Modeling risk factors for nicotine and other drug abuse in the preclinical laboratory

Abstract

Risk factors that predict vulnerability for nicotine and other drug abuse have been identified using preclinical models, and there is close agreement with clinical and epidemiological studies. The major risk factors to be discussed are age, sex/hormonal status, impulsivity, sweet-liking, novelty reactivity, proclivity for exercise, and environmental impoverishment (vs. enrichment). This discussion will focus on factors that preclinical research has determined are strong and translatable predictors of nicotine and other drug abuse. An advantage of using preclinical models is that prospective, longitudinal studies and within-subject designs can be used to reveal risk factors that are diverse yet maintain unique characteristics. The many interrelationships among these factors lead to an additive vulnerability that increases the predictability that drug abuse will occur. A feature that these risk factors have in common is that they consistently predict vulnerability to drug abuse over critical transition phases of addiction that are difficult to examine prospectively in humans, such as acquisition, escalation, and reinstatement of drug-seeking after abstinence (relapse). The models offer valuable information that has been transferred to effective prevention and treatment strategies for smoking and other drug abuse in humans.

Introduction

Researchers have identified several conditions that strongly predict an individual's risk for abuse of nicotine and other drugs. To better understand the impact and generality of these predictors, animal models have been developed that provide a useful approach to studying vulnerability to and mechanisms underlying nicotine and other drug abuse. One of the main advantages of using animal models is that prospective, longitudinal studies and within-subject designs can be used to reveal risk factors so that at-risk individuals can be identified and targeted for focused intervention and treatment attempts. There is close agreement between the results of studies from human and nonhuman animals; thus, the translational value of proceeding from preclinical investigations to clinical trials for screening, prevention, and treatment of drug abuse has been excellent (for a review see Carroll et al., 2001).

An advantage of preclinical studies has been to select, or selectively breed, animals for addiction-prone or addiction-resistant traits and to subsequently test their proclivity for drug-seeking behavior (Carroll et al., 2008b). Another advantage is that several phases of drug abuse that are difficult to study prospectively in humans can be modeled in nonhuman animals, including initiation of drug use, escalation of intake, and reinstatement of drug use after a drug-free period (relapse). A better understanding of these phases is needed, as they are hallmarks of this chronic relapsing disorder.

In this review, risk factors for nicotine and other drug abuse are considered, including age, sex and hormonal effects, impulsivity, dietary preferences, novelty reactivity, avidity for exercise, and impoverished vs. enriched environments. Other individual factors play a role in predicting drug abuse such as depression and aggression, stress, and relief of withdrawal symptoms; however, these risk factors are beyond the scope of this review and have been expertly reviewed elsewhere (Goeders, 2003, Miczek et al., 2008).

Preclinical models also offer the opportunity to examine ways in which these factors coexist and interact to produce additive vulnerability. The following discussion will focus on the risk factors mentioned above that preclinical research has defined as strong and translatable (to humans) as predictors of nicotine and other drug abuse and how they interact to confer additive vulnerability. Table 1 summarizes the major risk factors for nicotine and other drug abuse and illustrates many interactions among them. These factors and their interrelationships will be discussed in subsequent sections.