Peripheral involvement in nicotine-induced enhancement of ethanol intake

Abstract

It is a well-known fact that a large percentage of alcoholics smoke, and in the experimental rat, intermittent nicotine administration enhances ethanol intake and ethanol preference in a free-choice situation between 6% (v/v) ethanol and water. The present study focuses on the possible involvement of central and/or peripheral nicotine acetylcholine receptors (nAChR) in nicotine-induced sensitization to dopamine-related behavioral effects of ethanol. Wistar rats drinking less than 60% of their total daily fluid from a 6% ethanol solution were used in the study. Nicotine, vehicle, mecamylamine, hexamethonium, mecamylamine+nicotine, and hexamethonium+nicotine were administered subchronically for 15 days. All groups, except the vehicle pre-treated group, markedly increased their ethanol preference to approximately 80%, as well as their ethanol intake. NMRI mice received the same treatments for 10 days, after which ethanol (2.5 g/kg, intraperitoneal (i.p.)) was given acutely and locomotor activity was recorded. Ethanol-induced locomotor stimulation was enhanced in most groups, as compared to the vehicle pre-treated group. Administration of quarternary autonomic drugs to ethanol high-preferring rats (hexamethonium, methscopolamine, sotalol and phentolamine) according to different acute and chronic treatment protocols indicated that the enhanced ethanol intake may involve increased ganglionic and/or peripheral muscarinic neurotransmission. Taken together, the above results indicate that peripheral mechanisms may be involved in the enhancement of dopamine-related behavioral effects of ethanol observed after subchronic intermittent treatment with nicotinic drugs.

Introduction

Several clinical studies have revealed a positive correlation between nicotine and ethanol intake Deher & Fraser, 1967, Walton, 1972, Bobo et al., 1987, and this correlation becomes stronger the more the alcohol consumption approaches that of alcoholics (Craig & Van Natta, 1977). Moreover, some studies indicate that early onset of nicotine use may predispose to future alcoholism (DiFranza & Guerrera, 1990) or other drug abuse (Loimer et al., 1991). It is unclear whether this positive correlation is due to environmental (e.g., socioeconomic) or genetic factors, to pharmacological actions exerted by the drugs, or to a combination of these.

An argument for that the positive correlation observed in humans between nicotine and ethanol intake may be due to the pharmacological effects of nicotine comes from recent animal studies. Thus, both chronic (Potthoff et al., 1983) and intermittent (Blomqvist et al., 1996) nicotine administration to rats enhance ethanol intake and ethanol preference in a free-choice situation between ethanol and water. Moreover, in the latter study neurochemical evidence was presented indicating that the nicotine treatment used increased the dopamine releasing effect both of nicotine and ethanol in the limbic forebrain. Furthermore, studies in the mouse indicate that intermittent nicotine treatment increases ethanol-induced locomotor stimulation as well as dopamine turnover in this species (Johnson et al., 1995). These dopaminergic alterations are of great interest considering that mesolimbic dopamine systems since long have been implicated in the positive reinforcing effects of ethanol and other drugs of abuse, including nicotine Engel & Carlsson, 1977, Wise & Bozarth, 1987, Wise & Rompre, 1989, Koob, 1992.

Indeed, we have recently published a series of studies suggesting that the mechanisms of action of nicotine and ethanol in their mesolimbic dopamine activating and reinforcing effects may be partly similar. Thus, ethanol-induced dopamine overflow in the rat nucleus accumbens (nAcc) involves central but not peripheral nicotinic acetylcholine receptors (nAChR) Blomqvist et al., 1993, Blomqvist et al., 1997, and, just as is the case with nicotine (Nisell et al., 1994), nAChR in the ventral tegmental area rather than those located on dopaminergic neuronal terminals in the nAcc appear to be most important in this respect (Blomqvist et al., 1997). Moreover, a recent study employing the microdialysis technique in combination with an ethanol intake/preference paradigm revealed that blockade of ventral tegmental nAChR reduces ethanol intake and preference and antagonizes the elevation of extracellular accumbal dopamine levels that is associated with voluntary ethanol intake (Ericson et al., 1998). Further microdialysis studies have recently indicated that ethanol's interaction with ventral tegmental nAChR is indirect rather than direct and may involve enhanced endogenous acetylcholine release in the ventral tegmental area (Ericson et al., unpublished data).

The phenomenon of sensitization of the mesocorticolimbic dopamine system and of behaviors related to activation of this system has lately attracted much interest in drug abuse research Nestler, 1992, Kalivas, 1993. Thus, it has been suggested that long-term molecular alterations of the mesolimbic dopamine system in response to intermittent exposure to various drugs of abuse, including nicotine, result in a system that is hyperresponsive both to the drug itself and to internal and external cues previously associated with drug intake. These phenomena could underlie the development of drug craving and thus direct the individual towards renewed drug intake (Robinson & Berridge, 1993).

The above-mentioned findings regarding the consequences of subchronic, intermittent nicotine treatment for ethanol related effects were interpreted to reflect a cross-sensitization phenomenon between nicotine and ethanol Johnson et al., 1995, Blomqvist et al., 1996. However, it should be noted that in the mouse studies no locomotor activating or dopamine turnover enhancing effect of nicotine itself could be observed neither after acute nor subchronic administration. Furthermore, in the rat studies, no correlation between the locomotor stimulatory response to nicotine or the degree of sensitization to this response on the one hand and the ensuing enhanced ethanol intake and preference on the other was obtained. Thus, a more correct interpretation of these findings may be that subchronic nicotine treatment sensitizes to dopamine-related aspects of ethanol pharmacology but that this effect is not necessarily related to behavioral sensitization to nicotine. Hence, cross-sensitization, in its strict meaning, may not be at hand.

Considering the clear relationship between nicotine and ethanol intake, both in man and in experimental animals, and the indications that early nicotine exposure may predispose to alcoholism, as well as the possibility that this nicotine effect involves mechanisms different from those inducing sensitization to nicotine itself, in-depth studies of nicotine-induced sensitization to ethanol now become important. The present study focuses on the possible involvement of central and/or peripheral nAChR in nicotine-induced sensitization to dopamine-related behavioral effects of ethanol.