Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors

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Abstract

It was previously demonstrated that the central nicotinic acetylcholine receptor antagonist mecamylamine perfused in the ventral tegmental area (VTA) counteracts the elevation of extracellular dopamine levels in the nucleus accumbens after systemic ethanol, as measured by in vivo microdialysis. In the present study we investigated the effect of different concentrations of ethanol perfused locally in the VTA or in the nucleus accumbens on extracellular accumbal dopamine levels. Ethanol (10–1000 mM) perfused in the VTA did not influence dopamine output in the nucleus accumbens. However, ethanol (300 mM) perfused in the nucleus accumbens increased accumbal dopamine levels to approximately the same extent (30%) as observed after systemic ethanol, whereas ethanol (1000 mM) decreased the dopamine output by approximately 50%. Next, the hypothesis that endogenous acetylcholine is required for the increased accumbal dopamine levels after ethanol was challenged. It was shown that in animals pre-treated with vesamicol, a potent inhibitor of vesicular acetylcholine storage, ethanol (300 mM) in the nucleus accumbens failed to elevate extracellular accumbal dopamine levels. Similarly, in animals perfused with mecamylamine in the VTA, but not in the nucleus accumbens, ethanol in the nucleus accumbens (300 mM) failed to increase accumbal dopamine levels. However, whereas dihydro-β-erythroidine (antagonist for the nicotinic receptor subtype α4β2) perfused in the VTA prevented the increase in accumbal dopamine after systemic nicotine, the antagonist was unable to prevent the dopamine elevating effects of ethanol. Finally, to investigate whether mecamylamine exerts its antagonizing effect of ethanol induced accumbal dopamine levels through an interaction with the NMDA receptor MK-801, the effects of the prototypic NMDA receptor antagonist were examined and compared to those of mecamylamine. After perfusion in the VTA, MK-801 enhanced accumbal dopamine levels by itself but did not antagonize the enhancing effect of ethanol. The present set of experiments indicate that the mesolimbic dopamine activating effects of ethanol may be due to an indirect rather than direct activation of ventral tegmental nicotinic acetylcholine receptors of a subtype composition different from the α4β2. Furthermore, it is argued that the primary site of action of ethanol in its accumbal dopamine elevating effect may be located to the nucleus accumbens or nearby regions.

Introduction

Drugs of abuse, including ethanol, have repeatedly been shown to activate the mesocorticolimbic dopamine system Engel and Carlsson, 1977, Grenhoff et al., 1986, Imperato and Di Chiara, 1986, Clarke et al., 1988, Engel et al., 1988, Mifsud et al., 1989, Blomqvist et al., 1993, Blomqvist et al., 1997. This dopamine system, projecting from the ventral tegmental area to the limbic areas, i.a. the nucleus accumbens, the amygdala, the septum and the frontal cortex, is regarded as an important neuroanatomical substrate for drug dependence (Wise and Rompre, 1989) but has also been implicated in mediating natural rewards and hedonia. In order to prevent the dopamine activating effects of drugs of abuse without concomitantly altering the motivation for natural rewards or producing anhedonia, it is seemingly important to unravel the mechanisms of actions by which these drugs activate the system. While the mechanisms of action of psychostimulants, opiates and nicotine in this respect are fairly well established those of ethanol remain unidentified.

We have recently suggested that ethanol activates the mesocorticolimbic dopamine system via direct or indirect stimulation of central nicotinic acetylcholine receptors. Thus, both ethanol-induced dopamine release in the rat nucleus accumbens and the enhanced catecholamine synthesis rate observed in the limbic forebrain after ethanol were completely antagonized by mecamylamine, a blood–brain barrier penetrating nicotine acetylcholine receptor antagonist (Blomqvist et al., 1993). Furthermore, when perfused in the ventral tegmental area mecamylamine and the quaternary nicotine acetylcholine receptor antagonist hexamethonium completely antagonized the accumbal dopamine overflow after systemic ethanol (Blomqvist et al., 1997), whereas when perfused in the nucleus accumbens mecamylamine did not influence the effects of ethanol. Furthermore, we have demonstrated that acute mecamylamine but not hexamethonium reduces voluntary ethanol intake in high- but not low-preferring rats (Blomqvist et al., 1996), and recently it was shown that this phenomenon most likely involves antagonism of ventral tegmental nicotinic receptors (Ericson et al., 1998). Thus, ventral tegmental nicotinic acetylcholine receptors may play an important role in mediating the mesolimbic activating and reinforcing properties not only of nicotine (cf. Clarke et al., 1988, Corrigal et al., 1992), but also of ethanol, and provide a neurochemical basis for the often observed co-abuse of ethanol and nicotine in man (Dreher and Fraser, 1967, Crowley et al., 1974; for review, see Bien and Burge, 1990).

The present study was undertaken in order to investigate whether ethanol interacts directly or indirectly with ventral tegmental nicotinic acetylcholine receptors and whether the most common nicotine acetylcholine receptor subtype in the brain, the α4β2, is involved in the ethanol-induced dopamine activation described above. Furthermore, since mecamylamine interacts not only with nicotinic receptors but also with glutamatergic NMDA receptors in the brain (McDonough and Shih, 1995), the possibility that the mecamylamine effects related above derive from an interaction with NMDA receptors rather than with nicotine acetylcholine receptors was also examined. To this end, in vivo microdialysis to measure extracellular accumbal dopamine levels, and reversed microdialysis, to administer ethanol or various pharmacological tools locally, were employed with or without systemic injection of ethanol or other substances.

Section snippets

Animals

Male Wistar rats, supplied by Beekay (Stockholm, Sweden) and weighing 250–350 g, were housed five per cage (55×35×20) at a constant cage temperature (25 °C) and humidity (65%). The animals were kept under regular light–dark conditions (lights on at 7:00 a.m. and off at 7:00 p.m.) and had free access to “rat and mouse standard feed” (Beekay Feeds) and tap water. In all experiments, drug-naive animals were used. Animals were allowed to adapt for at least 7 days to the animal maintenance

Results

Ethanol (10, 100, and 300 mM or 1 M in the perfusate) administered by reversed microdialysis into the ventral tegmental area produced no significant change in extracellular accumbal dopamine levels as expressed as % of control. The lower concentrations (10 and 100 mM) of ethanol perfused in the nucleus accumbens also failed to alter the dopamine levels in this region. However, when ethanol was perfused in the nucleus accumbens at a concentration of 300 mM, accumbal dopamine levels increased by

Discussion

Previous studies from this group have demonstrated that local perfusion of mecamylamine in the ventral tegmental area prevents systemic ethanol-induced dopamine release in the nucleus accumbens (Blomqvist et al., 1997) and abolishes ethanol intake as well as the associated accumbal dopamine release in ethanol high-preferring Wistar rats (Ericson et al., 1998). These results indicate that ethanol produces its mesolimbic dopamine activating and reinforcing effects via activation of ventral

Conclusion

These findings indicate that the ethanol-induced activation of mesolimbic dopamine neurons may be mediated via an indirect rather than direct stimulation of ventral tegmental nicotine acetylcholine receptors and suggest that the primary locus of action of ethanol in this respect may be in the nucleus accumbens or nearby regions. The findings also suggest that the increase in accumbal dopamine levels after ethanol involves endogenous acetylcholine release in the ventral tegmental area. The

Acknowledgements

This study was financially supported by grants from the Swedish Medical Research Council (no. 4247 and no. 11583), the Swedish Alcohol Monopoly Foundation for Alcohol Research, Swedish Society for Medical Research, Swedish Match, Swedish Society of Medicine, Orion Pharma neurology, Lundbecks Fond för Psykofarmakologisk Forskning, Wilhelm och Martina Lundgrens vetenskapsfond, Clas Groschinskys minnesfond, Stiftelsen Lars Hiertas minne, Fredrik och Ingrid Thurings Stiftelse and National Institute

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