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PubMed2000

Reinforcing and discriminative stimulus effects of RTI 111, a 3-phenyltropane analog, in rhesus monkeys: interaction with methamphetamine.

RATIONALE: The neuronal actions of methamphetamine (MA) include an increase in extracellular levels of monoamines, presumably via reverse transport involving the monoamine transporters. This action is thought to play an important role in the effects of MA. Therefore, in the present experiment, it was hypothesized that a monoamine uptake blocker would block behavioral effects of MA related to its abuse. OBJECTIVE: RTI 111, a newly synthesized 3-phenyltropane analog with high affinity for the dopamine, norepinephrine, and serotonin transporters, was evaluated alone and in combination with MA for its ability to block the reinforcing and discriminative stimulus effects of MA in rhesus monkeys. METHODS: RTI 111 (0.0003-0.03 mg/kg, i.v.) was made available to four rhesus monkeys for self-administration under a fixed-ratio 25 (FR 25) schedule of reinforcement. RTI 111 (0.01-0.1 mg/kg, i.m.) was also administered as a pretreatment (15 min prior) to four monkeys self-administering MA (0.0-0.3 mg/kg per injection, i.v.) on a progressive-ratio schedule of reinforcement. MA (0.01-1.0 mg/kg, i.m.), RTI 111 (0.001-0.1 mg/kg, i.m.), or the combination of MA and RTI 111 were administered to four monkeys trained to discriminate (+)-amphetamine (AMPH; 1.0 or 1.7 mg/kg, intragastric) from saline. RESULTS: When RTI 111 was made available for self-administration under an FR 25 schedule it functioned as a positive reinforcer in all four monkeys tested. When RTI 111 was given as a pretreatment to monkeys self-administering MA under a progressive-ratio schedule, the MA dose-response function shifted to the left and down. When RTI 111 or MA were given to monkeys trained to discriminate AMPH from saline, full AMPH-like responding was observed for both drugs. Given in combination, RTI 111 shifted the MA dose-response function to the left. CONCLUSIONS: These data suggest that RTI 111 is behaviorally similar to traditional psychomotor stimulants that act at the DA transporter and that it increases, rather than blocks, the behavioral potency of MA.

Animals↗

PubMed2000

The serotonin-1A receptor antagonist WAY-100635 modifies fluoxetine's antidepressant-like profile on the differential reinforcement of low rates 72-s schedule in rats.

RATIONALE: Recent preclinical and clinical data suggest that co-administration of a serotonin-1A (5-HT-1A) receptor antagonist with an antidepressant drug has greater therapeutic efficacy than when the antidepressant drug is administered alone. OBJECTIVE: The purpose of the present experiment was to determine whether pretreatment with the selective 5-HT-1A receptor antagonist N-[2-[4-(2-methoxyphenyl)- 1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide (WAY-100635; 0.003, 0.03, 0.3 mg/kg, s.c.) would alter the effects of the antidepressant fluoxetine (2.5-10 mg/kg, i.p.) on the differential reinforcement of low-rate 72-s (DRL 72-s) schedule. The DRL 72-s schedule is a behavioral screen selective and sensitive to antidepressant drugs. RESULTS: WAY-100635 had no behavioral effects on its own. The lower doses of fluoxetine (2.5 mg/kg and 5 mg/kg) had no effects, but 10 mg/kg increased reinforcement rate without affecting response rate. The increase in reinforcement rate was blocked by pretreatment with 0.03 mg/kg and 0.3 mg/kg WAY-100635, although the combination of fluoxetine and WAY-100635 also significantly reduced response rate. Interestingly, 0.003 mg/kg or 0.03 mg/kg WAY-100635 administered with 5.0 mg/kg fluoxetine increased reinforcement rate, even though this dose of fluoxetine had no effect on performance. CONCLUSION: These data demonstrate that the behavioral effects of fluoxetine are modified by 5-HT-1A receptor blockade.

Animals↗

PubMed1998

Conditioned flavour preference negatively reinforced by caffeine in human volunteers.

This study examined whether 100 mg caffeine could reinforce preference for the flavour of a novel drink in moderate caffeine users, both after overnight caffeine abstinence and 2 h after receiving 100 mg caffeine, using a two-stage between-groups procedure with 36 volunteers. In the first stage, liking for a test drink (fruit tea) was assessed at breakfast following overnight caffeine abstinence, with half the subjects receiving caffeine. Liking for the tea increased significantly over four trials for subjects receiving caffeine, and decreased significantly in those without caffeine. These effects were greatest in subjects who rated the drink as highly novel. In stage two, subjects evaluated a second drink (fruit-juice) 2 h after receiving the tea, and again half the subjects received caffeine Those subjects who received caffeine in stage two but not stage one showed a significant increase in liking for the fruit-juice over the 4 test days, whereas subjects who did not receive caffeine at either stage showed a progressive decrease in liking for this drink. In contrast, no significant change in liking for the fruit-juice was seen at stage two for subjects who had received caffeine in stage one, regardless of the presence or absence of caffeine at stage two. Caffeine at breakfast increased ratings of energetic and lively, and energetic ratings also increased following caffeine in the fruit-juice in subjects who had not had caffeine at breakfast. Overall, these data are consistent with a negative reinforcement model of caffeine reinforcement, and demonstrate further the utility of the conditioned flavour preference method for evaluating reinforcing effects of drugs in humans.

Adult↗

PubMed1998

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine.

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.

Animals↗

PubMed1999

Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement.

Numerous studies have shown that withdrawal from sustained high doses of psychostimulant drugs such as cocaine or d-amphetamine produces depressive-like symptoms in both rats and humans. The majority of experiments with rodents have assessed the effects of amphetamine withdrawal on reinforcing electrical self-stimulation in different brain regions, but relatively few have examined effects on responding for natural reinforcers. In the present study, two groups of mildly food and water deprived male rats were trained to respond on a lever for a 4% sucrose solution under a progressive ratio schedule of reinforcement. One group was subsequently administered a 4-day regimen of injections of increasing doses of d-amphetamine based on a schedule shown previously to reduce self-stimulation behaviour. Break points were significantly reduced for up to 4 days after the termination of drug administration, suggesting a decreased motivation to obtain the natural reward. A further experiment demonstrated that the identical drug regimen produced no effect upon consumption of the 4% sucrose solution when it was freely available. These results demonstrate that the progressive ratio procedure may be a useful technique for evaluating changes in motivation for natural reinforcing stimuli following withdrawal from psychostimulant drugs.

Animals↗

PubMed1999

Nicotine self-administration in rats on a progressive ratio schedule of reinforcement.

RATIONALE: Robust intravenous (i.v.) nicotine self-administration (SA) in rats has been reported by several laboratories, including our own, using fixed ratio (FR) schedules of reinforcement. Studies on other drugs of abuse, however, suggest that progressive ratio (PR) schedules may provide additional information not gained using FR schedules. OBJECTIVE: Here, we attempt to establish and characterize nicotine SA on a PR. METHODS: One study allowed animals to acquire SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0. 09 mg/kg) before being switched to a PR. A second study examined extinction by saline substitution or pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary analysis into the role of secondary reinforcers in the extinction process. RESULTS: SA of nicotine on a PR was stable across repeated sessions. The number of infusions earned on a PR correlated with infusion rate on a FR; however, a large portion of the variance in SA on a PR could not be accounted for by infusion rate on a FR. Infusions on a PR increased across the same range of doses that produced a decrease in the infusion rate on a FR. Extinction of responding occurred after saline substitution or pretreatment with mecamylamine, and animals re-acquired when nicotine was again available without pretreatment. The presence of drug-paired stimuli appeared to lengthen the extinction process. CONCLUSIONS: Nicotine supports stable SA on a PR. Since PR and FR schedules may measure different aspects of nicotine reinforcement, PR schedules may be valuable in further characterizing group and individual differences in nicotine reinforcement.

Animals↗

PubMed2001

Physiological, subjective and reinforcing effects of oral and intravenous cocaine in humans.

RATIONALE: There is little comparative information on the qualitative similarity, relative potency and reinforcing effects of oral cocaine versus cocaine administered via other routes. METHODS: The present study used a within-subject, double-blind, double-dummy design to compare the physiological, subjective and reinforcing effects of placebo and oral (62.5, 125, 250 mg/70 kg) and intravenous (IV) (12.5, 25, 50 mg/70 kg) cocaine in volunteers with histories of cocaine abuse. RESULTS: Cocaine produced dose-dependent increases on heart rate and blood pressure, with effects lasting longer after oral than IV cocaine. Subjective ratings (e.g., "rush," "drug effect," "liking") were qualitatively similar and dose-dependently increased after oral and IV administration, and the duration of effects was similar under both routes. On a money versus drug choice measure of reinforcement, the monetary amounts at which participants chose drug over money increased as a function of cocaine dose under both routes of administration. At doses that produced comparable subjective, physiological, and reinforcing effects, oral cocaine was not identified as cocaine as frequently as IV cocaine. Across measures, the data suggested that IV cocaine was approximately 10 times more potent than oral cocaine. CONCLUSIONS: Overall, the results of this study support qualitatively similar effects of oral and IV cocaine and suggest that oral cocaine may be an effective tool for studying cocaine's effects in human laboratory studies.

Administration, Oral↗

PubMed2004

Biological arm motion through reinforcement learning.

The present paper discusses an optimal learning control method using reinforcement learning for biological systems with a redundant actuator. It is difficult to apply reinforcement learning to biological control systems because of the redundancy in muscle activation space. We solve this problem with the following method. First, we divide the control input space into two subspaces according to a priority order of learning and restrict the search noise for reinforcement learning to the first priority subspace. Then the constraint is reduced as the learning progresses, with the search space extending to the second priority subspace. The higher priority subspace is designed so that the impedance of the arm can be high. A smooth reaching motion is obtained through reinforcement learning without any previous knowledge of the arm's dynamics.

Animals↗

PubMed1983

Self-stimulation and task-related responding: the role of sensory reinforcement in maintaining and extending treatment effects.

The present study was aimed at (a) eliminating self-stimulation and increasing task-related responding in severely handicapped children, and (b) assessing maintenance and carry-over of treatment effects following the use of sensory reinforcement. The results showed that applying sensory or edible-liquid reinforcement, contingent on low rates of task-related responses, did not increase these responses nor decrease self-stimulation. These behavior changes were obtained with the combination of reinforcement and punishment. Sensory reinforcement was effective in maintaining and extending the treatment results, while edible-liquid contingencies were not.

Attention↗

PubMed1987

Treatment of severe self-injurious behavior by the mentally retarded using the bubble helmet and differential reinforcement procedures.

We examined the effectiveness of a bubble helmet and differential reinforcement procedures in the treatment of the self-injurious behavior (SIB) of three adult residents of a state hospital for the developmentally disabled. A multiple-baseline design across settings and an ABC design were used to assess the effectiveness of these procedures. Results indicated that the introduction of the bubble helmet in conjunction with differential reinforcement procedures produced notable reductions in SIB for all three participants. These reductions were significantly greater than those produced by using the differential reinforcement procedures alone. Social validity, generalization and follow-up data further documented the efficacy and acceptability of the bubble helmet plus differential reinforcement procedures. The advantages of the bubble helmet over other forms of restraint and the theoretical implications of these findings are also discussed.

Adult↗

PubMed1992

The possible function of positive reinforcement in home-bound agoraphobia: a case study.

We conducted an uncontrolled case study (ABA design) based upon the hypothesis that the behavior of a home-bound agoraphobic is at least partially maintained by positive reinforcement in the home and that a disruption of access to home-based reinforcement would lead to an increased frequency of out-of-the-home behavior. Data concerning the types and amounts of behavior engaged in by the subject within the confines of her home and yard were gathered during a 30-day base line period. In addition, potential reinforcers in the home were identified by a survey schedule and by self-report of time allocation. During an 18-day intervention period the subject agreed only to engage in certain reinforcing activities outside her home (e.g., only watching television at a neighbor's house). Postintervention results indicated that for the first time in over 7 years the subject began engaging in out-of-home activities, including walking to other parts of the street, visiting several neighbors' homes, and attending parties at neighbors' homes. Moreover, data suggested a positive trend in time spent outside the yard during both 2 and 18 month follow-up periods. However, significant restrictions in the range of mobility were still observed.

Activities of Daily Living↗

PubMed1976

Strength-duration analysis of the organization of reinforcement pathways in the medial forebrain bundle of rats.

Strength-duration curves were determined for electrical self-stimulation of the brain in rats implanted with lateral hypothalamic electrodes. The rats self-stimulated in different behavioral situations which required them to make different responses, and the parameters of the strength-duration curves determined in each situation were compared. The comparisons suggested that two distinct groups of neurons were involved in the mediation of brain stimulation reinforcement of the bar pressing response, and that one of these groups was primarily involved in mediating the reinforcement of an alley running response, while the other group primarily mediated the reinforcement of a responses suggested that the nature of the response a rat is response a rat is required to perform determines the exact combination of neurons from the two groups which participate in mediating the brain stimulation reinforcement of the task. The possible functional significance of these two neuron groups was discussed.

Animals↗

PubMed1982

Drug reinforcement studied by the use of place conditioning in rat.

Rats display a preference for an environment in which they previously received morphine. The present report provides behavioral and pharmacological data for this simple model of reinforcement produced by opiates and describes an aversion in rats for an environment in which they previously received naloxone. Preferences were produced with intravenous (i.v.) morphine sulfate at doses of 0.08-15 mg/kg and durations of the pairing between environment and morphine of 10 min to 1.5 h. Preferences were also seen with other opiate agonists (etorphine-HCl and levorphanol-tartrate), another route of drug administration (subcutaneous), and after 1-4 administrations of morphine. Cocaine-HCl (i.v.), a non-narcotic drug, known to be self-administered by humans, also produced a place preference. Lithium chloride (i.v.), an agent found to be a punishing stimulus in other situations, produced a place aversion. There was no appreciable preference for an environment paired with dextrorphan-tartrate and naloxone-HCl (2 mg/kg, i.p.) blocked the production of the preference produced by i.v. morphine. In contrast to the effect produced by morphine, aversions were produced with (-)-naloxone-HCl alone at doses of 0.1-45 mg/kg (i.v.). The aversion was not produced at (+)-naloxone. Implantation of rats with a 75 mg morphine pellet 3 days prior to place conditioning potentiated the aversive effect of naloxone. It was concluded that place conditioning produced by morphine and naloxone is mediated by specific opiate receptors and that stimulating and decreasing activity of the endogenous opioid peptide system with systemically administered drugs is positively reinforcing and aversive, respectively. The discussion emphasizes application of the simple and sensitive place conditioning model to drug reinforcement research, including analyses of reinforcement produced by microinjection of opiates into the brain.

Animals↗

PubMed1982

Reinforcing effects of brain microinjections of morphine revealed by conditioned place preference.

The previously documented place conditioning paradigm was used to study the reinforcing effects of cerebral microinjections of morphine. Rats with implanted cannulae experienced place conditioning procedures, involving morphine administration into the IV (0.5 or 10 microgram), III (10 microgram) or lateral (0.5-10 microgram) ventricles. Positive reinforcement, indicated by a significant preference for the place paired with morphine compared to the place similarly paired with control treatment, was seen in rats given 10 microgram morphine into the lateral ventricle. The rats given 10 microgram into the III ventricle also showed a preference, but the effect was not statistically significant. Positive reinforcement was subsequently demonstrated with morphine microinjections (10 microgram) into the lateral hypothalamus, periaqueductal gray or nucleus accumbens. No clear preferences were produced by morphine injections into the caudate-putamen, amygdala or nucleus ambiguus. Following the final place conditioning test, rats were re-administered the treatment dose and analgesia and body temperature were measured. All three sites associated with reinforcement evidenced hyperthermia, but only the periaqueductal gray evidenced a short-latency analgesia. Sites with null place conditioning were not associated with any major behavioral effects. Using (+) and (-)-morphine (10 microgram), it was demonstrated that only the active (-)-stereoisomer was effective in producing place preferences after injection into the periaqueductal gray. It was concluded that morphine administered directly into parts of the rat brain can produce place conditioning similar to that seen after systematically administered morphine. Morphine-produced place preference is not related to the acute depressant aspects of morphine, but may be related to the stimulant aspects.

Animals↗

PubMed1990

Methylxanthines elevate reinforcement threshold for electrical brain stimulation: role of adenosine receptors and phosphodiesterase inhibition.

Caffeine increases reinforcement threshold in a brain stimulation procedure that allows the rat to self-regulate the intensity of electric current delivered via an electrode in the medial forebrain bundle. In order to determine the generality of that finding, we used this same autotitration procedure to assess the behavioral effects of 5 methylxanthines in addition to caffeine. All of the methylxanthines produced significant dose-dependent elevations of reinforcement threshold with the following order of potency: 7-(beta-chloroethyl)theophylline greater than isobutylmethyl-xanthine greater than 1,7-dimethylxanthine greater than theophylline greater than caffeine greater than 8-chlorotheophylline. This order of potency correlates significantly with the reported order of potency for inhibiting adenosine-stimulated cAMP, an effect mediated by the adenosine A2 receptor. Some of the behavioral effects of methylxanthines have been attributed to antagonism of adenosine receptor binding and inhibition of phosphodiesterase. The nonxanthine phosphodiesterase inhibitors papaverine and Ro 20-1724, had small but significant effects on reinforcement threshold, papaverine increasing it and Ro 20-1724 decreasing it. Thus, as a pharmacologic class, methylxanthines appear to increase reinforcement threshold, an effect which may be mediated via adenosine receptor antagonism but probably not by inhibition of phosphodiesterase.

Animals↗

PubMed1994

Lesions of the pedunculopontine tegmental nucleus block drug-induced reinforcement but not amphetamine-induced locomotion.

It has been proposed that the positive reinforcing and motor stimulating effects of drugs involve the activation of a common neural substrate. Reinforcing effects of food, drugs and brain stimulation are blocked by lesions of the pedunculopontine tegmental nucleus (PPTg), which is a component of the mesencephalic locomotor region. This has suggested that the PPTg may be involved in both positive reinforcement and forward locomotion. In four separate experiments, rats were prepared with NMDA (0.5 microliters of 0.1 M solution) or sham lesions of the PPTg. Animals in the first two experiments were tested for the development of a conditioned place preference (CPP) to morphine (2 mg/kg x 3 pairings) or amphetamine (1.5 mg/kg x 3 pairings). Ten days later, spontaneous motor activity (SMA) was assessed in these animals following a subcutaneous injection of saline or amphetamine (1.5 mg/kg). In two further experiments, drug-naive lesioned and control animals were tested for SMA only (saline or 1.5 mg/kg amphetamine in Experiment 3, and saline, 0.5 mg/kg, or 3 mg/kg amphetamine in Experiment 4). Lesions of the PPTg blocked the development of a CPP to both morphine and amphetamine. In contrast, lesions had no effect on saline or amphetamine-stimulated SMA. The PPTg, therefore, appears to be involved in the reinforcing effects of amphetamine and morphine, but is not necessary for the expression of amphetamine-induced activity.

Amphetamine↗

PubMed1991

Similar effects of a beta-carboline and of flumazenil in negatively and positively reinforced learning tasks in mice.

Methyl beta-carboline-3-carboxylate (beta-CCM) and flumazenil (Ro15-1788) are known to be respectively an inverse agonist and an antagonist of the central benzodiazepine-receptor. Surprisingly, these two drugs have shown a similar enhancing effect in a negatively reinforced multiple-trial brightness discrimination task in mice. Thus, to evaluate the role of anxiety in this task, the action of these two drugs were compared in the same learning task with a positive or a negative reinforcement. Mice were trained for sessions of ten trials per day for six consecutive days. The sessions during the first three days took place after administration of beta-CCM (0.3 mg/kg), flumazenil (15 mg/kg) or vehicles of these drugs. A negative reinforcement (electric foot-shock) was used in a first experiment, and a positive one (food reward) in a second experiment. Results showed that, whatever the reinforcement, the two drugs enhance learning in a brightness discrimination task. The hypothesis is that flumazenil could have an inverse agonist profile in learning tasks. The question remains as to whether the flumazenil enhancing learning process results from increased arousal and/or anxiogenic factors, or from a negative modulatory influence of endogenous diazepam-like ligands for benzodiazepine receptors.

Animals↗

PubMed1975

Control of the rat's sniffing behavior by response-independent and dependent schedules of reinforcing brain stimulation.

The rat's sniffing response occurs in continuous bursts, at approximately 5-11 Hz. In the present experiments, the analog signal from a thermo-couple probe in the nasal cavity was digitized to provide a discrete logic pulse, defining a sniff, and permitting on-line presentations of reinforcing brain stimulation contingent on momentary sniffing patterns. Schedules of reinforcer presentation included response-independent fixed interval (temporal conditioning), continuous reinforcement (CRF), and differential reinforcement of low rates (DRL 10 sec). Under temporal conditioning, bursts of sniffing were observed immediately after stimulation, and an acceleration in sniffing developed preceding stimulation. Under CFR, operant rate-intensity functions were found to be similar to traditional bar-press data. Under DRL, sniffs were effectively paced by the criterion interval, and interresponse time analyses revealed evidence of temporal discrimination. The behavioral patterns were interpreted in terms of the interplay of operant and respondent functions.

Animals↗