Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys.

RATIONALE: Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects. OBJECTIVE: The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A. METHODS: Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018 mg/kg/injection). Once trained, cocaine (0.018 mg/kg/injection) or oxycodone (0.0056 mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1-3.2 µg/kg/injection), nalfurafine (0.0032-0.1 µg/kg/injection), triazole 1.1 (3.2-100.0 µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components. RESULTS: Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed. CONCLUSIONS: These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse.

Quantification of observable behaviors following oral administration of oxycodone and nalfurafine in male rhesus monkeys.

BACKGROUND: Recent preclinical studies have investigated the atypical kappa-opioid receptor (KOR) agonist, nalfurafine, as a co-formulary with mu-opioid receptor (MOR) agonists as a potential deterrent for misuse. However, no study has investigated effects of nalfurafine combined with a MOR agonist using an oral route of administration. The objective of the current study was to measure behavioral effects of orally administered oxycodone and nalfurafine, alone and combined, in rhesus monkeys using a quantitative behavioral observation procedure. METHODS: Adult male rhesus monkeys (N=5) were orally administered vehicle, oxycodone (0.56-1.8mg/kg), nalfurafine (0.001-0.0056mg/kg), or mixtures (1.0mg/kg oxycodone/0.001-0.0056mg/kg nalfurafine) in a Jell-O vehicle at multiple timepoints (10-320min). Species-typical and drug-induced behaviors were recorded by observers blinded to conditions. RESULTS: Oxycodone alone significantly increased scratch and face-rub behaviors without affecting other behaviors. Nalfurafine decreased baseline levels of scratch without affecting other behaviors, and oxycodone-nalfurafine combinations resulted in reduced oxycodone-induced scratching at a dose (0.001mg/kg) that did not produce sedation-like effects. Oxycodone combined with larger nalfurafine doses (0.0032-0.0056mg/kg) also reduced oxycodone induced scratch that were accompanied with sedation-like effects (i.e., increased lip droop). CONCLUSIONS: Nalfurafine was orally active in rhesus monkeys, and it reduced oxycodone-induced pruritus at a dose that did not produce sedation-like effects that are commonly observed with prototypical KOR agonists. Combinations of low doses of nalfurafine with MOR agonists such as oxycodone may be well-tolerated by humans who are prescribed MOR agonists for the treatment of pain.

Choice between food and cocaine reinforcers under fixed and variable schedules in female and male rhesus monkeys.

Illicit drugs like cocaine may be uncertain in terms of the time and effort required to obtain them. Behavior maintained by variable schedules resembles excessive drug-taking compared with fixed schedules. However, no prior research has examined fixed versus variable schedules in drug versus nondrug choice. The present study evaluated cocaine versus food choice under fixed- (FR) and variable-ratio (VR) schedules. The simpler food versus food and cocaine versus cocaine arrangements also were included. Adult female (n = 6) and male (n = 7) rhesus monkeys chose between cocaine (0.01-0.18 mg/kg/injection) and food (4 pellets/delivery), food and food (4 pellets/delivery), or cocaine and cocaine (0.018-0.03 mg/kg/injection) under FR and VR 100 and 200 schedules. In cocaine versus food choice, cocaine's potency to maintain choice was greatest when available under a VR 100 or 200 schedule and food under an FR schedule and was lowest when cocaine was available under an FR 200 schedule and food was available under a VR 200 schedule. In food versus food choice, males chose food associated with a VR schedule more than food associated with an FR schedule. In cocaine versus cocaine choice, females and males chose cocaine associated with a VR schedule more than cocaine associated with an FR schedule, particularly under VR 200. These findings suggest that uncertainty in terms of time and effort required to obtain cocaine, or perhaps the occasional low-cost access that results from VR schedules, results in greater allocation of behavior toward drug reinforcers at the expense of more certain, nondrug alternatives. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Environmental Uncertainty and Substance Use Disorders: A Behavior Analytic Perspective.

Substance use disorder (SUD) and drug overdose deaths represent major economic, health, and safety issues in the United States. The psychology of uncertainty provides a mechanism for understanding, reducing, and controlling the damage from substance misuse. Illicit drugs (such as heroin or cocaine) are uncertain in their availability, quality, and acquisition (the time and effort required to obtain them) compared with nondrug-related alternatives (such as consumable goods, hobbies, or paychecks). Furthermore, the severity and likelihood of negative outcomes associated with drug use likewise are uncertain. Such uncertainties worsen substance use outcomes. The current review conveys what is known about the impact of uncertainty on substance use: laboratory investigations of uncertain time and effort required to obtain a substance and uncertain drug quality show uncertainty exacerbates harm. Furthermore, uncertain negative outcomes are not likely to deter substance use in individuals with a SUD. Finally, several policy implications include access to agonist medications; creating a safer drug supply; access to clean syringes/needles, naloxone, and safe-injection sites; and ending incarceration for substance use.

The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys.

Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01-0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001-0.001 mg/kg) and triazole 1.1 (0.32-1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01-0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0-56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias.

Challenges to Conducting Contingency Management Treatment for Substance Use Disorders: Practice Recommendations for Clinicians.

A growing empirical literature supports contingency management (CM) as an efficacious treatment for substance use disorders, especially when reinforcers are immediate, frequent, and of sufficient magnitude on escalating schedules. However, in real world-practice, CM is often conducted in ways that are inconsistent with research protocols. One reason for these inconsistencies may be due to pragmatic challenges inherent in conducting CM. In this article, we described an outpatient CM treatment program for drug use disorders and several specific challenges associated with adherence to CM parameters from research protocols. Finally, we propose possible solutions for these challenges and discuss implications for practice.

Applied Quantitative Analysis of Behavior: What It Is, and Why We Care-Introduction to the Special Section.

Science evolves from prior approximations of its current form. Interest in changes in species over time was not a new concept when Darwin made his famous voyage to the Galapagos Islands; concern with speciation stretches back throughout the history of modern thought. Behavioral science also does and must evolve. Such change can be difficult, but it can also yield great dividends. The focus of the current special section is on a common mutation that appears to have emerged across these areas and the critical features that define an emerging research area-applied quantitative analysis of behavior (AQAB). In this introduction to the "Special Issue on Applications of Quantitative Methods," we will outline some of the common characteristics of research in this area, an exercise that will surely be outdated as the research area continues to progress. In doing so, we also describe how AQAB is relevant to theory, behavioral pharmacology, applied behavior analysis, and health behaviors. Finally, we provide a summary for the articles that appear in this special issue. The authors of these papers are all thinking outside the Skinner box, creating new tools and approaches, and testing them against relevant data. If we can keep up this evolution of methods and ideas, behavior analysis will regain its place at the head of the table!

Unpredictability as a modulator of drug self-administration: Relevance for substance-use disorders.

Drug self-administration has been regarded as a gold-standard preclinical model of addiction and substance-use disorder (SUD). However, investigators are becoming increasingly aware, that certain aspects of addiction or SUDs experienced by humans are not accurately captured in our preclinical self-administration models. The current review will focus on two such aspects of current preclinical drug self-administration models: 1) Predictable vs. unpredictable drug access in terms of the time and effort put into obtaining drugs (i.e., response requirement) and drug quality (i.e., amount) and 2) rich vs. lean access to drugs. Some behavioral and neurobiological mechanisms that could contribute to excessive allocation of behavior toward drug-seeking and drug-taking at the expense of engaging in nondrug-related activities are discussed, and some directions for future research are identified. Based on the experiments reviewed, lean and unpredictable drug access could worsen drug-seeking and drug-taking behavior in individuals with SUDs. Once more fully explored, this area of research will help determine whether and how unpredictable and lean cost requirements affect drug self-administration in preclinical laboratory studies with nonhuman subjects and will help determine whether incorporating these conditions in current self-administration models will increase their predictive validity.

Kappa opioid agonists reduce oxycodone self-administration in male rhesus monkeys.

RATIONALE: Combinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive ratio (PR) schedule of reinforcement. METHODS: In separate experiments, adult male rhesus monkeys (N = 4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01-0.1 mg/kg/injection) alone and combined with salvinorin A (experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (experiment 2; 0.0001-0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine's effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg; i.m.). RESULTS: All subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (experiment 1) or to levels that were significantly lower than oxycodone alone (experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI. CONCLUSIONS: These results demonstrate that KOR agonists, including the clinically used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys and that nalfurafine's punishing effect is KOR-dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability.

Self-administration of benzodiazepine and cocaine combinations by male and female rhesus monkeys in a choice procedure: role of α1 subunit-containing GABAA receptors.

RATIONALE: Compounds lacking efficacy at the α1 subunit-containing GABAA (α1GABAA) receptor appear to have reduced abuse potential compared with those having measurable efficacy at this receptor, though their self-administration in nonhuman primates is dependent upon past drug experience. OBJECTIVES: We used a drug vs. drug choice procedure to evaluate the hypothesis that L-838,417, a compound lacking efficacy at αGABAA receptors, would not enhance cocaine choice in monkeys trained to self-administer cocaine. We also hypothesized that zolpidem, a compound with preferential modulation of ⍺1GABAA receptors and midazolam, a nonselective benzodiazepine, would enhance cocaine choice in this procedure. METHODS: One female and three male rhesus monkeys chose between cocaine alone (0.1 mg/kg/injection) vs. the same dose of cocaine combined with midazolam (0.003-0.1 mg/kg/injection), zolpidem (0.003-0.3 mg/kg/injection), or L-838-417 (0.01-0.1 mg/kg/injection). In addition, we evaluated choice between saline and L-838,417 at select doses to determine whether L-838,417 would function as a reinforcer on its own. RESULTS: Consistent with our hypotheses, midazolam- and zolpidem-cocaine mixtures were chosen over cocaine alone at sufficiently high doses. However, L-838,417-cocaine mixtures also were chosen over cocaine alone in three of four subjects with at least one dose. When available alone vs. saline, L-838,417 did not function as a reinforcer in any subject. CONCLUSION: Compounds that lack efficacy at α1GABAA receptors may have low abuse potential compared to classic benzodiazepines, but self-administration of these compounds is context-dependent.

Shallow discounting of delayed cocaine by male rhesus monkeys when immediate food is the choice alternative.

Huskinson et al. (2015) recently examined delay discounting in monkeys choosing between an immediate drug (cocaine) reinforcer and a delayed nondrug (food) reinforcer. The present experiment examined the reverse situation: choice between immediate nondrug (food) and delayed drug (cocaine) reinforcers. Whereas the former choice situation exemplifies drug abuse from a delay-discounting perspective, our interest in the latter choice situation is derived from the observation that drug abusers, who characteristically are associated with impulsive choice, typically must devote considerable time to procuring drugs, often at the expense of immediate nondrug alternatives. Accordingly, we analyzed 3 male rhesus monkeys' choices between immediate food and delayed cocaine (0.1 and 0.2 mg/kg/injection) using a hyperbolic model that allowed us to compare discounting rates between qualitatively different reinforcers. Choice of immediate food increased with food amount, and choice functions generally shifted leftward as delay to cocaine increased, indicating a decrease in the subjective value of cocaine. Compared with our previous delay-discounting experiment with immediate cocaine versus delayed food, both doses of delayed cocaine were discounted at a shallow rate. The present results demonstrate that rhesus monkeys will tolerate relatively long delays in an immediate-food versus delayed-drug situation, suggesting that in intertemporal choices between cocaine and food, the subjective value of cocaine is less affected by the delay until reinforcement than is the subjective value of delayed food. More generally, the present findings suggest that although drug abusers may choose impulsively when immediate drug reinforcement is available, they exercise self-control in the acquisition of a highly preferred, delayed drug reinforcer. (PsycINFO Database Record

Delay discounting of food by rhesus monkeys: Cocaine and food choice in isomorphic and allomorphic situations.

Research on delay discounting has focused largely on nondrug reinforcers in an isomorphic context in which choice is between alternatives that involve the same type of reinforcer. Less often, delay discounting has been studied with drug reinforcers in a more ecologically valid allomorphic context where choice is between alternatives involving different types of reinforcers. The present experiment is the first to examine discounting of drug and nondrug reinforcers in both isomorphic and allomorphic situations using a theoretical model (i.e., the hyperbolic discounting function) that allows for comparisons of discounting rates between reinforcer types and amounts. The goal of the current experiment was to examine discounting of a delayed, nondrug reinforcer (food) by male rhesus monkeys when the immediate alternative was either food (isomorphic situation) or cocaine (allomorphic situation). In addition, we sought to determine whether there was a magnitude effect with delayed food in the allomorphic situation. Choice of immediate food and immediate cocaine increased with amount and dose, respectively. Choice functions for immediate food and cocaine generally shifted leftward as delay increased. Compared to isomorphic situations in which food was the immediate alternative, delayed food was discounted more steeply in allomorphic situations where cocaine was the immediate alternative. Notably, discounting was not affected by the magnitude of the delayed reinforcer. These data indicate that how steeply a delayed nondrug reinforcer is discounted may depend more on the qualitative characteristics of the immediate reinforcer and less on the magnitude of the delayed one.

Corn oil, but not cocaine, is a more effective reinforcer in obese than in lean Zucker rats.

Obesity is associated with abnormal brain reactivity in response to palatable food consumption, a factor that may contribute to non-homeostatic eating. However, little is known about how obesity interacts with the reinforcing effects of highly palatable constituents of food (e.g., fat), and if altered reinforcement processes associated with obesity generalize to non-food reinforcers. The current study compared the reinforcing effects of a fat (corn oil) and a drug of abuse (cocaine) in obese and lean Zucker rats. Specifically, obese and lean Zucker rats self-administered corn oil or intravenous cocaine in a behavioral economic demand procedure. For corn oil, maximum demand was higher and demand elasticity was lower in the obese rats compared to their lean counterparts. However, there were no differences in demand for cocaine between the obese and lean rats. These results demonstrate that a fat in the form of corn oil is a more effective reinforcer in obese Zucker rats. However, the fact that demand for cocaine was not different between the obese and lean rats suggests that differences in reward mechanisms may be reinforcer-specific and do not necessarily generalize to non-food reinforcers.

Discriminative-stimulus effects of second generation synthetic cathinones in methamphetamine-trained rats.

BACKGROUND: Synthetic cathinones are beta-ketophenethylamine analogs manufactured to avoid legal restrictions placed on illicit stimulants like methamphetamine. Regulating these "emerging" designer drugs require scientific evidence of abuse potential. METHODS: The present study evaluated the discriminative-stimulus effects of three synthetic cathinones, recently identified in commercial and confiscated products, in male Sprague-Dawley rats trained to discriminate methamphetamine (1.0 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food delivery. Three synthetic cathinones, 4-methyl-N-ethylcathinone (4-MEC; 1.0-8.0 mg/kg), 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP; 4.0-16.0 mg/kg), and alpha-pyrrolidinopentiophenone (alpha-PVP; 0.25-2.0 mg/kg) were tested for their ability to substitute for methamphetamine. RESULTS: Full substitution for the training dose of methamphetamine occurred at the highest doses for both 4-MePPP and alpha-PVP, and 4-MEC did not substitute at any dose tested. CONCLUSIONS: The present findings show that two synthetic cathinones, 4-MePPP and alpha-PVP, produced subjective effects similar to those of methamphetamine. The synthetic cathinone, 4-MEC, did not produce subjective effects similar to those of methamphetamine with the parameters used in the current experiment. Based on findings here and by others, these three compounds warrant further tests of abuse potential.

Self-administration of cocaine and remifentanil by monkeys under concurrent-access conditions.

RATIONALE: Cocaine and opioids are often co-abused. Laboratory research has focused largely on the reinforcing effects of mixtures of drugs relative to the drugs alone. Less research has examined drug mixing by the subject under concurrent-access conditions. OBJECTIVE: Self-administration of various doses of cocaine and remifentanil was examined under concurrent-access conditions. It was hypothesized that if cocaine and opioid combinations were more effective reinforcers than the single drugs, subjects would mix the two drugs by adjusting their responding to cocaine and an opioid alternative to maintain an optimal ratio of cocaine/remifentanil intake. METHOD: Three male rhesus monkeys were allowed to self-administer cocaine (0.05-0.2 mg/kg/inj) or saline on one lever and remifentanil (0.05-0.4 µg/kg/inj) or saline on the other lever under concurrent fixed-ratio (FR) 10 schedules. Daily sessions lasted 2 h, and there was a 1-s timeout after every 10-s injection. RESULTS: When saline and drug were concurrently available, responding on the saline-associated lever was low relative to the drug alternative. When cocaine and remifentanil were concurrently available, both drugs were self-administered above saline levels. Cocaine intake decreased, and remifentanil intake increased as a function of the remifentanil dose that was available. Conversely, cocaine intake and remifentanil intake did not change systematically as a function of the cocaine dose that was available. CONCLUSION: Monkeys will mix cocaine and an opioid when the two drugs are available concurrently. However, there was no indication that monkeys titrated drug intake to maintain an optimal ratio of intake of the two compounds.

Predicting abuse potential of stimulants and other dopaminergic drugs: overview and recommendations.

Examination of a drug's abuse potential at multiple levels of analysis (molecular/cellular action, whole-organism behavior, epidemiological data) is an essential component to regulating controlled substances under the Controlled Substances Act (CSA). We reviewed studies that examined several central nervous system (CNS) stimulants, focusing on those with primarily dopaminergic actions, in drug self-administration, drug discrimination, and physical dependence. For drug self-administration and drug discrimination, we distinguished between experiments conducted with rats and nonhuman primates (NHP) to highlight the common and unique attributes of each model in the assessment of abuse potential. Our review of drug self-administration studies suggests that this procedure is important in predicting abuse potential of dopaminergic compounds, but there were many false positives. We recommended that tests to determine how reinforcing a drug is relative to a known drug of abuse may be more predictive of abuse potential than tests that yield a binary, yes-or-no classification. Several false positives also occurred with drug discrimination. With this procedure, we recommended that future research follow a standard decision-tree approach that may require examining the drug being tested for abuse potential as the training stimulus. This approach would also allow several known drugs of abuse to be tested for substitution, and this may reduce false positives. Finally, we reviewed evidence of physical dependence with stimulants and discussed the feasibility of modeling these phenomena in nonhuman animals in a rational and practical fashion. This article is part of the Special Issue entitled 'CNS Stimulants'.

Effects of different fixed-ratio requirements on delay discounting in rats.

In delay discounting, choice is between two reinforcers that differ in amount and delay, and the subjective value of either reinforcer decreases as a function of delay to its receipt. The steepness of the discounting function is thought to reflect the degree of impulsive choice. Many factors can influence impulsive choice, including the addition of a constant delay or response requirement to the smaller sooner (SS) and larger later (LL) reinforcers. A delay-discounting procedure developed by Evenden and Ryan (1996) is commonly used in behavioral research, yet effects of adding a response requirement to both alternatives with this procedure has not been examined. If different delay-discounting procedures are measuring the same phenomenon, preference reversals should occur with the Evenden and Ryan procedure as they do with other procedures with an added response requirement. The current experiment used an Evenden and Ryan procedure, and choice was examined when the response requirement was a small, intermediate, and large fixed ratio (FR). Fewer LL choices occurred with the small FR, and more LL choices occurred with the intermediate and large FR. The present experiment extends preference-reversal findings to a different and commonly used delay-discounting procedure.

Effects of acute and chronic administration of diazepam on delay discounting in Lewis and Fischer 344 rats.

Impulsive choice is often examined using a delay-discounting procedure, where there is a choice between two reinforcers of different magnitudes presented at varying delays. Individual discounting rates can be influenced by many factors including strain differences and drug effects. Lewis (LEW) and Fischer 344 (F344) rats have behavioral and neurochemical differences relevant to delay discounting and were used to examine effects of acute and chronic administration of diazepam on impulsive choice. Consistent with the previous literature, larger-reinforcer choice decreased as a function of increasing delays for all rats, and steeper discounting functions were obtained for LEW relative to F344 rats. Acute and chronic administration of diazepam resulted in differential effects between rat strains and sometimes between subjects within the same rat strain. Overall, larger-reinforcer choice remained unchanged across multiple phases of the experiment for LEW rats. For F344 rats, larger-reinforcer choice increased following the acute administration of smaller doses of diazepam and decreased following the acute administration of the largest dose tested. Decreases in larger-reinforcer choice occurred for F344 rats during chronic and postchronic administration and persisted throughout a nondrug return-to-baseline phase. These results suggest potential directions for future investigation of environmental, genetic, and neurochemical variables involved in delay discounting.

Strain differences in delay discounting between Lewis and Fischer 344 rats at baseline and following acute and chronic administration of d-amphetamine.

Stimulant drugs have been shown either to increase or decrease rates of delay discounting (impulsive choice). These mixed findings may result from genetic, neurochemical, or environmental factors. Lewis (LEW) and Fischer 344 (F344) rats have neurochemical and behavioral differences that may be relevant to delay discounting and were used to examine effects of acute and chronic administration of d-amphetamine (d-AMP) on impulsive choice using a within-session delay-discounting procedure. Male LEW (n=8) and F344 (n=8) rats chose between one food pellet delivered immediately and three food pellets delivered after an increasing delay. Saline and d-AMP (0.1, 0.3, 1.0, and 1.7 mg/kg) were tested acutely and during chronic d-AMP exposure. Choice for the larger reinforcer decreased as the delay to its presentation increased for both strains at baseline. LEW rats made more impulsive choices than F344 rats as indicated by shorter indifference points, and this is consistent with previous research. Acute administration of d-AMP dose dependently increased larger-reinforcer choice and area under the curve (AUC) for LEW, but not F344 rats. During chronic exposure to d-AMP, larger-reinforcer choice and AUC increased relative to acute administration for F344 rats responding in shorter delay series, but not for F344 rats responding in longer delay series or for LEW rats. Differential effects of acute and chronic administration of d-AMP on impulsive choice in LEW and F344 rats may be a result of various factors, including genetic, neurochemical, and environmental variables. Future research should attempt to tease apart the relative contribution of each of these factors on impulsive choice.

Effects of rimonabant on behavior maintained by progressive ratio schedules of sucrose reinforcement in obese Zucker (fa/fa) rats.

This experiment reports on the ability of rimonabant to alter the reinforcing properties of food in the genetically obese Zucker (fa/fa) rat, a strain that exhibits higher levels of endocannabinoids in brain regions that correspond to heightened food intake. We characterized food reinforcement in obese and lean Zucker rats by placing behavior under progressive ratio schedules of sucrose reinforcement. Then, doses of rimonabant (1-10 mg/kg), a CB1 receptor antagonist, were administered. Obese Zuckers had slightly higher breakpoints for sucrose under baseline conditions compared with leans, and also demonstrated significantly higher response rates than leans. Rimonabant dose-dependently decreased breakpoints and response rates for both groups, though only obese Zuckers demonstrated suppressed behavior under the 1 mg/kg dose. The 10 mg/kg dose of rimonabant reduced breakpoints equally for both groups (by about 60%). This dose of rimonabant also reduced food intake by 20% in lean Zuckers, and by 30% in obese Zuckers. These findings extend the literature that rimonabant reduces food reinforcer efficacy, and suggest that obese Zuckers may exhibit a heightened sensitivity to rimonabant. The findings also suggest that the effort required to obtain food reinforcement may also play a role in the efficacy of rimonabant.