, 1997). Progesterone and its metabolites FG-4592 supplier are produced in the brain and participate in stress responses (Wirth, 2011), and thus progesterone and glucocorticoid receptors could contribute to interactions between nicotine and ethanol. Our demonstration that nicotine enhances ethanol-induced VTA GABA transmission through a stress hormone signal is consistent with evidence that GABAergic

neuroactive hormones contribute to ethanol self-administration (Biggio et al., 2007, Helms et al., 2012 and Morrow et al., 2009). These results complement previous studies showing a critical role for glucocorticoids in alcohol reward and in the transition to compulsive alcohol drinking (Rotter et al., 2012 and Vendruscolo et al., 2012). We found no evidence of long-term changes in nAChR function after one nicotine exposure. However, activation of nAChRs in the brain stem may contribute to the initial response of the HPA axis to nicotine (Armario, 2010), which our results suggest involves high-affinity β2∗ nAChRs (Figure 2A). Blocking the initial stress hormone response

locally in the VTA prevented the long-term alterations in ethanol-induced DA release (Figure 5B) and thus identified the VTA as a locus for mechanistic interactions between nicotine and ethanol. Interestingly, local VTA infusion of RU486 to antagonize stress receptors did not completely reverse the effects of nicotine pretreatment on ethanol-induced DA release compared to the saline control. This incomplete effect Navitoclax clinical trial could arise from a partial diffusion of RU486 in the VTA, but it is also feasible that nicotine pretreatment acted outside of the VTA to induce neuroadaptations that regulate DA signals. In summary, we provide evidence that nicotine pretreatment decreases ethanol-induced DA transmission owing to increased GABAergic inhibition onto DA neurons. These responses to nicotine pretreatment, including increased ethanol intake, required an initial stress hormone signal. These results support the hypothesis that the actions of drugs of abuse recruit neuroendocrine pathways (Kenna

et al., 2012, Koob, 2008 and Richards et al., Histone demethylase 2011). Our data suggest a neurophysiological basis for the observation that nicotine use can increase the reinforcing properties of alcohol. Long-Evans rats (Harlan Sprague) weighing between 300–500 g were used. The rats were handled and weighed for at least 3 days and commonly more than a week prior to surgery and testing, and the rats were housed in a humidity-and temperature-controlled (22°C) environment under a 12 hr light/dark cycle. The rats had food and water available ad libitum in the home cage. All procedures complied with guidelines specified by the Institutional Animal Care and Use Committee at Baylor College of Medicine. For the microdialysis experiments, each animal was implanted with an intravenous catheter through the jugular vein and a stainless steel guide cannula (21G) (Plastics One). The surgery occurred under isoflurane anesthesia (1.5%–2.