Aversion and reward: Two opposing drives mediating alcohol-seeking behavior

Alcohol use disorders (AUDs) have had a devastating impact on the health and lives of those who struggle with AUDs. Given the impact of AUDs on human health, the neural mechanisms that underlie ethanol-seeking behaviors are a topic of intense interest. In this dissertation, I investigated the neural mechanisms of ethanol-seeking. Motivation for seeking ethanol can be characterized by learning about both the rewarding and aversive properties of ethanol. Indeed, increased drinking would be observed if an animal was more motivated for ethanol's rewarding effects. Furthermore, similar increases in ethanol consumption would be accompanied by an attenuation in learning about ethanol's aversive effects. In this dissertation, I explore the neural mechanisms of reward and aversion that may contribute to increased ethanol-seeking behavior. First, to investigate how mechanisms of reward contribute to ethanol-seeking, I implemented the techniques necessary to record phasic dopamine (DA) signaling during ethanol-seeking (Chapter 2). Phasic dopamine release is distinguished by the subsecond release and reuptake of the neurotransmitter. Recent work has found that phasic DA release in the nucleus accumbens may be linked to motivation and performance of reward-seeking behavior but few studies have investigated phasic dopamine release during operant ethanol self-administration. In Chapter 3, I describe phasic DA release being evoked by cues predictive of ethanol availability. Furthermore, the magnitude of the DA was found to be predictive of shorter lever press latencies. Finally, phasic DA release was evoked during the performance of an ethanol-rewarded lever press. The dopamine recorded during ethanol-seeking is consistent with the hypothesis that dopamine may mediate both the motivation for ethanol and performance of ethanol-seeking behavior. Second, to investigate the mechanisms of aversive learning about ethanol, I focused on a brain region long associated with aversion, the lateral habenula (LHb). Recent work identified the LHb in learning about aversion to cocaine, thereby suggesting it may have a role in learning about the aversive effects of ethanol. In Chapter 4, I describe that lesions to the LHb caused an increase in home cage ethanol consumption. Furthermore, when an aversive injection of ethanol was paired to a novel tastant, the consumption of the novel tastant improved more rapidly than in intact animals. The above results implicate the LHb in learning about ethanol's aversive effects. Future studies must be performed to establish which LHb afferents mediate aversion to ethanol.