Insights from Preclinical Choice Models on Treating Drug Addiction

Abstract

Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food 'choice' procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures.

Keywords: addiction; choice; drug self-administration; preclinical model; substance-use disorder.

Figure 1

Conceptual Framework for Drug Addiction as a Disorder of Behavioral Misallocation between Concurrently Available Abused Substances and Nondrug Reinforcers. In a natural environment, a subject allocates its behavior based on numerous environmental, pharmacological, and biological factors. For most individuals, nondrug reinforcers (e.g., food, money, or social commendation) are effective to minimize or eliminate behavior directed towards the procurement and use of abused substances. However, for some individuals (A), behavior becomes predominantly misallocated (red arrow) to an abused substance at the expense of these nondrug reinforcers. This misallocation of behavior may be due to environmental, pharmacological, and biological factors that remain to be fully elucidated. Based on this conceptual framework, substance-use disorder treatments should not only decrease behavior maintained by abused drugs (faded red arrow), but also increase behavior (thicker black arrows) maintained by socially adaptive, nondrug reinforcers (B).

Figure 2

Illustration of a Concurrent Schedule of Heroin and Food Pellet Availability in a Prototypical Intravenous Rat Drug Self-Administration Environment. In a typical intravenous rat drug self-administration procedure, the red light (S^D1) over the right lever would be illuminated and responding (R1) on the right lever would produce intravenous heroin injections (S^C1). Responding on the left lever would have no programmed consequences. In a heroin versus food choice procedure, the red light (S^D1) over the right lever would also be illuminated and responding (R1) on the right lever would produce intravenous heroin injections (S^C1). In addition, the blue light (S^D2) over the left lever would also be concurrently illuminated and responding (R2) on the left lever would produce a food pellet (S^C2). The rat is free to allocate its behavior between these two concurrently available reinforcers, depending upon the programmed experimental parameters.

Figure 3

Effects of Continuous Treatment with the Prodrug Phendimetrazine on Choice between (−)-Cocaine and Food in Rhesus Monkeys (N = 4) [14]. (A,B) Saline and phendimetrazine treatment effects on cocaine choice dose–effect functions. Top and middle abscissae: unit cocaine dose in milligrams per kilogram per injection (log scale). Top Left ordinate: percent cocaine choice. Top Right ordinate: percent food choice. Middle ordinate: rates of responding in responses per second. (C) Summary data for response requirement completions ‘choices’ for the total session (total choices), food choices, and cocaine choices summed across all cocaine doses. All points and bars represent mean ± S.E.M. obtained during days 12–14 of each treatment period. Filled symbols indicate statistically different (P <0.05) from continuous saline treatment conditions (+ saline) within a cocaine dose.

Figure 4

Effects of Continuous Treatment with the Monoamine Uptake Inhibitor (+)-Methylphenidate on Choice between (+)-Methamphetamine and Food in Rhesus Monkeys (N = 4) [15]. (A,B) Saline and methylphenidate treatment effects on methamphetamine choice dose–effect functions. Top and middle abscissae: unit methamphetamine dose in milligrams per kilogram per injection (log scale). Top Left ordinate: percent methamphetamine choice. Top Right ordinate: percent food choice. Middle ordinate: rates of responding in responses per second. (C) Summary data for response requirement completions ‘choices’ for the total session (total choices), food choices, and methamphetamine choices summed across all methamphetamine doses. All points and bars represent mean ± S.E.M. obtained during days 5–7 of each treatment period. Filled symbols and asterisks indicate statistically different (P <0.05) from continuous saline treatment conditions (+ saline) within a methamphetamine dose. Numbers in parentheses denote the number of subjects contributing to that data point if less than the total number of subjects tested. This indicates that a subject failed to complete at least one response requirement during that component of the choice session.