Tolerance to the reinforcing effects of cocaine in a progressive ratio paradigm

This experiment used rats to test whether a regimen of chronic cocaine would produce tolerance to cocaine i.v. self-administration under a progressive ratio (PR) schedule of reinforcement. Under this PR schedule, an increasing number of responses was required to complete the ratio for each subsequent cocaine injection, and failure to complete the required ratio for the next injection within 1 h of the previous cocaine injection terminated the session. The number of injections taken in the session was termed the breaking point and used as the dependent variable. Rats were trained under this schedule until breaking point values were stable, after which cocaine dose-effect data were obtained: the breaking point increased as the dose of cocaine increased. Subsequently, rats were assigned to one of two groups for 7 days of chronic treatment: one group was infused with cocaine (18 mg/kg, given over 20 min once every 8 h) and the other group received 0.9% saline. Following termination of chronic treatment, cocaine dose-effect data were redetermined in both groups. Chronic cocaine treatment significantly decreased breaking point values across the entire dose-effect curve, although the effect was observed in only four of seven subjects. In contrast, chronic saline treatment produced no significant effect on the breaking point measures. Following a further 5 days of recovery from chronic treatment, cocaine dose-effect data were redetermined in both groups; these curves were essentially identical to those obtained before chronic treatments. These data support the hypothesis that tolerance occurs to the reinforcing effects of cocaine, as measured by a decrease in the breaking point, at least for a subset of animals.     

Lower reinforcing strength of the phenyltropane cocaine analogs RTI-336 and RTI-177 compared to cocaine in nonhuman primates

Drugs that inhibit brain dopamine transporters (DAT) have been developed as potential agonist medications for cocaine abuse and dependence. Because the mechanism of action of such drugs is similar to cocaine, one concern regarding their use is the abuse potential of the medications themselves. The present study compared the reinforcing strength of cocaine (0.003-0.3 mg/kg) and two 3-phenyltropane analogs of cocaine, RTI-336 (3β-(4-chlorophenyl)-2β-[3-(4′-methylphenyl)isoxazol-5-yl]tropane hydrochloride; 0.003-0.1 mg/kg) and RTI-177 (3β-(4-chlorophenyl)-2β-[3-phenylisoxazol-5-yl]tropane hydrochloride; 0.003-0.1 mg/kg), using a progressive-ratio (PR) schedule in rhesus monkeys (n = 4). PR schedules of reinforcement are frequently used to measure reinforcing strength of drugs. Earlier research using limited-access conditions reported that cocaine was a stronger reinforcer than either RTI-336 or RTI-177. Because the 3-phenyltropanes have longer durations of action, one purpose of the present study was to examine reinforcing strength using longer experimental sessions. Under these conditions, cocaine functioned as a reinforcer in all monkeys, and RTI-336 and RTI-177 functioned as a reinforcer in three of four subjects. Consistent with their documented slower onset of neurochemical and pharmacological effects, RTI-336 and RTI-177 were weaker reinforcers, resulting in fewer injections than cocaine. On average, the potencies of the two RTI compounds were not different than that of cocaine. These results support the view that slow-onset DA-selective uptake inhibitors have lower abuse liability than cocaine. In addition, the present findings suggest that changes in PR session length can influence potency comparisons between drugs, but not measures of reinforcing strength.     

Self-administration of cocaine: scopolamine combinations by rhesus monkeys

RATIONALE: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent dopamine (DA) uptake inhibitors with diminished reinforcing effects relative to cocaine. In addition to their effects on DA uptake, these compounds are potent muscarinic cholinergic antagonists.OBJECTIVES: The present experiments were designed to examine the hypothesis that the anticholinergic action of the BZT analogs contributes to their relatively low levels of self-administration.METHODS: Rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under either a fixed-ratio 25 (FR 25; n=5) or progressive-ratio (PR; n=5) schedule until stable responding was established. Saline, cocaine (0.0003-0.1 mg/kg per injection), scopolamine (0.001-0.1 mg/kg per injection), or various combinations of cocaine and scopolamine were then made available for self-administration.RESULTS: Cocaine maintained dose-related self-administration under both schedules whereas scopolamine did not. In the majority of cases, combinations of cocaine and scopolamine maintained less self-administration than cocaine alone.CONCLUSIONS: This study supports the hypothesis that anticholinergic actions contribute to the diminished self-administration of BZT analogs relative to cocaine. The mechanism may involve antagonism of the reinforcing effect of cocaine and/or punishment of the self-administration response by the addition of an anticholinergic component of action.     

Effect of HD-23, a potent long acting cocaine-analog,on cocaine self-administration in rats

Rationale. "Agonist" therapy for drug addiction proposes that a long acting analog, with similar properties to the abused substance might serve as a useful therapeutic agent. HD-23 is a very long acting tropane analog that displays a neurochemical profile similar to cocaine. Objective. To determine, using self-administration procedures and three different schedules of reinforcement, the effect of HD-23 on rate of cocaine intake (fixed ratio), the effect of HD-23 on the motivation to respond (progressive ratio) and the time course of HD-23 pretreatment (discrete trials). Methods. Male Sprague-Dawley rats were implanted with chronically indwelling intravenous cannulae and trained to self-administer cocaine (1.5 mg/kg per infusion) on a fixed ratio schedule. After a stable baseline was established, separate groups of rats (n=6–8) were given access to various doses of cocaine (0.37, 0.75, 1.5 or 3.0 mg/kg per injection) on a fixed ratio schedule during daily 3-h sessions, or to various doses of cocaine (0.18, 0.37, 0.75, 1.5 mg/kg per injection) on a progressive ratio schedule during daily 5-h sessions. A separate group of rats (n=10) was tested using a discrete trials procedure; animals were given the opportunity to self-administer cocaine (1.5 mg/kg per injection) during 10-min trials which were initiated every 20 min throughout the day/night cycle. Results. On the FR schedule, pretreatment with HD-23 (1.0 mg/kg) decreased the rate of cocaine intake. HD-23 shifted the dose-response curve on the PR schedule to the left. On the discrete trials schedule, animals displayed a circadian pattern of drug intake; pretreatment with HD-23 significantly increased cocaine intake for about 8 h during the light phase when the probability of responding would otherwise have been very low. Animals pretreated with HD-23 displayed a high probability of cocaine self-administration for about 14 h. Conclusions. The results are consistent with the idea that an acute pretreatment with the long-acting agonist, HD-23, augmented rather than diminished the motivation to self-administer cocaine. Electronic Publication     

Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat

The effect of the selective D1 antagonist, SCH 23390, and the selective D2 antagonist, spiperone, was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Both SCH 23390 and spiperone pretreatment increased responding up to doses of 10.0 µg/kg, and decreased responding at higher doses. Since rate of responding maintained by a drug can be influenced by factors other than its reinforcing efficacy, behavior maintained by cocaine was also investigated under a progressive-ratio schedule. The breaking point obtained under this schedule is used as a measure of the efficacy of the reinforcer and this value is not exclusively determined by response rate. With the progressive-ratio schedule, both SCH 23390 and spiperone produced dose-dependent decreases in the highest ratio completed in rats self-administering cocaine. The results obtained using the FR 5 and progressive-ratio schedules suggest that both D1 and D2 receptors are involved in mediating the reinforcing effects of cocaine.     

Time course of changes in cocaine self-administration behavior in rats during immunization with the cocaine vaccine IPC-1010

RATIONALE: Following a 6-week immunization period consisting of three biweekly injections of the cocaine vaccine IPC-1010, the reacquisition of cocaine self-administration behavior in rats was previously shown to be reduced in a manner that was dependant on serum antibody level. The present studies were conducted to examine additional issues relevant to the clinical use of the vaccine. OBJECTIVES: One experiment was conducted to address the issue of whether exposure to cocaine during the immunization period would influence the ability of the vaccine to block cocaine self-administration. A second experiment was conducted to determine if the reductions in drug-seeking behavior and drug intake by the vaccine were behaviorally specific, or if behavior maintained by a non-drug reinforcer would be similarly affected. METHODS: Identical second-order schedules of cocaine (1 mg/kg) or food pellet (45 mg) delivery were used in rats. In both studies, the time course of changes in behavior during the 6-week immunization period was examined in vaccine and alum-treated control rats following baseline and extinction conditions. RESULTS: The cocaine vaccine IPC-1010 induced average serum antibody levels of 0.07 mg/ml and significantly reduced self-administration behavior during the 2-week period following the third vaccine boost in a subgroup of rats with serum antibody levels greater than the average value. Cocaine self-administration behavior at this time point significantly correlated with serum antibody level. IPC-1010 did not alter responding maintained by food throughout the immunization period although serum antibody levels reached a similar average of 0.06 mg/ml in this group of rats. CONCLUSIONS: These findings suggest that the reductions in drug-seeking behavior and drug intake after immunization with IPC-1010 did not result from a reduced ability of the rats to respond on the lever. Furthermore, daily exposure to cocaine during the immunization period did not influence the ability of the vaccine to reduce cocaine self-administration behavior that emerged gradually over time. These findings also confirm the need for a sufficiently high antibody level to blunt the reinforcing effects 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     

Effects of cocaine in pigeons responding under a progressive-ratio schedule of food delivery

Although the progressive-ratio schedule has been used frequently to quantify the reinforcing effectiveness of self-administered drugs, it has seldom been used to examine the effects of drugs on food-maintained behavior and has never been used to evaluate the effects of cocaine on such behavior. In the present study, the effects of acute administrations of cocaine were evaluated in pigeons responding under a progressive-ratio 5 schedule of food delivery that continued for 1 h or until responding ceased for 5 consecutive min, whichever occurred first. The largest ratio completed each session (breaking point) was the primary dependent variable. In general, acute administrations of cocaine at 0.56 to 3.2 mg/kg increased breaking points, whereas doses above 5.6 mg/kg decreased breaking points. Although cocaine reduces food intake and subjective hunger for food, the present data indicate that the drug reduces the reinforcing effectiveness of food only at high doses.     

A labor-supply analysis of cocaine self-administration under progressive-ratio schedules: antecedents, methodologies, and perspectives

RATIONALE: Under a progressive-ratio (PR) schedule, a subject must complete increasing fixed-ratio (FR) response requirements to obtain reinforcers. Response requirements are increased until responding stops; the final ratio completed being the "break point" and providing an index of the relative effectiveness, or value, of the reinforcer to maintain behavior. OBJECTIVES: This review examines the historical and conceptual framework underlying the PR procedure and examines the concept of relative reinforcer value. Pharmacological analysis (based on receptor theory), and behavior analysis (based on microeconomic theory) are reviewed. METHODS: Using a microeconomic adaptation of the reinforcement model referred to as conservation, a mathematical model of PR performance is proposed based on the curvilinear relationship between economic supply and labor. Drug consumption and instrumental responding were assumed to reflect deviations from a balance point, defined as the levels of consumption and responding under no scheduled restraint. Data sets were re-analyzed in which several response sequences were examined in rhesus monkeys maintained on PR schedules of intravenous cocaine delivery. RESULTS: The modified conservation equation fitted the PR data accurately, and results consistent with both linear and concave labor-supply functions were obtained. These results suggest that cocaine self-administration under PR schedules conforms to labor-supply relationships characterized as inelastic (consumption is resistant to increases in schedule requirements) and unit elastic (at high response costs, consumption declines with no corresponding increase or decrease in total responding). CONCLUSIONS: The labor-supply methodology allows for a definition of the relative value of a drug reinforcer in PR studies based on changes in consumption across response costs. Specifically, relative reinforcer value is defined in terms of changes in behavior from a balance point, rather than as a property that determines the strength of the instrumental response.     

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.     

GABA mechanisms in the pedunculopontine tegmental nucleus influence particular aspects of nicotine self-administration selectively in the rat

RATIONALE: The pedunculopontine tegmental nucleus (PPTg) is part of the neuronal circuit activated by self-administered nicotine. The cholinergic neurons of the PPTg comprise a prominent projection to midbrain dopamine neurons. However, anatomical studies of Fos expression suggest that nicotine targets primarily non-cholinergic neurons in the PPTg, especially GABAergic and glutamatergic neurons. OBJECTIVE: The objective of these experiments was to examine the role of GABA manipulations in the PPTg on nicotine self-administration. METHODS AND RESULTS: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the GABA agonists muscimol (10-50 ng) and baclofen (30-60 ng) reduced nicotine self-administration maintained on a fixed-ratio schedule of reinforcement (30 microg/kg per infusion); self-administration of cocaine (0.3 mg/kg per infusion) under an identical schedule was not affected. Muscimol and baclofen were also examined after intra-PPTg microinfusion in animals trained to self-administer nicotine on a progressive-ratio schedule (10 and 30 microg/kg per infusion). Progressive-ratio responding was sensitive to pharmacological manipulations such as a change in the nicotine dose available for self-administration, or intra-PPTg microinfusion of the nicotinic antagonist dihydro-beta-erythroidine (30 microg). However, nicotine self-administration on a progressive-ratio schedule was not altered by intra-PPTg microinfusions of GABA agonists. CONCLUSIONS: These data confirm that the PPTg is involved in nicotine self-administration, a conclusion that is independent of the schedule of reinforcement that is used. GABAergic mechanisms in the PPTg play a selective role in nicotine reinforcement compared to cocaine, and that role is restricted to the characteristics of reinforcement measured by fixed-ratio responding.     

Effects of chronic<Emphasis Type="Italic"> d</Emphasis>-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys

Rationale. d-Amphetamine is a candidate agonist medication for the treatment of cocaine dependence, and evaluation of d-amphetamine effects on abuse-related effects of cocaine in preclinical assays is warranted. Objective. This study was designed to assess the effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys. The effects of schedule manipulations on cocaine and food-maintained responding were also examined for comparison with d-amphetamine effects. Methods. Key-press responding under a progressive-ratio schedule resulted in the delivery of cocaine (0.032 mg/kg per injection) or 1 g food pellets. The effect of manipulating cocaine dose (saline, 0.001–0.1 mg/kg per injection) or the number of food pellets delivered (0, 1 and 4 pellets) was determined. Subsequently, three schedule parameters were manipulated: (1) starting ratio value, (2) increments of the ratio progression, and (3) duration of post-reinforcer time-outs when the ratio value was constant. Finally, the effects of 10-day treatment with d-amphetamine (0.01–0.1 mg/kg per hour) were examined. Results. Break points increased as a function of cocaine dose or the number of food pellets, and similar break points were maintained by delivery of 0.032 mg/kg per injection cocaine and 1 food pellet. Manipulation of schedule parameters produced similar effects on responding maintained by cocaine (0.032 mg/kg per injection) or food (1 pellet). In contrast, d-amphetamine produced a dose-dependent decrease in cocaine-maintained responding and had less consistent effects on food-maintained responding. Conclusions. These results are consistent with the hypothesis that chronic treatment with d-amphetamine decreases cocaine self-administration in rhesus monkeys, possibly by attenuating the reinforcing effects of cocaine. Electronic Publication     

Attenuation of cocaine-seeking behaviour by the AMPA/kainate receptor antagonist CNQX in rats

Abstract Rationale. It has been suggested previously that conditioned effects on drug-seeking behaviour are in part mediated through glutamatergic neurotransmission. Objectives. To optimise a second-order schedule of IV cocaine reinforcement in Wistar rats and investigate the effects of the systemic AMPA/kainate receptor antagonist CNQX on cocaine-seeking behaviour under this schedule. Methods. Free-feeding Wistar rats were trained to respond for an IV cocaine infusion (0.25 mg/infusion) under a FI15 min(FR7:S) schedule, whereby the completion of FR7 responses led to the presentation of a conditioned stimulus (CS). After two 15-min fixed intervals, rats were allowed to respond for cocaine under an FR4(FR7:S) second-order schedule for another 120 min. After acquisition of stable responding, the cocaine unit dose was increased to 0.50 mg/infusion. The effects of CNQX (0, 0.75, 1.5, and 3 mg/kg IP) on cocaine seeking were then examined using a within-subjects design. Results. Increasing the cocaine unit dose increased responding during the first and second intervals, with a decrease in the latency to the first CS. CNQX decreased the number of cocaine responses in a dose-dependent manner during the first 15-min cocaine-free interval, but did not affect cocaine responding during either the second interval or the latter part of the session under the FR4(FR7:S) schedule. In the locomotor activity test, reductions in rearing were produced by higher CNQX doses than those that attenuated significantly responding during the first fixed interval. Conclusions. These results suggest that AMPA/kainate receptors are involved in mediation of cocaine-seeking behaviour controlled partly by cocaine-associated cues. Electronic Publication     

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

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

Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys

Rhesus monkeys were trained in a discretetrials choice procedure and allowed to choose between intravenous injections of cocaine (0.01–1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When each reinforcer was available under a fixed-ratio (FR) 30 schedule, the frequency of cocaine choice and the total drug intake increased in a dose-related manner for all monkeys. When the FR for cocaine was differentially increased, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right and/or downward. When the FR for cocaine was at least 480, cocaine preference could not be recovered up to doses of 1.0 mg/kg/injection. In a second experiment, when the response requirement for food was differentially increased, the frequency of cocaine choice increased. These results demonstrate that altering the response requirement for cocaine or for alternative reinforcers that are available can substantially affect cocaine self-administration.     

Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones

Rationale Previous work has shown that adult female rats are more sensitive than adult male rats to the reinforcing effects of cocaine, an effect that appears to be due, at least in part, to ovarian hormones. Objective In this study, we examine sex differences in cocaine self-administration during adolescence, a period of marked hormonal change. Materials and methods Adolescent male and female Sprague–Dawley rats were trained to self-administer cocaine (0.75 mg/kg per infusion) under a fixed ratio 1 schedule (i.e., each response was reinforced by an infusion of cocaine) beginning on postnatal day 30. After acquisition, responding was assessed under a progressive-ratio schedule until postnatal day 50 with blood sampling occurring before the first five sessions to determine the relationship between gonadal hormones (i.e., estradiol, progesterone, and testosterone) and motivation for cocaine. Estrous cycle phase was monitored throughout the study. Separate groups of adolescent male and female rats were compared on the acquisition of and progressive-ratio responding for sucrose reinforcement. Results Females acquired cocaine self-administration more readily than did males, and a greater percentage of females acquired self-administration. Under progressive-ratio testing conditions, adolescent females responded at higher levels than adolescent males to obtain cocaine infusions, and in females, responding was positively associated with levels of estradiol and greatest during estrus. No sex differences were observed for sucrose reinforcement. Conclusion These findings suggest that sex differences are relevant during adolescence with evidence implicating circulating estradiol level as a factor that contributes to the enhanced sensitivity in females to the reinforcing effects of cocaine.     

Influence of a conditioned light stimulus on cocaine self-administration in rats

RATIONALE: A number of studies have suggested that the continued presentation of stimuli associated with cocaine may contribute to drug-seeking and drug-taking. The influence of conditioned stimuli on the maintenance of self-administration has not, however, been systematically investigated. OBJECTIVES: This study was designed to determine whether omission of a stimulus that had been paired with self-administered cocaine would influence the maintenance of cocaine self-administration and whether the effect was dependent on cocaine dose or session length. METHODS: During self-administration training, self-administered cocaine infusions were always paired with the illumination of a light. On test days, self-administered cocaine was delivered either with or without the cocaine-associated cue. For one group of rats, responding maintained by cocaine (0.50 mg/kg per infusion) was measured during daily 18-h sessions. For other groups, responding maintained by additional doses of cocaine (0.125, 0.25, or 1.0 mg/kg per infusion) was measured during daily 8-h sessions. For a final group, daily test sessions (4-5 h) produced the dose-effect curve (0.015-1.0 mg/kg per infusion) by repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion. RESULTS: Removal of the light cue decreased cocaine self-administration. The magnitude of this effect was dependent on the dose of self-administered cocaine and on the test session duration. Greater decrements in responding were produced as session length increased or when low doses of cocaine were self-administered. CONCLUSIONS: These findings demonstrate that in the absence of a cocaine-associated stimulus, cocaine self-administration is attenuated and that maintenance of cocaine self-administration is maximally affected by the presence or absence of the conditioned stimulus when the self-administered dose is low and/or when session duration is long.     

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     

Self-administration of the dopamine D3 agonist 7-OH-DPAT in rhesus monkeys is modified by prior cocaine exposure

Cocaine self-administration was compared with responding maintained by the dopamine D₃ agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) in rhesus monkeys. In the first experiment, monkeys (n=3) with an extensive cocaine history responded under a fixed-interval (FI) 5-min schedule of IV cocaine (0.03 mg/kg per injection) presentation, during daily 4-h sessions. When responding was stable, dose-response curves were determined for cocaine (0.01-0.3 mg/kg per injection) and 7-OH-DPAT (0,001–0.1 mg/kg per injection); each dose was available for at least five consecutive sessions. When substituted for the baseline dose of cocaine, other doses of cocaine and 7-OH-DPAT maintained rates higher than responding maintained by saline injections, in all monkeys. 7-OH-DPAT maintained response rates equal to or higher than rates of cocainemaintained responding in all monkeys. In a second experiment, acquisition of 7-OH-DPAT self-administration was evaluated in a group of cocaine-navie monkeys (n=3). Various doses of 7-OH-DPAT (0.003–0.03 mg/kg during daily 4-h sessions. After 10–13 sessions, 7-OH-DPAT self-administration could not be trained in any cocaine-naive monkey. When cocaine was made available to these monkeys, responding was reliably maintained within one to four sessions and the schedule was gradually increased to FI 5-min. After stable responding under an FI 5-min schedule of 0.03 mg/kg per injection cocaine presentation, 7-OH-DPAT (0.01 mg/kg per injection) was again made available to two of the monkeys, and maintained responding at rates higher than saline. To determine better whether a history of responding maintained by another reinforcer would result in high rates of 7-OH-DPAT self-administration, two cocaine-naive monkeys were trained to respond under an FI 5-min schedule of food presentation. Substituting 7-OH-DOAT (0.003–0.03 mg/kg per injection) for food resulted in very low rates of responding. Taken together, these results suggest that despite comparable reinforcing effects in cocaine-substitution studies, 7-OH-DPAT and cocaine differ in their rate of acquisition, perhaps indicating a lower abuse liability for 7-OH-DPAT.     

Effects of acute and chronic aripiprazole treatment on choice between cocaine self-administration and food under a concurrent schedule of reinforcement in rats

Rationale  Dopamine D2-like partial agonists such as aripiprazole have received some attention as potential pharmacotherapies for the treatment of psychostimulant addiction. However, the preclinical evaluations so far have focused on acute effects of aripiprazole. Objectives  We tested the hypothesis that aripiprazole, both as acute and as chronic treatment, would preferentially decrease cocaine self-administration while sparing behavior maintained by a natural reinforcer, resulting in a shift in the allocation of behavior from cocaine-taking towards the alternative reinforcer. Materials and methods  Rats were trained to self-administer intravenous cocaine in a concurrent choice procedure, with a palatable food as the competing reinforcer, under a fixed ratio (FR) 1 FR 5 chain schedule. Aripiprazole was then administered as continuous infusion by osmotic minipumps for 5 days, during which performance in the choice procedure was assessed daily. Results  An intermediate dose of aripiprazole decreased cocaine self-administration and shifted the cocaine choice curve to the right as an acute treatment. However, as a chronic treatment, aripiprazole failed to decrease cocaine self-administration or cocaine choice, despite a dose-dependent decrease in overall response rates and food-maintained behavior. Conclusions  Our results confirm and extend earlier findings and indicate that acute administration of aripiprazole can decrease cocaine self-administration. However, based on the present data, chronic treatment with aripiprazole does not show much promise as a potential pharmacotherapy for cocaine addiction. Both acute and chronic treatment data are in agreement with published clinical findings, suggesting that the concurrent choice procedure in rats has predictive validity of efficacy in humans.