UCLA

Alcohol use disorder (AUD) is a chronic, relapsing disorder that represents a substantial societal burden at a global scale. In the US alone, AUD is associated with societal and financial costs exceeding $249 billion per year. While many use alcohol for its reported anxiolytic and gregarious properties, consuming alcohol directly activates the hypothalamic stress axis. Persons with AUD, that are consistently exposed to this stressful stimulus, are known to have alterations in the acute response to alcohol. Little is known about how chronic ethanol exposure alters the plastic and metaplastic responses of stress, per se.Relapse remains a main barrier in the pharmaceutical treatment of AUDs. While there are some medications currently available for AUD, none explicitly target the hypothalamic-pituitary-adrenal (HPA) axis. Further, sex is an essential variable to consider when pharmacologically targeting the HPA axis, as both acute and developmental effects of gonadal hormones can influence neuronal signaling in various brain regions. In Chapter 1, I investigate the effect of chronic intermittent vapor exposure to progressively increasing doses of ethanol (CIE) followed by protracted withdrawal on the physiological response to norepinephrine (NE; 10�M). I also investigate the mechanistic contributions of specific α adrenergic receptors (AR; α1AR & α2AR) on the CIE-induced neurophysiological effects. The paraventricular nucleus of the hypothalamus initiates a robust glutamate signal to start the overcome tonic GABAergic inhibition and adaptively coordinate stress-associated behaviors. We have previously shown that this metaplastic feature is disrupted in gavage models of CIE due to altered function of N-methyl D-aspartate receptor. In Chapter 2, I demonstrate that the CIEvapor model produces a similar impairment in hypothalamic metaplasticity. I also demonstrate how this effect is impacted by blockade of α1AR (with prazosin; 10�M). Astrocytes and neurons undergo a complex interplay in response to changes in the chemical gradient of various neurotransmitters. Both neurons and astrocytes have distinct responses during acute alcohol intoxication and protracted withdrawal. In Chapter 3, I investigate differences in how astrocytes and/or neurons may impact the noradrenergic activation and subsequent glucocorticoid receptor mediated inhibition of the HPA axis. The tripartite synapse is very likely involved in the regulation of stimulation-induced plasticity due to the critical role astrocytes play in glutamate shuttling, neurotransmitter release and regulation of synaptic activity. Despite this, we have not found studies evaluating the contribution of astrocytes to the metaplastic short-term glutamatergic potentiation onto CRF neurons following high-frequency stimulation. In Chapter 4, I investigate cell-specific differences to spontaneous Ca2+ events and event kinetics following CIEvapor. Various preclinical models of AUD can reliably induce anxiety-like behavior. However, AUD models fail to have full penetrance of ethanol (EtOH) preference and escalation of consumption behaviors. There are also noted genetic differences that contribute to EtOH preference. In Chapter 5, I investigate differences to stress-associated and consummatory alcohol behaviors following CIEvapor treatment. I also investigate the convergence and divergence of stress-related and consummatory behaviors with neurophysiological features of ex vivo Ca2+ signals