Preclinical Determinants of Drug Choice under Concurrent Schedules of Drug Self-Administration

Abstract

Drug self-administration procedures have played a critical role in the experimental analysis of psychoactive compounds, such as cocaine, for over 50 years. While there are numerous permutations of this procedure, this paper will specifically focus on choice procedures using concurrent schedules of intravenous drug self-administration. The aims of this paper are to first highlight the evolution of drug choice procedures and then review the subsequent preclinical body of literature utilizing these choice procedures to understand the environmental, pharmacological, and biological determinants of the reinforcing stimulus effects of drugs. A main rationale for this paper is our proposition that choice schedules are underutilized in investigating the reinforcing effects of drugs in assays of drug self-administration. Moreover, we will conclude with potential future directions and unexplored scientific space for the use of drug choice procedures.

Figure 1

Baseline choice between different doses of cocaine (0–0.1 mg/kg/injection) and food pellets in rhesus monkeys (n = 4) under a concurrent FR10 : FR100 schedule of cocaine injections and food availability. Abscissae: unit dose of cocaine in milligrams per kilogram per injection. Top ordinate: percent cocaine choice. Middle ordinate: rates of responding in responses per second. Bottom ordinate: number of choices completed. All points represent mean data SEM obtained during the last 3 days of saline treatment. These unpublished data demonstrate two key observations from choice procedures. First, cocaine choice increases in a monotonic function as the unit cocaine dose increases. Second, while rates of responding display the prototypic, inverted-U-shaped dose-effect function, rates of responding are not predictive of cocaine choice, nor are rates of responding predictive of the number of choices completed per component.

Figure 2

Effects of chronic intravenous m-fluoroamphetamine (0.1 mg/kg/hr) administration on choice between cocaine and food in rhesus monkeys (n = 4). Abscissae: unit dose of cocaine in milligrams per kilogram per injection. Top ordinate: percent cocaine choice. Middle ordinate: rates of responding in responses per second. Bottom ordinate: number of choices completed. All points represent mean data SEM obtained during the last 3 days of m-fluoroamphetamine treatment. These published data [17] demonstrate that experimental manipulations can selectively decrease cocaine choice without also decreasing rates of responding and the number of choices completed. This profile would be considered ideal for a candidate medication to treat cocaine dependence.

Figure 3

Effects of chronic intravenous methadone (0.32 mg/kg/hr) administration on choice between cocaine and food in rhesus monkeys (n = 3). Abscissae: unit dose of cocaine in milligrams per kilogram per injection. Top ordinate: percent cocaine choice. Middle ordinate: rates of responding in responses per second. Bottom ordinate: number of choices completed. All points represent mean data SEM obtained during the last 3 days of methadone treatment. These published data [18] demonstrate that experimental manipulations can selectively decrease rates of responding and the number of choices completed without decreasing cocaine choice.