Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction

Abstract

Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d-amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

Keywords: addiction; choice; medication; nonhuman primate; preclinical model.

Figure 1

Choice between different unit cocaine doses (0 – 0.1 mg/kg/injection) and 1-g food pellets in rhesus monkeys under a concurrent FR10:FR100 schedule of cocaine injections and food availability. Amphetamine [21] and lisdexamfetamine treatment [32] results have been previously published. Abscissae: unit dose of cocaine in milligrams per kilogram per injection. Top left ordinate: percent cocaine choice. Top right ordinate: percent food choice. Bottom ordinate: rates of operant responding in responses per second. All dashed lines represent the mean (± s.e.m.) of three consecutive days of saline treatment before pharmacological treatment initiation. Data points represent the mean of last 3 treatment days of each 7-day treatment period. Filled symbols indicate statistical significance (p<0.05) compared to saline conditions. These results demonstrate three main findings from drug vs. food choice procedures. First, cocaine vs. food choice increases in a monotonic function as the unit cocaine dose increases. Second, rates of operant responding are not predictive of cocaine vs. food choice nor are rates of responding predictive of pharmacological treatment effects. Finally, continuous treatment with amphetamine and repeated administration of lisdexamfetamine decreased cocaine choice and produced a reciprocal increase in food choice.