Alcohol-induced changes in stress-related neuropeptide circuitry

点击翻译按钮获取中文摘要

ABSTRACT Alcohol use disorders (AUDs) are serious medical conditions that afflict approximately 17 million Americans and cost the U.S. $400 billion annually. Whereas men are diagnosed twice as frequently as women, a greater vulnerability to adverse effects of alcohol occurs in women. Despite the sex differences in prevalence and effects of AUD, the factors mediating the sex differences in the effects of alcohol use are not fully understood. Animal models showed an escalation of alcohol drinking from baseline in male rodents while higher baseline drinking was evident in female rodents. Withdrawal from chronic alcohol exposure induced a greater anxiety in male compared to female. Research is needed on the neural circuitry underlying sex differences to advance the field of alcohol neurobiology. AUD development involves the actions of critical neuropeptides in the central nucleus of the amygdala (CeA), including corticotropin-releasing factor (CRF) and neuropeptide Y (NPY). CRF is an excitatory stress neuropeptide that orchestrates stress responses, while NPY may act as an inhibitory or excitatory neuropeptide. The CeA ubiquitously receives NPY-ergic afferents and is enriched with CRF neurons. Alcohol exposure and withdrawal reduced the NPY signaling in the CeA while alcohol withdrawal increased CRF levels in the CeA. We have shown that CRF neurons in the CeA project to the locus coeruleus (LC), a major source of norepinephrine (NE) to the forebrain. The CRF CeA-LC pathway relays emotion-related information. We propose that the specific NPY CRF-CeA LC pathway mediates sex differences in alcohol drinking and anxiety-like behavior following withdrawal. The goal of the proposed work is to test the overarching hypothesis that the specific NPY CRF-CeA LC-NE pathway mediates sex differences in alcohol drinking and anxiety-like behavior during withdrawal. We will use a well-established rodent alcohol model, the intermittent-access ethanol drinking (IED) paradigm. In this model, females initially consume more alcohol than males, while males escalate intake, resulting in matched intake in males and females following 30 days of drinking. We will use IED to test circuit and molecular mechanisms mediating alcohol effects on alcohol drinking and anxiety-like behavior. We will integrate pharmacological, chemogenetics, behavioral, and cellular approaches including immunohistochemistry, immunoelectron microscopy and tract tracing. AIM 1 tests the hypothesis that CRF- containing neurons contacted by NPY in the CeA project to the LC-NE system, and that withdrawal from chronic alcohol exposure alters the NPY-CRF synaptic organizations in male and female rats. Aim 2 tests the hypothesis that Y1r agonism within the CRF-CeA neurons that project to LC will reverse the elevated alcohol drinking and anxiety-like behavior during alcohol withdrawal in male and female rats. Elucidating sex differences in the peptidergic interactions in the CeA that impact NE transmission under alcohol withdrawal, and the role of NPY in modulating the LC-NE via the amygdalar CRF circuitry has significant clinical implications in developing individualized therapies and novel targets for the treatment of AUDs.