Sunil Sirohi, Ph.D. - US grants

Summary: Alcohol use disorder (AUD) presents a significant social and economic burden to modern society. Notably, impaired physiological and metabolic status observed in alcoholic patients adversely affects treatment outcome. Furthermore, many alcoholics are malnourished and resultant nutritional deficiencies may contribute to the pathology of alcoholism. However, nutrition is often overlooked as an important treatment component for AUD. Our preliminary data indicate that a patterned feeding (produced by an intermittent availability) of a nutritionally complete palatable diet (NPD), a treatment that does not influence body weight or composition, induces anxiolytic behavior and attenuates alcohol intake in non-dependent rodents, which has important clinical implications in the management of AUD. However, a critical first step involves determining if such dietary intervention would be successful in regulating alcohol intake in preclinical models of AUD. Addressing these critical questions is important to understand the role of compromised nutritional status in regulating various symptoms associated with this multifaceted disorder. P-line of rats has been shown to display proposed criteria (e.g., voluntary excessive and relapse-like alcohol drinking and the emergence of alcohol dependence following chronic alcohol exposure) to be considered as a suitable animal model for studying AUD. The objective of this application is to evaluate excessive and relapse-like alcohol consumption in the alcohol-preferring (P) and non-preferring (NP) rats following patterned feeding of NPD. In addition, we will also determine the underlying behavioral and neurobiological mechanisms mediating the effects of our feeding paradigm. Aim 1 will examine the impact of patterned feeding of NPD on non-dependent excessive and relapse-like alcohol drinking behavior. Aim 2 will evaluate the effect of a similar dietary approach on alcohol dependence-induced negative emotional states, escalated alcohol intake and neurobiological changes in the cortico-striatal circuitry. Aim 3 will examine the role of medial prefrontal cortex (mPFC) neurotensin signaling in regulating effects of NPD on alcohol drinking. The central prediction is that patterned feeding of NPD attenuates problematic alcohol consumption and negative emotional states in rodent?s models of AUD by recruiting mPFC neurotensin signaling. This hypothesis is supported by our preliminary data and work of others. Treating metabolic deficiencies present in the alcoholic condition is a significant conceptual innovation as none of the currently approved approaches target both altered nutritional and emotional states associated with AUD. In addition to restoring nutritional deficits, exposure to NPD could also serve to restore emotional state thereby enhancing other behavioral and pharmacological strategies for the management of alcoholism which will facilitate the pathway to abstinence.