10 mg/kg), and as comparators, haloperidol (0.001–0.1 mg/kg) and cocaine (0.01–1 mg/kg), were administered 5 min before experimental sessions. Results Memantine (0.3–3 mg/kg) produced decreases in responding maintained by BS presentations at some doses which failed to affect cocaine self-administration when measured during equivalent periods early in the experimental session. Memantine (3 mg/kg) increased cocaine self-administration, however, later in the session. A low dose of haloperidol (0.001 mg/kg) increased the number of BS presentations, whereas higher doses decreased their number. Cocaine self-administration was not significantly affected by haloperidol until a behaviorally suppressant dose (0.1 mg/kg) was administered. Pretreatment with high doses of cocaine (0.3 and 1 mg/kg) decreased responding maintained by both reinforcers. Conclusion These results suggest that while memantine may attenuate the conditioned reinforcing effects of cocaine-associated stimuli, it may also occasion increase levels of cocaine self-administration. These findings support the hypothesis that the NMDA receptor can play a role in modulating the conditioned and primary reinforcing effects of cocaine.     

Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats.

Treatment of attention deficit hyperactivity disorder with the psychostimulant drug methylphenidate (MP) has increased dramatically among schoolchildren. We tested whether repeated exposure to moderate doses of MP (5 and 10 mg/kg IP for 5 or 7 days) in adolescent rats increased reactivity to cocaine measured by motor responses (ambulations and rearing) to a cocaine challenge in adulthood. We later tested whether repeated exposure to a low dose of MP (2 mg/kg IP for 7 days) enhanced the psychomotor effects of cocaine, measured by different challenge doses (0-30 mg/kg) as well as to the reinforcing effects of cocaine, measured by self-administration of low-dose infusion (75 microg/kg, IV). We found that exposure to moderate doses of MP enhanced psychomotor responses to cocaine but exposure to a low dose only increased cocaine self-administration. These results suggest that adolescent exposure to low doses of MP in rats may increase the incentive value of low reinforcers, thereby rendering adult rats more susceptible to cocaine self-administration.     

Effects of haloperidol and physostigmine on self-administration of local anesthetics

Four rhesus monkeys were maintained under a FR 10 schedule of cocaine (0.1 mg/kg) or procaine (0.4 or 1.6 mg/kg) delivery. Haloperidol (0.01–0.08 mg/kg), physostigmine (0.0125–0.1 mg/kg) or saline treatments were administered prior to sessions in which responding was maintained by each of these drugs. Haloperidol produced dose-related increases in the self-administration of cocaine and dose-related decreases in the self-administration of both doses of procaine. Physostigmine produced dose-related decreases in the self-administration of both cocaine and procaine. These results suggest that the reinforcing properties of cocaine are specifically modified by drugs which interact with catecholamines. On the other hand, it seems unlikely that the reinforcing properties of procaine are mediated by the same mechanism. While the results of this experiment indicate that cholinergic mechanisms may not play a major role in mediating the reinforcing properties of either drug, additional studies with other cholinergic agonists and particulary antagonists as well as additional procedures are needed.     

Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys.

The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n=7) were trained to self-administer cocaine (0.03-0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03-0.3 mg/kg) or haloperidol (0.01-0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01-0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused dose-related decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine self-administration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n=3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The results indicate that olanzapine can effectively suppress cocaine self-administration behavior in nonhuman primates at doses that enhance dopamine release but do not maintain drug self-administration.     

Cocaine-induced place conditioning: importance of route of administration and other procedural variables

It has been shown that pretreatment with dopamine (DA) receptor blockers disrupts the effect of intravenously (IV) and intracerebrally (ICV), but not intraperitoneally (IP) administered cocaine on place preference conditioning (PPC). The present study was undertaken to further evaluate possible differences between IV and IP cocaine PPC. To this end, several factors which may differentially influence IV and IP cocaine PPC were examined. Firstly, dose-response effects were studied. Intravenous cocaine produced PPC within a narrow dose range (0.5–2.5 mg/kg). Animals receiving IV injections of 5 and 10 mg/kg cocaine experienced convulsions and did not show PPC. For IP cocaine a 10-fold increase in dose (10 mg/kg) and twice the number of training trials was required in order to obtain PPC equal in magnitude to that with IV cocaine (0.5 mg/kg; two trials). Cocaine PPC was retained at least 1 month. Following IV cocaine preference developed for the side associated with the drug regardless of whether the conditioning was to the least or most preferred side. After IP cocaine, preference developed for the drug side only when the drug was paired with the least preferred side. Rats trained with IV, but not IP, cocaine significantly preferred the drug familiar side to a novel compartment. Preference for the IV or IP cocaine side developed regardless of whether testing was carried out in the drugged or undrugged state, excluding possible state-dependent effects as an explanation of the cocaine PPC. The results show PPC procedure to be a valid test for evaluating rewarding properties of IV cocaine. However, they fail to show rewarding effects of IP cocaine.     

Self-administration of GBR 12909 on a fixed ratio and progressive ratio schedule in rats

Intravenous self-administration of GBR 12909, an indirect dopamine agonist, was examined on a Fixed Ratio (FR 1) and a Progressive Ratio (PR) schedule of reinforcement in rats. Subjects were first trained to self-administer cocaine (1.5 mg/kg/inj) during daily 5 h sessions, after which GBR 12909 (0.187–1.5 mg/kg/inj) was substituted. On the FR 1 schedule, the inter-infusion interval for GBR 12909 self-administration was directly related to dose and was approximately three times longer than that established for equivalent doses of cocaine. Breaking points on the PR schedule were comparable for GBR 12909 and cocaine self-administration. The data indicate that, compared to cocaine, GBR 12909 has a longer duration of action and a similar reinforcing efficacy.     

Acquisition of lever pressing for cocaine in C57BL/6J mice: effects of prior Pavlovian conditioning

The purpose of this study was to determine (1) if C57BL/6J (C57) mice would lever-press for intravenous cocaine infusions in a limited-access paradigm without previously establishing the instrumental response with natural reinforcers and (2) if prior Pavlovian conditioning of cocaine to the response contingent stimulus complex used in the cocaine self-administration sessions would facilitate acquisition of lever responding for cocaine. After implanting jugular catheters, some mice received Pavlovian conditioning during which 12 passive cocaine infusions (0.1 or 1 mg/kg unit doses) were paired with the tone/light/pump sound stimulus complex used in the self-administration sessions. The remaining mice simply began the cocaine self-administration sessions for 0.1 or 1 mg/kg unit doses of cocaine. Twenty-seven of the 33 mice with patent catheters acquired stable lever responding within an average of 5 to 6 days without previously establishing the instrumental response with natural rewards. Prior Pavlovian pairing of cocaine with the response contingent stimulus complex used in the self-administration sessions did not influence the acquisition of cocaine self-administration at the highest cocaine dose (1 mg/kg). This conditioning procedure using the low cocaine dose (0.1 mg/kg/infusion) reduced the number of mice acquiring cocaine self-administration to 50%, and the number of mice developing stable response patterns was only 25%. The results establish that C57 mice can acquire cocaine self-administration over several unit doses in a limited-access paradigm without previously establishing the instrumental response with natural reinforcers. Furthermore, prior pairing of response contingent cues with cocaine via Pavlovian conditioning did not facilitate the acquisition of cocaine self-administration.     

Evaluation of the role of norepinephrine in the reinforcing effects of psychomotor stimulants in rhesus monkeys

Rhesus monkeys were surgically prepared with intravenous catheters and allowed to self-administer cocaine (0.03-0.1 mg/kg/injection) under a fixed-ratio 10 schedule of drug delivery during daily 2-hour experimental sessions. When responding was stable for cocaine, saline or various doses of nisoxetine, a selective norepinephrine (NE) reuptake blocker, was substituted for cocaine for 5-7 consecutive sessions. Nisoxetine failed to maintain self-administration responding at any dose in 3 of 4 monkeys tested. Pre-session administration of the selective alpha 1 NE receptor blocker prazosin (0.2-1.6 mg/kg, IV, 15 minutes pre-session) did not systematically alter cocaine self-administration in any monkey. The results are in contrast to what has been found with DA agonists and antagonists and are consistent with the belief that NE does not play a primary role in the reinforcing properties of psychomotor stimulants.     

Diurnal patterns of cocaine and heroin self-administration in rhesus monkeys responding under a schedule of multiple daily sessions

A number of non-pharmacological factors have been shown to influence drug self-administration in experimental animals. This report examines diurnal changes in drug self-administration by rhesus monkeys trained to self-administer food (1gm fruit-flavored pellets) and cocaine (0.01 or 0.032mg/kg/injection) under a second order FR4 (VR16:S) schedule during four daily food and drug self-administration sessions. Saline, different unit doses of cocaine (0.001-0.1mg/kg/injection) or different unit doses of heroin (0.0001-0.01mg/kg/injection) were substituted for the maintenance dose of cocaine during drug sessions. Dose-effect curves relating unit dose of cocaine or heroin to the number of injections per session displayed an inverted U-shape during each of the four daily drug sessions. When 0.032mg/kg/injection cocaine or 0.0032mg/kg/injection heroin were available, monkeys usually self-administered the maximum number of injections during all four drug sessions. Substitution of saline or lower unit doses of cocaine (0.001-0.01mg/kg/injection) or heroin (0.0001-0.001mg/kg/injection) decreased the number of injections/session; however, these decreases were consistently greater during the evening (20.00-21.00h) and morning (07.00-08.00h) sessions than during the afternoon sessions (12.00-13.00h and 16.00-17.00h). As a result, the ascending limbs of the cocaine and heroin dose-effect curves for the evening and morning sessions were shifted to the right of the ascending limbs of the dose-effect curves for the afternoon sessions. Moreover, when saline was substituted for cocaine for only two sessions per day, drug self-administration decreased more during the evening and morning sessions even when the cocaine was available during those sessions. These findings suggest a diurnal variation in cocaine and heroin self-administration. Specifically, drug self-administration during the evening and morning sessions appears to be more sensitive to a decrease in reinforcer magnitude than responding during the afternoon sessions. These findings confirm and extend previous reports of the influence of non-pharmacological factors on drug self-administration.     

Effects of Extended Cocaine Access and Cocaine Withdrawal on Choice Between Cocaine and Food in Rhesus Monkeys

Chronic drug use may lead to sufficient drug intake to produce dependence and the emergence of abstinence signs during withdrawal. Although withdrawal can increase the reinforcing effects of some drugs (eg opioids), the impact of withdrawal on the reinforcing effects of stimulants like cocaine is less clear. This study used a novel cocaine vs food choice procedure to examine the relative reinforcing strength of cocaine before, during, and after exposure to graded levels of extended cocaine access. Responding in four rhesus monkeys was maintained by cocaine (0–0.1 mg/kg/injection) and food delivery under a concurrent-choice schedule during daily 2-h sessions. Under baseline conditions, cocaine maintained a dose-dependent increase in cocaine choice. Subsequently, subjects were exposed to and withdrawn from periods of extended cocaine access, which was accomplished by implementing daily 21-h supplemental sessions of cocaine self-administration in addition to daily choice sessions. During supplemental sessions, cocaine (0.1 mg/kg/injection) was available under a fixed-ratio 10/time-out X schedule, and the duration of the time-out was varied from 30 to 7.5 min. Cocaine intake increased 10-fold to >11 mg/kg/day during exposure to supplemental sessions with the shortest post-injection time-out. However, parameters of cocaine choice were not significantly affected either during or after extended cocaine access. These results do not support the hypothesis that cocaine withdrawal increases the reinforcing strength of cocaine. This differs from results with the opioid agonist heroin and suggests that withdrawal may have different functions in the maintenance of opioid and stimulant abuse.     

GR38032F, a serotonin 5-HT3 antagonist, fails to alter cocaine self-administration in rats.

Recent data have supported a role for serotonin (5-HT) in the self-administration of cocaine by laboratory rats. More specifically, it has been suggested that 5-HT3 receptor antagonists may be useful in the treatment of drug abuse. To assess this possibility, we compared the effects of the 5-HT3 antagonist, GR38032F, with the dopamine D2 receptor blocker, haloperidol, on the intravenous self-administration of cocaine (0.5 mg/kg/infusion) in rats. The serotonin antagonist (0.01, 0.1 or 1.0 mg/kg, IP) failed to alter self-administration (0.5 mg/kg/infusion). In contrast, haloperidol (0.125 mg/kg, IP) increased responding for cocaine (0.5 mg/kg/infusion), and shifted the dose-response curve for cocaine self-administration to the right. These data fail to support a role for the serotonin 5-HT3 receptor system in the reinforcing properties of this psychostimulant. Rather, the 5-HT1 or 5-HT2 receptors may be the critical subtype.     

A comparison of the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") with cocaine in rhesus monkeys

The purpose of the present study was to compare the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to cocaine. Rhesus monkeys (n=4) responded under a within-session, exponentially increasing, progressive-ratio (PR) schedule of cocaine reinforcement. Breaking point (BP) for the PR schedule was defined as the final response requirement completed before 2 h had elapsed without an injection delivered. Saline and doses of cocaine (0.003-0.3 mg/kg/injection) and MDMA (0.01-0.56 mg/kg/injection) were substituted for the training dose of cocaine for at least five consecutive sessions. Both cocaine and MDMA functioned as reinforcers, but self-administration of MDMA occurred at fewer doses and a significantly lower peak BP was obtained for MDMA. These data demonstrate that MDMA functions as a reinforcer, although its reinforcing efficacy appears to be less than that of cocaine.     

Systemic pretreatment with MK-801 (dizocilpine) increases breaking points for self-administration of cocaine on a progressive-ratio schedule in rats

 The effects of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, on cocaine self-administration were investigated. Forty-six male Wistar rats were trained to intravenously self-administer four unit doses of cocaine (0.19, 0.38, 0.75 and 1.5 mg/kg per injection) on a progressive-ratio schedule of reinforcement. The effects of increasing doses of MK-801 (0.05, 0.1, 0.15 and 0.2 mg/kg, IP, 30 min before test sessions) on breaking point (BP) for cocaine self-administration were investigated. The results showed that pretreatment with MK-801 produced effects on cocaine BPs that fit on an inverted-U function. That is, the 0.05 and 0.1 mg/kg doses of MK-801 produced no effect or a small enhancement of BPs across all doses of cocaine, respectively. The 0.15 mg/kg dose of MK-801 produced a significant treatment effect characterized by increased BPs, relative to baseline BPs, across all doses of cocaine. The 0.2 mg/kg dose of MK-801 produced a nonsignificant decrease in BPs across most doses of cocaine. The dose-dependent effects on cocaine BPs after pretreatment with MK-801 suggest that MK-801 can potentiate, and at higher doses attenuate, the rewarding effects of self-administered cocaine. Received: 3 January 1996 / Final version: 12 June 1996     

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.     

The pharmacokinetic determinants of the frequency and pattern of intravenous cocaine self-administration in rats by pharmacokinetic modeling.

We investigated the pharmacokinetic determinants of the frequency of intravenous cocaine self-administration in 2.5-h sessions. Two groups of rats were implanted with dual catheters that permitted cocaine infusion and blood sampling via the femoral and jugular vein catheters, respectively. Half of the animals in each group self-administered one of the two cocaine unit doses (0.5 and 1 mg/kg/infusion) by pressing a lever under a continuous schedule of reinforcement. To monitor serum cocaine concentrations, the remaining animals received concurrent, response-independent infusions whenever the matched animals self-administered cocaine infusions. Multiple concentration-time data in two successive self-administrations were determined to monitor the extent of fluctuation in concentrations by pharmacokinetic modeling. Behavioral analyses revealed the higher unit dose (1 mg/kg) resulted in less frequent cocaine self-administration, and a longer interinfusion interval, whereas the total doses were similar for the two groups (24.5-27.0 mg/kg/2.5 h). Cocaine decayed biexponentially. Both the values of clearance and terminal elimination rate constant for the self-administration paradigm were significantly greater than those after the bolus cocaine dosing series (0.5 and 1 mg/kg, separated by 3 days). The regularity in cocaine self-administration produced relatively stable serum cocaine concentrations that oscillated between maximum (C(max)) and minimum (C(min)) values regardless of dose size and interinfusion interval. Although the C(max) for the 1-mg/kg unit dose (1.47 microg/ml) was significantly higher than that for the 0.5-mg/kg dose (0.82 microg/ml), the C(min) values between the groups approximated each other (0.28, and 0.34 microg/ml, respectively). Hence, the C(min) is the determinant of the initiation of the next drug-taking behavior.     

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.     

Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys

Effective treatment of opioid dependence with methadone and of tobacco dependence with nicotine illustrates the potential usefulness of agonist medications for drug abuse treatment. The monoamine-releaser d-amphetamine is one drug under consideration as an agonist pharmacotherapy for cocaine dependence. To assess the concordance between preclinical evaluations and ongoing clinical trials, the present study examined the effects of chronic treatment with saline or d-amphetamine on cocaine- and food-maintained responding in rhesus monkeys. Cocaine injections and food pellets were available under a second-order schedule during alternating daily sessions of cocaine and food availability. d-Amphetamine (0.01-0.1 mg/kg per h i.v. for 7 consecutive days) dose-dependently decreased self-administration of a unit dose of cocaine (0.01 mg/kg per injection) at the peak of the cocaine self-administration dose-effect curve. d-Amphetamine (0.032-0.1 mg/kg per h for 7 days) also decreased self-administration of a broad range of cocaine doses (0.0032-0.1 mg/kg per injection) and produced rightward and downward shifts in the cocaine dose-effect curve. Food-maintained responding was usually decreased less than cocaine self-administration, and few signs of toxicity were noted. To evaluate the effects of a longer treatment regimen, d-amphetamine (0.1 mg/kg per h) was administered for 28 consecutive days. d-Amphetamine nearly eliminated self-administration of cocaine (0.01 mg/kg per injection) throughout this treatment, whereas food-maintained responding returned to baseline levels after approximately 9 days. These preclinical findings are concordant with recent clinical studies and suggest that chronic d-amphetamine may selectively decrease cocaine-taking behavior in rhesus monkeys, possibly by producing a selective decrease in the reinforcing effects of cocaine.     

Effects of chronic methadone treatment on cocaine- and food-maintained responding under second-order, progressive-ratio and concurrent-choice schedules in rhesus monkeys

The effects of chronic infusion with saline or methadone (0.032-1.0 mg/kg/h) were examined on cocaine- and food-maintained responding in rhesus monkeys using three procedures. In one procedure, cocaine injections (0.0032-0.032 mg/kg per injection) and food pellets were available under a second-order schedule during alternating daily sessions. During saline treatment, cocaine maintained a dose-dependent increase in the number of cocaine injections per day, and monkeys usually responded for the maximum number of pellets. Methadone dose-dependently decreased cocaine self-administration, and methadone doses that decreased cocaine self-administration had variable effects on food-maintained responding. In the second procedure, 0.032 mg/kg per injection cocaine or food pellets were available under a progressive-ratio schedule. During saline treatment, cocaine and food maintained similar break points. Methadone produced a dose-dependent and non-selective decrease in break points maintained by both cocaine and food. In the third procedure, cocaine injections (0-0.1 mg/kg per injection) and food pellets were available under a concurrent-choice schedule. During saline treatment, increasing unit doses of cocaine produced a dose-dependent increase in cocaine choice. Methadone had little effect on the cocaine choice dose-effect curve up to doses that eliminated responding. These results provide little evidence to suggest that chronic methadone altered the reinforcing effects of cocaine; rather methadone appeared to non-selectively decrease rates of operant responding.     

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.