Nicotine-induced behavioral disinhibition and ethanol preference correlate after repeated nicotine treatment

Abstract

This study investigated the effects of repeated daily nicotine (0.35 mg/kg; 15 days) treatment on behavioral inhibition and locomotor activity in the elevated plus-maze and on voluntary ethanol consumption. When challenged with nicotine before the test, rats pretreated with repeated nicotine spent more time on and made more entries onto the open arms of an elevated plus-maze than did vehicle-pretreated animals. The ethanol preference and intake, measured during 3 h after a nicotine injection, was also higher in the nicotine-pretreated animals. In ethanol consumption experiments, there was a positive correlation between the % time and % entries made onto open arms vs. the ethanol preference and intake. However, no correlation between the total number of entries made in the elevated plus-maze and the measures of ethanol consumption was observed. These findings suggest that the ability of repeated nicotine administration to increase ethanol consumption is related to development of a nicotine-induced reduction of inhibitory control rather than development of locomotor sensitization.

Introduction

Drugs of abuse produce a variety of neurochemical effects which are drug-specific, but a common feature appears to be their ability to activate the mesolimbic dopamine system Di Chiara and Imperato, 1988, Koob, 1992 and to stimulate locomotor activity (Wise and Bozarth, 1987). In experimental animals, repeated treatment with most addictive drugs, including nicotine, progressively enhances the drug-induced effects mediated via this dopamine pathway, leading to a long-lasting behavioral and neurochemical sensitization Post and Rose, 1976, Segal and Mandell, 1974, Clarke and Kumar, 1983, Kalivas et al., 1993, Nestler and Aghajanian, 1997, Pierce and Kalivas, 1997, Balfour et al., 1998. The neurobiological processes underlying drug-induced sensitization have been proposed to be involved in transforming the wanting of a drug into craving, and may thus involve an enhancement of the incentive motivational qualities of the drugs and other drug-associated (conditioned) stimuli (Robinson and Berridge, 1993). Supporting this theory, previous drug experience increases subsequent self-administration Horger et al., 1990, Horger et al., 1992, Piazza et al., 1990, Pierre and Vezina, 1997, and enhances the rewarding and reinforcing effects of the drug itself and that of conditioned stimuli Lett, 1989, Shippenberg and Heidbreder, 1995, Taylor and Horger, 1999. However, few studies have demonstrated a direct relationship between locomotor sensitization to dependence producing drugs and drug intake. Therefore, it is possible that the role of sensitization in drug-taking behavior is permissive rather than causally related to the increased drug-intake observed after repeated drug exposure, and that other neural mechanisms are more directly related to the quantity of drug consumed.

The role of inhibitory control and impulsivity has lately received increased attention in the research on drug abuse Jentsch and Taylor, 1999, Olausson et al., 1999, Olausson et al., 2000, Robbins and Everitt, 1999, Rogers et al., 1999, Söderpalm and Svensson, 1999. It is well established that drug addicts abusing different kinds of dependence-producing drugs display decreased inhibitory control when assessed in different neuropsychological tests Allen et al., 1998, Lejoyeux et al., 1998, Bickel et al., 1999, Kirby et al., 1999. It is possible that this inhibitory control deficit may contribute to the inability of the drug addict to control the drug use. Repeated drug exposure has been proposed to impair inhibitory control that, in addition to the effects on incentive motivation, may be involved in the compulsive drug-seeking and drug-intake encountered in drug addicts Jentsch and Taylor, 1999, Olausson et al., 1999, Olausson, 2000.

We have previously demonstrated that repeated intermittent treatment with compounds acting at peripheral or both peripheral and central nicotinic acetylcholine receptors, including nicotine, increases voluntary ethanol consumption in rats Blomqvist et al., 1996, Ericson et al., 2000a. Interestingly, these same treatments were recently found to promote the development of nicotine-induced behavioral disinhibition in the elevated plus-maze Olausson et al., 1999, Ericson et al., 2000b, but, with the exception of nicotine, not locomotor sensitization to nicotine. Therefore, interestingly, there appears to be a dissociation between the effects of nicotinergic compounds on locomotor sensitization and behavioral disinhibition. Moreover, these data provide circumstantial evidence that this dissociation is reflected also in the relation between these effects and voluntary ethanol intake, and behavioral disinhibition appears more closely related to the intake of ethanol in rats than locomotor sensitization. Consequently, it is possible that the neuronal mechanisms underlying nicotine-induced behavioral disinhibition after repeated nicotine treatment are more closely related to those involved in the increased voluntary ethanol consumption observed after such treatments rather than to those mediating sensitization to the locomotor stimulatory effects of nicotine. Therefore, this study was designed to directly investigate the relationship between the nicotine-induced behavioral disinhibition and voluntary ethanol consumption. In order to do so, we used a dose of nicotine (0.35 mg/kg s.c.) that we previously have found to produce both locomotor sensitization and behavioral disinhibition as well as to increase ethanol intake. The effects of repeated treatment with this nicotine dose on nicotine-induced behavioral inhibition and locomotor activity in the elevated plus-maze and on voluntary ethanol consumption were examined and the data subjected to correlation analysis.