Molecular Mechanisms of Alcohol Actions in the Adolescent Brain

在青少年和青年时期开始的酗酒或过度饮酒是成瘾的一个很强的危险因素

Binge or excessive drinking initiated early in teenage and young adult life is a strong risk factor for addiction development and other mental health problems in this vulnerable age-group. Effective treatment strategies against the growing epidemic of adolescent alcohol abuse and alcoholism demand greater scientific understanding of the long-term impact that early-life alcohol abuse wields on brain function throughout life. We identified previously a novel role for endogenous sigma-1 receptors in modulating hippocampal function through effects on synaptic long-term potentiation processes in the maturing adolescent brain. Projects proposed herein will further advance our understanding of sigma-1 receptor function in the cognitive or memory aspects of alcohol abuse in early adolescence. Specific Aims of the project are to test the hypotheses that: (1) chronic alcohol abuse in early-adolescent rats upregulates sigma-1 receptor protein expression, triggering a switch in synaptic plasticity signaling pathways in hippocampus where memories are initially formed and sorted; (2) sigma-1 receptors induction following early-adolescent alcohol abuse results in altered activity of select voltage-dependent ion channels involved in experience-induced neuroplasticity in hippocampus; (3) neuroadaptive changes arising from alcohol x sigma-1 receptor interactions reflect activation of intracellular signaling cascades that interfere with normal signal processing in hippocampus of the maturing adolescent brain. Hypotheses will be tested by combining electrophysiological techniques (i.e., brain slice recordings and in vivo EEG analyses) with biochemical approaches (Western blot analyses) using an adolescent rat model of binge-like abuse and dependence induction via chronic intermittent exposure to ethanol vapors. Testing will occur after varying lengths of alcohol abstinence to determine the long-range consequences of binge exposure at different times during adolescent-to-young adult development. Central administration of sigma-1 receptor selective agonists/antagonists will help substantiate sigma-1 receptors as functionally relevant targets of alcohol actions in the maturing adolescent brain, providing critical insights into the molecular mechanisms for persistent cognitive pathologies related to alcohol abuse initiated early in life.