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

RATIONALE: Illicit drugs may be unpredictable in terms of the time and effort required to obtain them, and this can be modeled with variable- (VR) vs. fixed-ratio (FR) schedules. In a recent experiment (Zamarripa et al. 2023), the potency of cocaine to maintain choice was greatest under a VR (compared with a FR) when food was available under a FR schedule. OBJECTIVES: The goal of the current study was to extend prior choice results with VR vs. FR schedules to a more efficient procedure with cocaine or fentanyl vs. food. Furthermore, the FR schedule of food delivery was manipulated to determine whether increased drug choice under a VR (compared with a FR) schedule depends on the size of the schedule of nondrug reinforcement. METHODS: Adult female (n = 2) and male (n = 4) monkeys chose between cocaine (0-30 µg/kg/injection) or fentanyl (0-1.0 µg/kg/injection) and food (2 pellets/delivery) under a 5-component procedure. In different conditions, food was available under a FR 25, 50, or 100 and cocaine or fentanyl were available under FR or VR 100 schedules. RESULTS: Cocaine's potency to maintain choice was greatest under a VR 100 (compared with FR 100) when food was available under a FR 50 or 100, and fentanyl's potency to maintain choice was generally greatest under a VR 100 (compared with FR 100) when food was available under a FR 25 or 100. However, outcomes between FR and VR schedules with fentanyl were less robust compared with cocaine. CONCLUSION: Variability in the time and effort required to obtain illicit drugs could contribute to excessive allocation of behavior toward drug use at the expense of more predictable nondrug alternatives, supporting treatment or policies aimed at making drug access more predictable through agonist medications or a safe supply. The impact of variable requirements on drug choice may be reduced if nondrug reinforcers are relatively less costly, supporting the use of low-cost reinforcers in behavioral therapies like contingency management.

Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys.

RATIONALE: Kappa-opioid receptor (KOR) agonists are antinociceptive but have side effects that limit their therapeutic utility. New KOR agonists have been developed that are fully efficacious at the KOR but may produce fewer or reduced side effects that are typical of KOR agonists. OBJECTIVES: We determined behavioral profiles for typical and atypical KOR agonists purported to differ in intracellular-signaling profiles as well as a mu-opioid receptor (MOR) agonist, oxycodone, using a behavioral scoring system based on Novak et al. (Am J Primatol 28:124-138, 1992, Am J Primatol 46:213-227, 1998) and modified to quantify drug-induced effects (e.g., Duke et al. J Pharmacol Exp Ther 366:145-157, 2018). METHODS: Six adult male rhesus monkeys were administered a range of doses of the typical KOR agonists, U50-488H (0.0032-0.1 mg/kg) and salvinorin A (0.00032-0.01 mg/kg); the atypical KOR agonists, nalfurafine (0.0001-0.001 mg/kg) and triazole 1.1 (0.01-0.32 mg/kg); the MOR agonist, oxycodone (0.0032-0.32 mg/kg); and as controls, cocaine (0.032-0.32 mg/kg) and ketamine (0.32-10 mg/kg). For time-course determinations, the largest dose of each KOR agonist or MOR agonist was administered across timepoints (10-320 min). In mixture conditions, oxycodone (0.1 mg/kg) was followed by KOR-agonist administration. RESULTS: Typical KOR agonists produced sedative-like and motor-impairing effects. Nalfurafine was similar to typical KOR agonists on most outcomes, and triazole 1.1 produced no effects on its own except for reducing scratch during time-course determinations. In the mixture, all KOR agonists reduced oxycodone-induced scratching, U50-488H and nalfurafine reduced species-typical activity, and U50-488H increased rest/sleep posture. CONCLUSIONS: Atypical "biased" KOR agonists produce side-effect profiles that are relatively benign (triazole 1.1) or reduced (nalfurafine) compared to typical KOR agonists.

Choice between variable and fixed cocaine injections in male rhesus monkeys.

RATIONALE: The schedule of drug availability may enhance choice of a drug. In non-human subjects, reinforcers are chosen more often when available under variable schedules of reinforcement relative to fixed schedules. OBJECTIVE: To determine whether variable-drug access is an important determinant of cocaine choice by manipulating the schedule, drug dose, and combination of schedule + dose. METHOD: Four male rhesus monkeys chose between cocaine doses (0.025-0.4 mg/kg/injection). In control conditions, the schedule and dose of each drug delivery were fixed. In other conditions, the reinforcement schedule (i.e., variable-ratio schedule), dose of each cocaine delivery, or both were variable on one lever while all aspects on the other lever remained fixed. RESULTS: When cocaine dose was equal on average (0.1 mg/kg/injection), 2 of 4 subjects chose cocaine associated with the variable schedule more than the fixed schedule. All subjects chose the variable dose that was equal on average to the fixed dose, and this difference was statistically significant. Three of 4 subjects chose cocaine associated with the variable combination over the fixed option (when the dose was equal on average). During dose-response determinations (when dose on the variable and fixed options were not equal), making the schedule, dose, or both variable generally did not alter cocaine's potency as a reinforcer. CONCLUSION: While many factors contribute to drug choice, unpredictable drug access is a feature that may be common in the natural environment and could play a key role in the allocation of behavior to drug alternatives by patients with substance-use disorders.

Self-administration and behavioral economics of second-generation synthetic cathinones in male rats.

RATIONALE: Synthetic cathinones have become increasingly available as drugs of abuse. Distribution of these drugs is made possible by altering the chemical structures of prohibited cathinones and marketing them under misleading labels. Very little is known about the relative reinforcing effectiveness of new synthetic cathinones relative to known drugs of abuse. OBJECTIVE: We examined self-administration of three second-generation synthetic cathinones: alpha-pyrrolidinopentiophenone (alpha-PVP), 4-methyl-N-ethylcathinone (4-MEC), and 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP) relative to methamphetamine. METHOD: Male, Sprague-Dawley rats, implanted with intravenous catheters, were trained to self-administer methamphetamine (0.05 mg/kg/injection) under a fixed-ratio schedule. Following training, various doses of methamphetamine (0.006-0.1 mg/kg/injection), alpha-PVP (0.0015-0.1 mg/kg/injection), 4-MEC (0.1-3.2 mg/kg/injection), or 4-MePPP (0.1-0.8 mg/kg/injection) were available for self-administration in separate groups, followed by a behavioral-economics evaluation of the reinforcing effectiveness of each drug. RESULTS: For all drugs, at least one dose functioned as a reinforcer. Alpha-PVP and 4-MePPP maintained the highest numbers of infusions per session and both were more effective reinforcers relative to methamphetamine. 4-MEC and methamphetamine were not significantly different in terms of infusions per session or reinforcing effectiveness. CONCLUSION: Emerging synthetic cathinones whose primary pharmacological mechanism is to block dopamine uptake but with little effects on monoamine release or serotonin uptake may have a greater degree of abuse potential compared with known abused stimulants.