William C. Griffin - US grants

DESCRIPTION (provided by applicant): Ethanol tolerance is a complex phenomenon that encompasses a wide range of ethanol-induced processes. The role of ethanol tolerance in sustaining excessive drinking behavior that consequently can lead to the development of ethanol dependence remains to be determined. Studies proposed in this application are responsive to the RFA (AA-08-009) in that they test a novel hypothesis related to the role of tolerance to the aversive properties of ethanol in the context of ethanol dependence. More specifically, we propose that tolerance develops to the aversive properties of ethanol and that this tolerance, in turn, maintains excessive drinking in dependent animals. Moreover, we hypothesize that an underlying mechanism for tolerance to the aversive properties of ethanol relates to neuroadaptation in glutamatergic neurotransmission in the basolateral amygdala (BLA). Our overall research strategy and approach involves employing a well-characterized mouse model of ethanol dependence that reliably produces excessive voluntary ethanol consumption. Using this model, studies will be conducted to: (a) examine tolerance to the aversive properties of ethanol, as defined by reduced sensitivity to ethanol-induced condition taste aversion (Specific Aim I);(b) measure basal levels and the capacity for ethanol to stimulate extracellular levels of glutamate in the BLA (Specific Aim II);and (c) examine the effects of direct manipulation of BLA glutamatergic neurotransmission on ethanol-induced conditioned taste aversion and drinking behavior (Specific Aim III) in ethanol dependent and non-dependent mice. The findings will fill a general void in the literature regarding the role of glutamate in the BLA for tolerance to the aversive consequences of ethanol, and should delineate a potential link to increased risk for excessive ethanol consumption and increased relapse associated with dependence. PUBLIC HEALTH RELEVANCE: Tolerance to the aversive properties of alcohol may facilitate increased consumption that, in turn, can lead to the development of dependence along with sustained excessive drinking. Using an animal model of alcohol dependence and drinking, we aim to advance knowledge regarding factors and mechanisms associated with tolerance and dependence that promote excessive drinking behavior. Further discovery about mechanisms underlying tolerance to the aversive properties of alcohol in animals may lead to a better understanding of alcohol tolerance and dependence in humans and, ultimately, better treatment strategies and outcomes for those suffering with alcohol dependence.

PROJECT ABSTRACT An important goal of contemporary health research is to understand the adaptations that occur in the brain that cause excessive alcohol drinking. Using a well-established preclinical model of alcohol (ethanol) dependence and relapse, our laboratory recently demonstrated increased glutamatergic transmission in the nucleus accumbens (NAc), a brain region important for regulating motivated behaviors. Glutamatergic afferents reaching the NAc come from several different regions, but the ventral hippocampus (vHC) provides particularly rich innervation to the NAc Shell. Preliminary data indicate that inactivating the vHC using chemogenetic procedures reduces ethanol drinking. Further, inactivating the vHC to NAc pathway reduces (GLU) glutamate release, while activating this same pathway increases GLU release in the NAc. Expression of pre-synaptic mGluR2 receptors, important regulators of neuronal glutamate release, is reduced in the NAc Shell of ethanol dependent mice. Because of the dense vHC to NAc Shell projections, the reduction in mGluR2 receptors likely contributes to the increased glutamate transmission we reported previously. Our proposed studies will determine if this is the case. Taken together, these exciting new findings implicate a relatively un-studied pathway (vHC to NAc) in ethanol drinking and glutamate release in the NAc. The overarching hypothesis of this proposal is that activity of the vHC-NAc pathway regulates ethanol drinking (Aim 1) and significantly contributes to glutamate release in the NAc of dependent mice (Aim 2). In Aim 1, we will determine effects of manipulating activity of the vHC-NAc pathway on ethanol drinking in dependent and non-dependent mice. Our working hypothesis is that increasing activity of the pathway will increase drinking, while decreasing activity of the pathway will reduce drinking. In Aim 2, we will determine whether increased activity of the vHC-NAc pathway leads to increased glutamate levels in the NAc and, additionally, whether adaptations in mGluR2 expression contribute to dependence-related increased glutamate activity and escalated drinking. Our working hypothesis for Aim 2 is that glutamate release will be greater in ethanol dependent mice because mGluR2 expression is reduced on the terminals of this pathway. Identification of critical pathway(s) involving the NAc, whether it is the VHC-NAc, or another pathway, will inform and guide subsequent targeted medication development to prevent and/or treat alcohol addiction.