Drug and Alcohol Dependence 100 (2009) 83–90 Contents lists available at ScienceDirect Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep Induction of brain CYP2E1 changes the effects of ethanol on dopamine release in nucleus accumbens shell Lucía Hipólito, María J. Sánchez-Catalán, Ana Polache, Luis Granero ∗ Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Valencia, Avda Vicente Andrés Estellés s/n, 46100 Burjassot, Spain article info Article history: Received 16 May 2008 Received in revised form 8 September 2008 Accepted 12 September 2008 Available online 6 November 2008 Keywords: Ethanol CYP2E1 Dopamine Nucleus accumbens Core Shell abstract CYP2E1 is an important enzyme involved in the brain metabolism of ethanol that can be induced by chronic consumption of alcohol. Recent works have highlighted the importance of this system in the context of the behavioural effects of ethanol. Unfortunately, the underlying neurochemical events for these behavioural changes, has not been yet explored. In this work, we have started this exploration by analyzing the possible changes in the neurochemical response of the mesolimbic system to ethanol after pharmacological induction of brain CYP2E1. We have used the dopamine extracellular levels in nucleus accumbens (NAc) core and shell, measured by means of microdialysis in vivo, as an index of the effects of ethanol. Acetone 1% in the tap water was used to induce brain CYP2E1. Efficacy of the induction protocol was assessed by immunoblotting. Intravenous administration of 1.5g/kg of ethanol in control rats provoked a significant increase of the dopamine levels in both the core (up to 127% of baseline) and the shell (up to 122% of baseline) of the NAc. However, the same dose of ethanol in acetone-treated rats only increased the dopamine extracellular levels in the core (up to 142% of baseline) whereas dopamine levels in the shell subregion remain unaltered relative to baseline. The results of this study indicate that induction of CYP2E1 changes the response of the mesolimbic system to ethanol in a region-dependent manner. Two hypotheses are postulated to explain the observed effects. © 2008 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The enzymatic machinery necessary to metabolize ethanol has been reported to be present in the brain. Several studies have revealed that the same enzyme systems involved in the hepatic metabolism of ethanol are also involved in the brain metabolism, although their particular contributions are clearly different in brain and liver (Zimatkin et al., 2006). Catalase is thought to be the major contributor to ethanol metabolism in the brain, although cytochrome P-450 2E1 (CYP2E1) and alcohol dehydrogenase (ADH) also participate, in a significant way, in this process. Initial studies discarded the CYP2E1 involvement in brain ethanol metabolism, however, a recent study has presented solid data supporting its par- ticipation in this process (Zimatkin et al., 2006). These data indicate that the contribution of CYP2E1 to the overall brain metabolism of ethanol is clearly lower than that provided by catalase, but it is not negligible. Thus, catalase accounts for 60% of ethanol oxida- tion in brain whereas CYP2E1 activity accounts for an additional 20%. The rest of brain ethanol-oxidizing activity is probably due to ADH and other as yet unknown factors (Zimatkin et al., 2006). ∗ Corresponding author. E-mail address: lfgran@uv.es (L. Granero). So, CYP2E1 can be considered the second enzymatic system in importance for ethanol metabolism in brain. This enzyme is widely expressed in brain structures (Hansson et al., 1990; Upadhya et al., 2000), including the mesocorticolimbic system (Sánchez-Catalán et al., 2008). Brain CYP2E1 levels are inducible by chronic (Roberts et al., 1994; Sánchez-Catalán et al., 2008) and acute (Tindberg and Ingelman-Sundberg, 1996; Warner and Gustafsson, 1994) ethanol exposure and, hypothetically, the effects of ethanol on brain sys- tems may change throughout the history of alcohol consumption. This is indeed what happens at liver. So, it has been reported that CYP2E1 activity is inducible in liver by chronic ethanol consump- tion under conditions which leave ADH and catalase unchanged (Koop and Coon, 1984; Lieber and Decarli, 1970; Lieber et al., 1988). In some studies it has been shown that CYP2E1 is increased 4- to 10- fold in liver biopsies of recently drinking subjects (Tsutsumi et al., 1989), with a corresponding rise in mRNA (Takahashi et al., 1993). Numerous studies have shown that pharmacological manipula- tions of brain ethanol metabolism, mainly through modifications of catalase activity, are able to modulate the ethanol-induced behaviours (Aragon et al., 1992; Aragon and Amit, 1993; Correa et al., 1999a,b, 2000, 2004a,b; Pastor et al., 2002; Sanchis-Segura et al., 1999a,b,c). Recently, it has been demonstrated that pharmaco- logical manipulations of brain CYP2E1 and the genetic deficiency of CYP2E1 (Correa et al., 2006) are also able to modulate the 0376-8716/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2008.09.004