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.
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.
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