Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats.

Nociceptin/orphanin FQ peptide (NOP) receptor agonists attenuate morphine-induced conditioned place preference in rodents. However, it is not known whether NOP agonists have reinforcing properties or can inhibit mu opioid receptor (MOP)-mediated reinforcement as measured by drug self-administration in rodents. Further understanding the behavioral effects of NOP agonists could suggest them as having potential in attenuating reinforcing effects of opioids. In the first part of the study, reinforcing properties of selective NOP agonist SCH221510 were determined and compared with the full MOP agonist remifentanil under fixed-ratio 5 (FR5) and progressive-ratio (PR) schedules of drug self-administration. In the second part, effects of systemic and intracisternal pretreatment of SCH221510 were determined and compared with MOP antagonist naltrexone in attenuating reinforcing effects of remifentanil and a non-drug reinforcer (sucrose pellets). Remifentanil self-administration (0.3-10 µg/kg/infusion) generated a biphasic dose-response curve, characteristic of drugs with reinforcing properties. SCH221510 (3-300 µg/kg/infusion) self-administration resulted in flat dose-response curves and early break-points under the PR, indicative of drugs lacking reinforcing value. Intracisternally, but not systemically, administered SCH221510 (0.3-3 µg) attenuated remifentanil self-administration, comparable with systemic naltrexone (0.03-0.3 mg/kg). SCH221510 (1-3 µg), unlike naltrexone (0.03-1 mg/kg), attenuated responding for sucrose pellets. Both effects of SCH221510 were reversed by the NOP antagonist J-113397 (0.3-3 µg). These results suggest that SCH221510 does not function as a reinforcer in rats, and that it can attenuate the reinforcing value of MOP agonists; therefore, the potential utility of NOP agonists for the treatment of drug addiction warrants further evaluation.

Random-ratio schedules produce greater demand for i.v. drug administration than fixed-ratio schedules in rhesus monkeys.

RATIONALE: Organisms emit more responses when food is provided according to random as compared with fixed schedules of reinforcement. Similarly, many human behaviors deemed compulsive are maintained on variable schedules (e.g., gambling). If greater amounts of behavior are maintained by drugs of abuse when earned according to variably reinforced schedules, this would suggest that excessive drug-taking behavior may be due in part to the nature of drug availability. OBJECTIVES: The aim was to determine whether random schedules of contingent intravenous drug delivery would produce more responding than similarly priced fixed schedules. METHODS: Six rhesus macaque subjects responded to produce cocaine (0.003-0.03 mg/kg/inj), remifentanil (0.01-1.0 µg/kg/inj), or ketamine (0.01-0.1 mg/kg/inj) according to either fixed or random ratio requirements that increased systematically across sessions. Demand curves were generated with the most effective dose of each drug and compared across drug and schedule type. RESULTS: Cocaine and remifentanil maintained higher levels and rates of responding when earned according to random-ratio schedules as compared with fixed-ratio schedules. This difference was most pronounced when drugs were available at high unit prices. Differences in responding across the schedule types generated by ketamine-a lesser-valued reinforcer-were qualitatively similar but smaller in magnitude. CONCLUSIONS: The current study provides a systematic replication across reinforcer type demonstrating that drugs delivered after a random number of responses generate more behavior than those delivered according to a fixed schedule. The variable nature of the availability of drugs of abuse-particularly those that are scarce or expensive-may be a contributing factor to excessive drug intake by humans. This effect is most likely to be observed when more highly demanded (reinforcing) drugs are being consumed.

Risky choice in pigeons: preference for amount variability using a token-reinforcement system.

Pigeons were given repeated choices between variable and fixed numbers of token reinforcers (stimulus lamps arrayed above the response keys), with each earned token exchangeable for food. The number of tokens provided by the fixed-amount option remained constant within blocks of sessions, but varied parametrically across phases, assuming values of 2, 4, 6, or 8 tokens per choice. The number of tokens provided by the variable-amount option varied between 0 and 12 tokens per choice, arranged according to an exponential or rectangular distribution. In general, the pigeons strongly preferred the variable option when the fixed option provided equal or greater numbers of tokens than the variable amount. Preference for the variable amount decreased only when the alternatives provided widely disparate amounts favoring the fixed amount. When tokens were removed from the experimental context, preference for the variable option was reduced or eliminated, suggesting that the token presentation played a key role in maintaining risk-prone choice patterns. Choice latencies varied inversely with preferences, suggesting that local analyses may provide useful ancillary measures of reinforcer value. Overall, the results indicate that systematic risk sensitivity can be attained with respect to reinforcer amount, and that tokens may be critical in the development of such preferences.

Risky choice in pigeons and humans: a cross-species comparison.

Pigeon and human subjects were given repeated choices between variable and adjusting delays to token reinforcement that titrated in relation to a subject's recent choice patterns. Indifference curves were generated under two different procedures: immediate exchange, in which a token earned during each trial was exchanged immediately for access to the terminal reinforcer (food for pigeons, video clips for humans), and delayed exchange, in which tokens accumulated and were exchanged after 11 trials. The former was designed as an analogue of procedures typically used with nonhuman subjects, the latter as an analogue to procedures typically used with human participants. Under both procedure types, different variable-delay schedules were manipulated systematically across conditions in ways that altered the reinforcer immediacy of the risky option. Under immediate-exchange conditions, both humans and pigeons consistently preferred the variable delay, and indifference points were generally ordered in relation to relative reinforcer immediacies. Such risk sensitivity was greatly reduced under delayed-exchange conditions. Choice and trial-initiation response latencies varied directly with indifference points, suggesting that local analyses may provide useful ancillary measures of reinforcer value. On the whole, the results indicate that modifying procedural features brings choices of pigeons and humans into better accord, and that human-nonhuman differences on risky choice procedures reported in the literature may be at least partly a product of procedural differences.

Toward an animal model of gambling: delay discounting and the allure of unpredictable outcomes.

Laboratory investigations of gambling are sometimes criticized as lacking ecological validity because the stakes wagered by human subjects are not real or no real monetary losses are experienced. These problems may be partially addressed by studying gambling in laboratory animals. Toward this end, data are summarized which demonstrate that laboratory animals will work substantially harder and prefer to work under gambling-like schedules of reinforcement in which the number of responses per win is unpredictable. These findings are consistent with a delay discounting model of gambling which holds that rewards obtained following unpredictable delays are more valuable than rewards obtained following predictable delays. According to the delay discounting model, individuals that discount delayed rewards at a high rate (like pathological gamblers) perceive unpredictably delayed rewards to be of substantially greater value than predictable rewards. The reviewed findings and empirical model support the utility of studying animal behavior as an ecologically valid first-approximation of human gambling.

Delay discounting of real and hypothetical rewards III: steady-state assessments, forced-choice trials, and all real rewards.

Human research in delay discounting has omitted several procedures typical of animal studies: forced-choice trials, consequences following each response, and assessment of stable response patterns. The present study manipulated these procedures across two conditions in which real or hypothetical rewards were arranged. Six college students participated in daily sessions, in which steady-state discounting of hypothetical and real rewards was assessed. No systematic effects of repeated exposure to hypothetical rewards was detected when compared with first day assessments of discounting. Likewise, no systematic effect of reward type (real versus hypothetical) was detected. When combined with previous research failing to detect a difference between hypothetical and potentially real rewards, these findings suggest that assessing discounting of hypothetical rewards in single sessions is a practical and valid procedure in the study of delay discounting.

Delay discounting of potentially real and hypothetical rewards: II. Between- and within-subject comparisons.

Prior studies comparing discounting of delayed hypothetical or potentially real rewards have reported no differences, but they used within-subjects designs. This raises the possibility that participants remembered their choices in one condition and repeated them in the other. In Experiment 1, between-subjects comparisons were made with an adjusting-amount procedure. No significant effect of reward type on delay discounting was detected. Experiment 2 increased the proportion of real rewards and made between- and within-subject comparisons. These comparisons also failed to reveal a significant effect of reward type. Although these findings are consistent with prior findings, caution is urged because choices involving hypothetical rewards have yet to be compared with choices involving real rewards (i.e., the consequences of every choice are obtained) in an experiment using forced-choice trials and steady-state methodology.