The enhanced inhibitory input seemed to neutralize the excitatory drive, as firing rates of dopamine neurons were largely insensitive to bath-applied ethanol in tissue from nicotine-pretreated rats. Consistent with this observation, GABAA receptor blockade in brain slices eliminated the differential effect of ethanol on dopamine neuron firing rates between saline- and nicotine-pretreated animals. Together, these data indicate that exposure to nicotine can sensitize GABAergic transmission to the effects of ethanol. 5-FU chemical structure Nicotinic receptors are extremely diverse and widely expressed, so uncovering how they alter GABAergic signaling in

response to ethanol is a daunting task. Fortunately, Doyon et al. (2013) focused their attention on neuroendocrine signals, with the rationale that stress-related hormones are known to cause long-term alterations in dopamine and GABA transmission (Joëls and Baram, 2009 and Sparta et al., 2013). Furthermore, nicotine can potently activate the hypothalamic-pituitary-adrenal axis

and increase plasma levels of corticosterone, the principle glucocorticoid in rodents (Caggiula et al., 1998). To test whether glucocorticoid receptors were involved in the interaction between nicotine and ethanol, Doyon et al. (2013) pretreated selleck products animals with the glucocorticoid receptor antagonist RU486 prior to the nicotine exposure. This pretreatment completely blocked the interaction between nicotine and ethanol on both dopamine neuron physiology and ethanol self-administration. When RU486 was on board during the nicotine pretreatment, GABAergic transmission onto dopamine neurons was not sensitized to the effects of ethanol. Furthermore, ethanol-induced increases in dopamine levels in these animals were just as robust as they were in naive animals, not blunted as was observed in animals pretreated with nicotine alone. Remarkably, this restoration of dopamine neuron reactivity correlated with a moderation of ethanol self-administration, restoring it to the levels

typical of saline-pretreated animals. In human users, the interactions between tobacco and alcohol are bound to be complex and multifaceted. The 3-mercaptopyruvate sulfurtransferase present study cleverly took advantage of naive animals and controlled environments to provide insight into the cellular mechanisms by which these drugs interact. In doing so, it has provided an intriguing potential explanation for why smokers drink more alcohol than their peers. It also offers potential targets for pharmaceutical interventions designed to attenuate heavy drinking in people codependent on alcoholic and tobacco. Key questions regarding the interaction between nicotine and ethanol remain to be answered, however. For example, how would more naturalistic exposure to nicotine alter drinking behavior? Doyon et al.