Choice between variable and fixed cocaine injections in male rhesus monkeys

Abstract

Rationale The schedule of drug availability may enhance choice of a drug. In nonhuman 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.

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

“…Thus, "indifference" represented here is the result of averaging from the extremes. We have found that a biased pattern of behavior is typical under identical FR schedules when choice is between identical reinforcers or between different reinforcers (e.g., food and drug) that are subjectively equivalent (Freeman et al, 2014;Huskinson et al, 2016Huskinson et al, , 2017Huskinson et al, , 2019Woolverton, 2003) and is consistent with predictions of the matching law (Baum, 1974;Herrnstein, 1961), because exclusive choice of one option maximizes reinforcement, as does allocating choice among both options. Importantly, the test lever was held constant between Fixed and Variable conditions so that a lever bias had an equal impact on choice across conditions.…”

“…This was driven largely by conditions in which the Variable Cocaine or Variable Food option were chosen less frequently (i.e., low-and high-dose conditions) compared with conditions in which the variable option was chosen more frequently (i.e., middle-dose conditions). Fewer VR trials resulted in skewed means, and we have seen this before (Huskinson et al, 2017). However, these values are still close to the programmed VR values.…”

“…A total of six female and seven male adult rhesus monkeys (Macaca mulatta) served as subjects. Similar choice studies with rhesus monkeys in our laboratory have shown that 3-6 subjects are typically sufficient to draw meaningful conclusions on a withinsubject basis (e.g., Huskinson et al, 2016Huskinson et al, , 2017Huskinson et al, , 2019. However, previous work has largely been conducted with males, and the goal of the current experiments was to include 3-4 subjects per sex per condition.…”

“…A response on either lever made the other lever inactive and engaged the requirement on the active lever. This feature has been used by others examining choice between VR and FR schedules of food (e.g., Johnson et al, 2011Johnson et al, , 2012 and cocaine delivery (Huskinson et al, 2017) and prevents switching between levers once an initial choice has been made. The outcome associated with the chosen lever was delivered after completion of the response requirement.…”

“…For drug conditions, subjects had a catheter surgically implanted using aseptic technique similar to that described previously (Huskinson et al, 2017(Huskinson et al, , 2019. All monkeys were given atropine (0.04 mg/kg, i.m.)…”