Delay Discounting of Cocaine‐Food Choice in Socially Housed Female and Male Cynomolgus Macaques

Abstract

At present, there are no FDA-approved pharmacological treatments for cocaine use disorders (CUD). Because there is evidence of sex differences in vulnerability to cocaine abuse (O’Brien and Anthony, 2005) and treatment outcomes (Sugarman et al., 2017), research needs to include both sexes in evaluating treatment strategies. Weafer and de Wit (2014) have suggested that impulsivity is a stronger predictor of drug abuse in females compared to males and lack of inhibitory control may be a mechanism mediating the faster progression of drug use in women compared to men. The overarching goal of the present research is to utilize a “personalized medicine” approach to evaluating the role of environmental and pharmacological interventions on the reinforcing effects of cocaine. In this study, socially housed female (N=5) and male (N=6) cynomolgus monkeys, each implanted with an indwelling intravenous catheter and self-administering cocaine (0.01-0.1 mg/kg/injection) under a concurrent schedule with food (1.0-g banana-flavored pellets) as the alternative, served as subjects. Under these conditions, the frequency of cocaine choice increases in a dose-dependent manner, from <20% choice when 0.01 mg/kg/injection cocaine was available as an alternative to food, to >80% choice when 0.1 mg/kg/injection was the alternative to food; in this preliminary study, no sex or social rank differences were noted. Next, environmental manipulations were studied at both ends of the cocaine dose-response curve in order to assess whether there were sex differences in sensitivity to the reinforcing effects of cocaine. To study impulsivity, we used a delay discounting procedure similar to that described by Woolverton and colleagues (Huskinson et al., 2015, 2016). Differences in sensitivity to changes in cocaine preference when the preferred cocaine dose was available would provide information as to potential sex differences in the reinforcing strength of cocaine. In contrast, when low, non-preferred, cocaine doses were studied and food reinforcement was delayed, sex differences would provide information related to sensitivity of adverse environmental changes on vulnerability to cocaine abuse. In preliminary findings, when delays were imposed on high-dose cocaine, the indifference points (IP; 50% choice between cocaine and food) were not different between males and females (168.88 ± 75.6 seconds vs. 154.94 ± 39.1 seconds, respectively). However, when low-dose cocaine was available and food reinforcement was delayed, males were more sensitive to changes in the environment, as represented by lower IP values (46.74 ± 16.8 seconds vs. 114.39 ± 44.9 seconds, respectively). Studies are currently underway to determine if pharmacological manipulations, with and without delays, would provide additional reductions in cocaine choice, at both ends of the cocaine dose-response curve. An interesting behavioral pharmacology study would involve examine drug effects under conditions in which delayed high-dose cocaine and food-delayed low-dose cocaine produce similar behaviors (i.e., % cocaine choice).