Amphetamine pretreatment accelerates the subsequent escalation of cocaine self-administration behavior

Abstract

It has been proposed that some neuroadaptations that underlie behavioral sensitization may play a role in the development and persistence of addiction. However, whether or not sensitization facilitates the development of symptoms specific to addiction, such as the escalation of drug intake, is not known. We examined, therefore, the effect of pretreatment with a sensitizing regimen of amphetamine on the escalation of subsequent drug intake in rats given the opportunity to self-administer cocaine. Amphetamine pretreatment produced psychomotor sensitization and also accelerated the subsequent escalation of cocaine intake. This suggests that the neural circuits that are altered as a consequence of repeated amphetamine treatment, and the induction of sensitization, may overlap with those responsible for the development of some addiction-like behaviors.

Introduction

The repeated intermittent administration of psychostimulant drugs produces an enduring hypersensitivity to their psychomotor activating effects, a phenomenon known as psychomotor sensitization (Segal, 1975, Robinson and Becker, 1986). Psychomotor sensitization is associated with persistent neuroadaptations in mesocorticolimbic structures (Vanderschuren and Kalivas, 2000, Robinson and Kolb, 2004, Vezina, 2004), which are important in mediating the incentive motivational properties of addictive drugs and of natural rewards (Wise and Bozarth, 1987, Kelley and Berridge, 2002). It is been proposed, therefore, that sensitization-related changes within this circuitry may alter the process of incentive motivation, and thus contribute to the development and persistence of addiction (Robinson and Berridge, 1993, Robinson and Berridge, 2003).

Consistent with this hypothesis, drug treatments that produce psychomotor sensitization facilitate the subsequent acquisition of drug self-administration behavior and a conditioned place preference for drug (Lett, 1989, Piazza et al., 1989, Horger et al., 1990, Vezina et al., 1999), and produce enhanced incentive motivation for drug (Mendrek et al., 1998, Deroche et al., 1999, Lorrain et al., 2000). However, these studies do not directly address whether or not treatments that induce psychomotor sensitization also facilitate the development of addiction. Addiction refers to a cluster of symptoms, including the compulsive pursuit of drugs, which are not necessarily reflected in self-administration behavior or a conditioned place preference. For this reason, there have been a number of attempts to develop animal models of addiction that better capture key behavioral symptoms of the disorder (Wolffgramm and Heyne, 1995, Ahmed and Koob, 1998, Heyne and Wolffgramm, 1998, Deroche-Gamonet et al., 2004, Vanderschuren and Everitt, 2004). In one such model, animals allowed extended access to drug self-administration (6 h per session) develop several addiction-like behaviors that are not present, or are less pronounced, in animals given limited access to drug (1–3 h per session). For example, animals allowed extended access to cocaine self-administration gradually escalate their intake such that drug consumption within the first hour of a test session almost doubles relative to the intake of rats given more limited access (Ahmed and Koob, 1998). Also, compared to rats given limited access, rats given extended access, either by increasing daily drug availability or by making drug available for months, show other symptoms of addiction, including an increased motivation to obtain cocaine as assessed by break-point (Paterson and Markou, 2003, Deroche-Gamonet et al., 2004), continued pursuit of drug despite the risk of adverse consequences (Vanderschuren and Everitt, 2004) and enhanced cocaine-induced reinstatement of drug seeking (Ahmed and Cador, 2006).

We recently reported that extended access to cocaine self-administration not only results in escalated drug intake, but also produces especially robust psychomotor sensitization, compared to that produced by limited access self-administration (Ferrario et al., 2005). The association between psychomotor sensitization and escalated drug intake suggests that both may be due to related neuroadaptations in mesocorticolimbic systems. If this is true, then the induction of sensitization prior to being given the opportunity to self-administer cocaine may facilitate the development of addiction-like behaviors, including the escalation of drug intake. To address this hypothesis, we asked whether or not amphetamine pretreatment, resulting in robust psychomotor sensitization, would alter the escalation of subsequent cocaine self-administration behavior in rats given extended access to cocaine.