Ethanol-induced dopamine elevation in the rat — Modulatory effects by subchronic treatment with nicotinic drugs Elin Löf a, ⁎ , Pei Pei Chau b , Rosita Stomberg b , Bo Söderpalm b a Institute of Neuroscience and Physiology, Section of Pharmacology, Sahlgrenska Academy, Göteborg University and Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden b Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, Göteborg University and Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden Received 18 July 2006; received in revised form 10 October 2006; accepted 12 October 2006 Available online 28 October 2006 Abstract Chronic nicotine administration is associated with increased ethanol consumption in laboratory animals and in humans. Some smokers report less sedation during acute ethanol intoxication after nicotine administration and the sedative effects from ethanol are mediated by inhibitory GABA A -receptors. In a series of in vivo microdialysis experiments we investigated whether subchronic pre-treatment with nicotinic drugs known to enhance ethanol consumption in the rat (nicotine or the peripheral nicotinic antagonist hexamethonium) could modulate the alterations in extracellular dopamine observed in response to administration of ethanol or the sedative GABA A -agonist diazepam. In the nucleus accumbens and the dorsal striatum, systemic and/or local ethanol administration resulted in transient increases in extracellular dopamine levels that returned to baseline before the local levels of ethanol started to decline. In hexamethonium pre-treated rats, however, the nucleus accumbens dopamine levels were time-locked to the ethanol levels in the same area after systemic or local ethanol administration. Perfusion of diazepam into the nucleus accumbens produced a significant reduction in nucleus accumbens dopamine in controls. Prior subchronic treatment with nicotine or hexamethonium abolished this effect. The present results suggest that subchronic treatment with the nicotinic acetylcholine receptor antagonist hexamethonium reduces a GABA A -R mediated counteraction of the nucleus accumbens dopamine response to ethanol. Additionally, we demonstrate that modulation of nicotinic receptors may reduce the sensitivity of GABA A receptors to benzodiazepines. These phenomena may offer a novel explanation to why nicotine and alcohol are often co-abused. © 2006 Elsevier B.V. All rights reserved. Keywords: Ethanol; Nicotine; Dopamine; GABA [gamma-amino-butyric-acid]; Accumbens; (Rat) 1. Introduction Nicotine and alcohol are commonly co-abused (Craig and Van Natta, 1977; DiFranza and Gurrera, 1990; Mello et al., 1987; Walton, 1972; Zacny, 1990). For instance, there is a positive correlation between the amount of nicotine used and the reported ethanol consumption (Wickholm et al., 2003), as well as between the risk of being a heavy smoker and the severity of ethanol dependence (for review, see Madden and Heath, 2002). These relationships may not only be explained by environmental or psychosocial factors, since subchronic, intermittent nicotine exposure increases voluntary ethanol intake and preference also in the experimental rat (Blomqvist et al., 1996; Ericson et al., 2000; Olausson et al., 2001). Thus, increased alcohol intake could be a pharmacological conse- quence of chronic nicotine exposure. The present study aimed at examining tentative nicotine-induced alterations of ethanol- induced dopamine activity in the reward-related mesolimbic and/or mesostriatial dopamine systems in the rat. The increase in ethanol consumption observed in the rat following subchronic nicotine treatment was unexpectedly not antagonized by subchronic co-treatment with nicotinic acetyl- choline receptor antagonists (Ericson et al., 2000). Thus, blocking nicotinic receptors with the non-selective nicotinic receptor antagonist mecamylamine or the peripherally acting European Journal of Pharmacology 555 (2007) 139 – 147 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Göteborg University, Box 410, SE-405 30 Gothen- burg, Sweden. Tel.: +46 31 7733977; fax: +46 31 828163. E-mail address: elin.lof@pharm.gu.se (E. Löf). 0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2006.10.056