Project 3: Adolescent vulnerability to chronic ethanol: neurophysiological, biochemical, and behavioral mechanisms of adult AUD

总结

SUMMARY The neurobiological mechanisms controlling the transition from alcohol use to abuse are poorly understood. Our overall approach is to examine vulnerable populations to highlight specific cellular/molecular pathways involved in this transition. For example, human adolescents exposed to heavy alcohol use are at much greater risk for the development of alcoholism as adults. Recent studies suggest similar liabilities for adolescent animals including rodents. Our published work indicates adolescent chronic ethanol exposure differentially modulates both glutamatergic and GABAergic neurotransmission in the lateral/basolateral amygdala (BLA), a `node' within circuits critical for the integration cognitive and sensory information during emotional responses, in an input-specific fashion. Our data also suggest a critical role for mammalian target of rapamycin (mTOR)- dependent signaling cascades in synaptic strengthening. Further, we provide preliminary data suggesting that many of these synaptic effects are absent or greatly diminished in adult animals. This suggests that mTOR- dependent signaling directly regulates synaptic modulation during adolescent ethanol exposure. The overall goal of the current project is to therefore use a well-established ethanol vapor exposure in adolescent rats to understand the long-term impact of this exposure in adult animals by integrating cellular, molecular, and behavioral methodologies. The proposed work includes three specific aims: Aim 1 will characterize the effects of adolescent ethanol exposure on adult BLA glutamatergic and GABAergic neurotransmission using whole- cell patch clamp electrophysiology; Aim 2 will describe the effect of adolescent ethanol exposure on mTOR signaling in both postsynaptic and presynaptic compartments in the BLA; and, Aim 3 will examine pharmacological intervention along the mTOR-signaling pathway and its impact on the long-term behavioral consequences of adolescent ethanol exposure. Together these aims are significant because they leverage a vulnerable population (adolescents), innovative technical and conceptual approaches, and the substantial expertise of our research team to help identify specific cellular signaling processes governing the impact of ethanol exposure across multiple levels of analysis. We will directly test if these signaling processes represent potential therapeutic targets for treatments designed to interrupt the transition from ethanol use to abuse.