Impact of the Aversive Effects of Drugs on Their Use and Abuse

Abstract

Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential.

Figure 1

Transition from the impulsive (acute) to the compulsive (abuse) patterns of drug-taking. Adapted from Meyer and Quenzer [8] using BioRender.com.

Figure 2

Median saccharin preference scores for animals previously given saccharin access during radiation exposure. Redrawn from Garcia et al. [33].

Figure 3

A hypothetical model of the aversive and rewarding effects of a drug and their potential interaction to impact its self-administration (which is a function of the overall affective response to the drug). The drug produces both aversive and rewarding effects in a dose-dependent manner. As illustrated in this specific example, the drug's rewarding effects are produced at lower doses that increase the drug's overall affective property that, in turn, drives the drug's intake. With increases in the dose, the drug's rewarding effects asymptote while the drug's aversive effects increase, reducing the overall affective value of the drug and decreasing the drug's self-administration. In this model, the drug's rewarding effects are assumed to initiate and maintain drug intake (at least under acute conditions) while its aversive effects limit it. The nature of such an interaction is not static and depends upon a host of factors (see Sections 11 and 12). Further, the relative contributions of the aversive effects in limiting intake change as drug intake go from regulated to dysregulated given the change in the reward valence from positive to negative. Created with BioRender.com.