Neurochemical control of ethanol consumption: Differential systems for initiation and prolongation of drinking behavior

Abstract

Recent studies of alcoholism have demonstrated that specific patterns of drinking differentially impact the development of certain medical conditions. Notably, clinical medications for alcoholism differentially affect distinct components of this disorder, preventing relapse, related to effects on the initiation or frequency of drinking episodes, or reducing overall consumption, reflecting effects on the intensity or duration of drinking. This underscores the importance of investigating neural mechanisms that underlie specific patterns of alcohol drinking. Preclinical studies suggest that the perifornical lateral hypothalamus (PF/LH) and its local peptide orexin (OX), through positive interaction with peptide systems in the paraventricular nucleus (PVN), have an important function in stimulating alcohol consumption and may also affect specific patterns of alcohol drinking. The research described in this dissertation investigates this possibility using Sprague-Dawley rats trained to voluntarily drink ethanol. Chapter 2 tests the hypothesis that OX in the PF/LH stimulates ethanol consumption through its specific effect on the initiation of ethanol drinking. This is in contrast to the PVN peptides, galanin (GAL) and enkephalin (ENK), which primarily determine the size and duration of the drinking response and can also be stimulated by OX in the PVN. To more fully understand the function of OX in controlling ethanol drinking, the next three chapters examine PF/LH neurotransmitter systems that are stimulated by ethanol consumption and may, in turn, modulate the PF/LH peptides. Chapter 3 focuses on the glutamatergic system and tests the hypothesis that glutamatergic inputs act as an initiation signal to stimulate OX and induce ethanol drinking. Chapter 4 investigates the role of DA and the idea that it has receptor-specific actions, acting at the dopamine 1 receptor to enhance OX and stimulate ethanol drinking and at the dopamine 2 receptor to suppress OX and terminate the drinking process. Chapter 5 then investigates opioid signals, which in the PF/LH may inhibit drinking as well as the OX system. Collectively, these experiments provide new information regarding OX and its function in controlling patterns of ethanol drinking, elucidating the neural basis of alcohol drinking patterns and offering insight into how casual alcohol drinking may eventually become a chronic, debilitating disorder.