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 time-out duration on the reinforcing strength of cocaine assessed under a progressive-ratio schedule in rhesus monkeys

Progressive-ratio (PR) schedules of reinforcement have provided valuable information regarding the reinforcing strength of cocaine and the underlying neurobiological mechanisms. Parametric manipulations, such as altering time-out (TO) values, can affect the shape of the cocaine dose-response curve. Earlier studies have used PR schedules with widely varying parameters, thus complicating comparisons across experiments. This study evaluated the reinforcing strength of cocaine (0.005-0.9 mg/kg) as a function of post-reinforcement TO duration (5, 10, 30, or 60 min) under a PR schedule in rhesus monkeys. Daily sessions ended when 2 h elapsed without an injection; the breakpoint value was defined as the total number of injections. When the TO was 10 min, the relationship between cocaine dose and the number of injections received (i.e. BP) was characterized by an inverted U-shaped curve in all monkeys. Increasing the TO to 30 min resulted in a rightward shift of the ascending limb of the dose-response curve, but did not affect self-administration of higher doses. The number of injections received of a low cocaine dose was not further increased when the TO was shortened to 5 min, nor did increasing the TO to 60 min alter self-administration of the highest tested dose. These results suggest that drug accumulation plays a role in determining the reinforcing strength of low and intermediate cocaine doses under PR schedules. However, the reinforcing strength of higher cocaine doses was unaffected by manipulating TO, suggesting that the BP value is a useful measure of reinforcing strength.     

The effects of cocaine in combination with other drugs of abuse on schedule-controlled behavior in the pigeon

The present experiment sought to provide information regarding the consequences of combining cocaine with other drugs of abuse. The effects of cocaine alone and in combination with d-amphetamine, caffeine, morphine or delta-9-tetrahydrocannabinol were determined in five male white Carneaux pigeons responding under a multiple fixed-ratio 30, fixed-interval 600 schedule (mult FR FI). Drug interactions were studied by redetermining the cocaine dose-response curve in the presence of various fixed doses of the other drugs. Under the mult FR FI schedule, when cocaine (1 to 10 mg/kg) was combined with inactive doses of d-amphetamine (0.1, 0.3, 1.0, and 1.8 mg/kg), caffeine (10, 30, and 100 mg/kg), morphine (0.3, and 1.0 mg/kg), and delta-9-tetrahydrocannabinol (0.1 mg/kg), the FR and FI response rate dose-response curves were not shifted relative to the cocaine-alone curves. When cocaine was combined with an active dose of a drug which decreased response rate when given alone (0.3 mg/kg delta-9-tetrahydrocannabinol and 3 mg/kg morphine), the position of the response rate dose-response curves shifted compared to the cocaine-alone curves. The most frequent and consistent outcome of these interactions can be described as less than or approximately equal to an effect-additive interaction. Thus, these data indicate that the potential consequences of coabusing cocaine with the drugs tested in the present experiment can most often be predicted from the effects of each drug when taken alone.     

The effects of cimetidine on schedule-controlled responding and locomotor activity in rats

The effect of intraperitoneal injections of cimetidine, a selective histaminergic H₂-receptor blocking agent, on operant behavior and locomotor activity were examined in rats. Cimetidine (1–100 mg/kg) failed to show any significant effect on responding maintained under a fixed-ratio (FR) 30 fixed-interval (FI) 5-min schedule of food presentation. A higher dose of cimetidine (300 mg/kg) produced decreases in both FR and FI rates of responding. In contrast, 100 mg/kg of cimetidineincreased the response rate and decreased reinforcement rate in rats performing under a schedule requiring the temporal spacing of responses (DRL-10 sec). Cimetidine (10–300 mg/kg) did not induce significant changes in locomotor activity in the rat. These data suggest that cimetidine is more potent in altering the steady low rate of responding under a DRL schedule of food presentation, than responding maintained under a multiple FR FI schedule, and that cimitidine is even less potent in altering locomotor activity.     

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     

Effects of cocaine and morphine under mixed-ratio schedules of food delivery: support for a behavioral momentum analysis

Previous studies have shown that ratio size influenced the development of tolerance under simple and multiple schedules, but not under progressive-ratio (PR) schedules. PR schedules share certain features with mixed-ratio (MR) schedules, and pilot data suggested that ratio size fails to modulate tolerance to cocaine or morphine under MR schedules. The present study examined more comprehensively the pre- and postchronic effects of cocaine and (in separate birds) morphine under MR schedules with fixed-ratio (FR) 5 and FR 95, FR 25 and FR 75, and FR 50 and FR 50 components. Acute doses of cocaine and morphine initially were given in an ascending series (beginning with 0.56 mg/kg) until responding was reduced to near-zero levels. Chronic (daily) dosing with a dose that reduced, but did not eliminate, responding then occurred until response rates stabilized. Finally, postchronic dose-response determinations were conducted. Both cocaine and morphine reduced response rates at all FR values. Tolerance was consistently observed to the effects of morphine, but not to those of cocaine. With both drugs the degree of tolerance observed did not vary as a function of FR value. These findings, like those obtained under PR schedules, indicate that ratio size does not always modulate drug tolerance. A behavioral momentum analysis of drug action appears to account for whether or not ratio size modulates tolerance, and such an analysis is provided.     

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 ketocyclazocine alone and in combination with naloxone on schedule-controlled responding in squirrel monkeys

A multiple, fixed interval 5 minutes, fixed ratio 30, schedule of food presentation (Mult FI FR) was used to evaluate the effects of ketocyclazocine, a kappa-receptor agonist, in four squirrel monkeys. Two monkeys were initially trained with 1-minute time-out (TO) periods between the components of the multiple schedule and two monkeys were initially trained without these TO periods. Ketocyclazocine dose-response functions were determined for each monkey under their original training conditions and then the conditions were reversed and dose-response functions were re-determined under the new conditions. Ketocyclazocine consistently decreased rates of responding during the FR component of the multiple schedule under both TO and no TO conditions. Under the FI component, ketocyclazocine's effects differed dependent upon dose, conditioning history, and the presence or absence of TO periods. Intermediate doses of ketocyclazocine (0.01-0.056 mg/kg) increased FI rates of responding under the no TO condition in monkeys originally trained under this condition; however, ketocyclazocine did not increase FI rates of responding under the no TO condition in monkeys originally trained under the TO condition. Under the TO condition, intermediate doses of ketocyclazocine did not increase FI rates of responding. High doses of ketocyclazocine (0.1 and 0.17 mg/kg) decreased FI rates of responding in all monkeys under both the TO and no TO conditions Naloxone, in doses up to those which decreased responding when given alone, failed to antagonize completely the rate decreasing effects of ketocyclazocine.     

Schedule control of quantal and graded dose-effect curves in a drug-drug-saline discrimination

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 5 mg/kg morphine, and saline when responding was maintained under fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. After the discrimination was established, other drugs were substituted for the training drugs. After low doses of pentobarbital and chlordiazepoxide, responding shifted from the saline key to the pentobarbital key under both FR and FI schedules. After low doses of morphine and methadone, responding shifted from the saline key to the morphine key under both reinforcement schedules. After all doses of d-amphetamine, responding occurred largely on the saline key under both schedules. Responding also was confined largely to the saline key after phencyclidine administration under the FR schedule, but under the FI schedule, responding shifted from the saline key to the pentobarbital key at high doses of phencyclidine. When responding was maintained under the FR schedule, the dose-response curves for drugs that generalized to the training drugs were quantal in shape, while under the FI schedule, the dose-response curves for drugs that generalized to the training drugs were graded. These data extend observations that FR schedules generate quantal dose-response curves, and FI schedules generate graded dose-response curves to complex three-key drug discriminations.     

Effects of marihuana extract on the operant behavior of chimpanzees

Six chimpanzees were trained to panel push under a food reinforcement baseline in which three operant schedules, each associated with a different stimulus, were presented successively. The fixed ratio (FR) reinforcement schedule required the emission of 40 responses for reinforcement. Reinforcement under the differential reinforcement of low rate (DRL) schedule was delivered only when successive responses were spaced by at least 10 sec. During the extinction or time out from positive reinforcement schedule (TO), no responses were reinforced. In Experiment 1, amounts of marihuana extract containing from 0.2 to 4.0 mg/kg (?)-Δ ⁹-trans-tetrahydrocannabinol (Δ ⁹-THC) were orally administered 1 h prior to experimentation. In Experiment 2, 1.0 mg/kg Δ ⁹-THC was orally administered between 1 and 23 h prior to experimental sessions. No disruption of stimulus control or drug effects during TO were observed. Both DRL and FR response suppression occurred at the highest drug dose. Lower Δ ⁹-THC doses produced facilitation of DRL responding up to 12 h following drug administration. Although FR responding was less sensitive, Δ ⁹-THC stimulated FR behavior from 2 to 5 h following drug administration. It was concluded that marihuana has a biphasic effect on food reinforcement schedule controlled operant behavior.     

Effects of continuous infusions of SCH 23390 on cocaine- or food-maintained behavior in rhesus monkeys

Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025-0.10 mg/kg/injection, i.v.) was available under a FR 30 schedule. There was a brief time-out period after each reinforcer was delivered. When responding was stable, monkeys received continuous (24 h/day) i.v. infusions of several doses of SCH 23390 (0.8-6.4 mg/kg/day) for at least the same number of sessions as was required for responding to decline to low levels when saline was available for self-administration. In two of four monkeys, SCH 23390 produced larger decreases in responding maintained by cocaine than in responding maintained by food. The effects of SCH 23390 on drug- and/or food-maintained responding progressively diminished over several days of continuous infusion such that, at the end of the infusion period, responding approximated control rates. Termination of daily infusions of SCH 23390 caused minimal effects on food-maintained responding, whereas in three of four monkeys decreases in responding maintained by cocaine were observed. These latter effects were greater following exposure to the higher doses. Following recovery from these effects, consistently higher rates of responding were maintained by doses of cocaine on the ascending limb of the dose-response function. These results suggest that a D(1) antagonist may decrease the reinforcing effects of cocaine. However, these effects diminish over time and exposure to SCH 23390 may result in long-lasting enhancement of sensitization to the reinforcing effects of cocaine.     

Effects of acute and chronic administration of phenobarbital and d-amphetamine on schedule-controlled behavior

The effects of acute and chronic administration of phenobarbital and d-amphetamine were determined in rats responding under a multiple fixed-interval five minute fixed-ratio 30 (mult FI 5 FR 30) schedule of food presentation. After determining the acute effects of each drug, the drugs were injected daily with one group of rats receiving the drugs before each behavioral session while another group received the drugs immediately after each daily session. After four to seven consecutive injections, tolerance developed to the effects of phenobarbital on the average rates of responding under FI and FR schedule components only if the drug was administered before each session. Tolerance was more pronounced for responding during the terminal portions of the FI component than for responding during either the initial portions of the FI or the FR component. Evidence for a selective tolerance to the effects of the drug on responding during the final segments of the FI was also obtained in rats responding under an FI 5 schedule. In contrast, injections of d-amphetamine for seven to eight consecutive days failed to produce any tolerance to the effects of the drug on responding under mult FI 5 FR 30, FI 5, or FR 30 schedules. These results indicate that the development of tolerance to the effects of phenobarbital depended both upon the temporal relationship of the drug effects to the behavioral testing and upon the schedules controlling behavior. These findings are discussed in terms of theories of behavioral tolerance.     

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

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

Acute effects of oral pyridostigmine bromide on conditioned operant performance in rats

Pyridostigmine bromide (Pyr), the current drug of choice in the management of myasthenia gravis, has been suggested for use in Alzheimer's dementia, and as a prophylactic treatment for intoxication with organophosphate cholinesterase inhibitors. The present study was undertaken to evaluate the dose-response and time-course effects of acute oral administration of Pyr over a broad dose range (3-40 mg/kg) on the lever pressing of rats maintained under a multiple fixed-ratio (FR-20) time-out schedule of reinforcement for water reward. The drug produced a dose-dependent biphasic response depression in the overall rate of FR responding. Low doses of Pyr (less than or equal to 12 mg/kg) that caused no gross signs of toxicity only moderately decreased rates of responding, primarily due to a decrease in response rates. Whereas high doses of Pyr (greater than 24 mg/kg) which produced overt signs of peripheral cholinergic intoxication markedly suppressed overall responding, primarily due to cessation of responding. The lowest effective dose of performance disruption was 6 mg/kg, and the ED50 was calculated as 23.3 (17.9-28.7) mg/kg. The time-course data of performance disruption showed that low doses of Pyr (less than or equal to 12 mg/kg) had an onset latency within 40-80 min and a duration of 20-80 min, whereas high doses (greater than or equal to 24 mg/kg) had an onset latency of 20-40 min and a duration greater than 80 min. These results suggest the recommended human therapeutic or prophylactic regimen of 30-120.mg Pyr, orally taken each 8 hours, might adversely affect behavioral performance.     

Fenfluramine and N-ethyl amphetamine: Comparison of the reinforcing and rate-decreasing actions in the rhesus monkey

N-ethyl amphetamine HCl (NEA) and fenfluramine HCl (meta-trifluoromethyl N-ethyl amphetamine) were evaluated as reinforcers in rhesus monkeys that had been previously trained to press a lever using food presentations and cocaine HCl injections as reinforcers. Each daily session consisted of episodic opportunities to obtain reinforcers under a fixed-ratio schedule of 30. A drug period was interpolated between two periods in which lever-press responding was maintained by food presentations. Compared to saline, none of the drugs altered the rate of responding in the food periods which preceded the drug sessions, indicating the absence of residual response-disrupting drug actions from previous sessions. However, NEA and fenfluramine self-injection resulted in dose-related decreases in response rates during the food periods which immediately followed the drug sessions. Cocaine HCl (30 g/kg/injection) maintained high response rates at over one response/second during the drug periods, as did the same dose of NEA. Doses of 10 and 100 g/kg/injection of NEA as well as all doses of fenfluramine HCl (10 through 300 g/kg/injection) maintained rates that were not different from those associated with saline injections. These results substantiate and extend earlier findings with fenfluramine and indicate that its failure to act as a reinforcer is attributable to its meta-trifluoromethyl group.Supported in part by USPHS Grant DA-00154.R. E. T. was an NIH Predoctoral Trainee in Pharmacology, USPHS Grant GM-00198.     

Effects of corticosterone and its synthesis blockade on the cocaine-induced discriminative stimulus effects in rats

Several studies have argued that the hypothalamo-pituitary-adrenal (HPA) axis is of significance to behavioral effects evoked by drugs of abuse (e.g. cocaine). The role of the HPA axis in the subjective effects of cocaine was investigated in rats trained to discriminate cocaine (10 mg/kg, ip, -15 min) from saline (ip, -15 min) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, neither the exposure to a novel environment nor the social defeat stress, applied to rats after a dose of cocaine (2.5 mg/kg) which induced a ca. 42% drug-appropriate responding, influenced cocaine discrimination. Given alone, corticosterone (20 and 40 mg/kg, sc, -60 min) elicited a ca. 7% drug-appropriate responding. Combined injections of corticosterone and cocaine (0.625-5 mg/kg) did not affect the dose-response curve for cocaine. Surgical adrenalectomy did not modify the effects of cocaine; using a cumulative dosing procedure in the drug discrimination paradigm we found, that the dose-response curves for cocaine in adrenalectomized rats and sham-operated controls practically did not differ. Ketoconazole (an inhibitor of adrenocorticosteroid synthesis; 50 mg/kg, ip) given acutely (60 min) did not affect cocaine discrimination. Given subacutely (24, 16 and 1 h before tests), ketoconazole (50 mg/kg) produced a left-ward shift in the dose-response curve for cocaine and decreased its ED50 value. Another inhibitor of corticosterone secretion, metyrapone (50 mg/kg, sc), given acutely (120 min) did not affect the dose-response curve for cocaine. However, repeated injections (24, 16 and 2 h before tests) of metyrapone (50 mg/kg) with different doses of cocaine resulted in a rightward shift in the dose-response curve for cocaine and an increase in its ED50 value. The obtained results seem to exclude any role of the HPA axis in mediating subjective effects of cocaine, since neither corticosterone and stress nor adrenalectomy modified the discriminative stimulus effects of cocaine in rats. The reduction and potentiation of cocaine discrimination following subacute metyrapone and ketoconazole, respectively, may depend on changes in the levels of intermediate neurosteroids "upstream" from corticosterone in its biosynthesis pathway.     

Reduction in oral ethanol self-administration in the rat by the 5-HT uptake blocker fluoxetine

Long-Evans rats (N = 4) maintained on ad lib food and water were initiated to self-administer ethanol using the sucrose-substitution procedure. Following initiation, the rats received IP injections of fluoxetine HCl in sterile water 30 minutes before selected daily self-administration sessions. On other sessions, the rats were injected with sterile water only. Doses of 1, 2, 3, and 5 mg/kg were tested in a random order. Only one drug dose was given each week and each dose was tested at least twice except the 5 mg/kg dose. As dose increased, responding for ethanol decreased with significant reductions at both the 3 and 5 mg/kg dose. The nature of the decrease was such that the duration of continuous responding at the beginning of the session was reduced respective to control and noninjection performance. Overall, the findings of this study support prior work with fluoxetine and other 5-HT blockers which appear to affect satiety mechanisms and possibly reinforcement efficacy.     

Effects of drugs on food- and cocaine-maintained responding III: Dopaminergic antagonists

 The effects of three dopamine (DA) antagonists (SCH23390, pimozide, and chlorpromazine), with various degrees of selectivity for D₁ and D₂ receptors, and an agonist (the cocaine analog, CFT) were studied on responding maintained under a multiple fixed-ratio (FR) 30 food, FR30 cocaine (1–100 μg/kg per injection) delivery, with an interposed 10-min time-out (TO), schedule in rhesus monkeys. The effects of each drug depended upon the unit dose of cocaine. With an intermediate (10 μg/kg per injection) unit dose of cocaine, each antagonist decreased rates of responding maintained by either event in a dose-related manner. At higher (56–100 μg/kg per injection) unit doses of cocaine, antagonists generally increased and then decreased both food- and cocaine-maintained responding in a dose-related manner. These increases appeared to result from the blockade of non-specific rate-decreasing effects of self-administered cocaine, questioning their relevance to the reinforcing effects of cocaine. The results failed to support a role for pharmacological selectivity in this rate-decreasing effect of cocaine, as both D₁ and D₂ antagonists were able to reverse the effect. In contrast, CFT decreased cocaine-maintained responding at doses less than those that decreased food-maintained responding, and failed to shift the cocaine dose-effect function to the left. These results, together with previous work, suggest that agonists can selectively decrease drug-seeking behavior. Received: 5 January 1996 / Final version: 5 August 1996     

Pentobarbital discrimination and generalization to other drugs under multiple fixed-ratio fixed-interval schedules

Pigeons were trained to discriminate 5mg/kg pentobarbital from saline under several multiple fixed-ratio fixed-interval schedules of food presentation. The following schedules were studied: multiple fixed-ratio 40 fixed-interval 18s (mult FR40 FI18), mult FR10 FI18s, mult FR10 FI180s and mult FR90 FI10s. After responding stabilized under each multiple schedule, generalization curves were determined for pentobarbital, amobarbital, diazepam, phencyclidine and d-amphetamine. Pentobarbital generated dose-dependent increases in responding under all schedule components; however, there was more responding on the drug key after low doses of pentobarbital under FI components than under FR components, except for the FR90 component of the mult FR90 FI10 schedule. This tendency for more responding on the drug key after low doses of pentobarbital under FI components than under FR components generally was observed for low doses of all of the drugs. Examination of data from individual subjects revealed that there was a greater tendency for birds to distribute responding on both keys (mixed responding) under FI components than under FR components, where responding after each dose was confined largely to one of the two response keys. Analysis of local rates of responding within the FI component of the schedules showed that responding under the FI components developed the typical FI scallop at all FI-component durations. These data suggest that FI schedules with values between 10 and 180s generate similar dose-effect curves with higher rates of responding on the drug key after low doses of drugs than under FR schedules with low response requirements; however, under schedules with higher FR requirements, the dose-effect curves for some drugs begin to look more like those under FI schedules.     

Situational specificity of tolerance to decreased operant responding by cocaine

Responding of rats was maintained in three different environmental situations each day. Interruption of a photobeam was maintained under a shock avoidance schedule in the first session, lever pressing was maintained under a 5-min fixed-interval (FI) schedule of food presentation in a second session, and nose-key pressing was maintained under a 30-response fixed-ratio (FR) schedule of food presentation in a third session. After receiving once-weekly injections of cocaine (3-17 mg/kg) prior to each of the sessions, animals received daily administration of 13 mg/kg after responding in the third daily session for four weeks, before responding in the third session for four weeks, before responding in the second daily session for four weeks, and then before responding in the first daily session for four weeks. Tolerance that developed in the environment that was coincident with the pharmacological actions of cocaine did not extend to operants in other environmental situations. Instead, tolerance to the behavioral effects of cocaine was specific to particular stimulus conditions associated with drug administration, indicating that the expression of tolerance depended on both pharmacologic action as well as concurrently operating behavioral processes.