Alcohol and inhibition in the prefrontal cortex

描述（由申请人提供）：酗酒对美国公众的后果是深远的，无论是在个人福祉和对家庭结构的影响，以及在生产力损失和相关的医疗保健费用方面对社会的巨大成本。尽管不断努力，我们对酒精影响和酒精使用障碍发展的神经生物学机制的理解仍然不完整。流行病学研究指出，青春期是酒精障碍发展的关键时期。大脑中特别容易受到酒精影响的一个区域是前额叶皮层（PFC），它在青春期开始时仍然不成熟。前额叶皮层参与决策、记忆和冲动控制，这些行为通常在饮酒后被破坏，并被认为是长期成瘾的基础。在前额叶皮层，已知过量的酒精会抑制神经元的活动（Tu et al.2007），但对其与抑制剂受体GABA和甘氨酸的相互作用知之甚少，尽管GABA-A受体亚型在PFC中表达，（Hoestgaard-Jensen et al. 2010），其在其他脑区介导紧张性抑制，并表现出对酒精的高敏感性（Wei et al. 2004，Jia et al. 2008）。 此外，我们注意到PFC中也存在功能性甘氨酸受体（Ye et al. 2011），但几乎没有受到关注。本研究的目的是研究酒精对神经元兴奋性和GABA和甘氨酸介导的突触和紧张性抑制在青少年PFC的药理作用，并确定在青春期长期饮酒是否会导致影响神经元兴奋性的抑制的具体变化。这些信息可以提高我们对青春期饮酒的负面影响的理解，并且更多地关注所涉及的细胞机制可以帮助制定治疗酒精使用障碍的治疗策略。

DESCRIPTION (provided by applicant): The consequences of alcohol abuse on the American public are profound, both in terms of individual well-being and impact on the family structure, as well as the enormous cost to society in terms of lost productivity and associated health care expenses. Despite increasing efforts, our understanding of the neurobiological mechanisms that underlie the effects of alcohol and the development of alcohol use disorders remains incomplete. Epidemiological research has pointed to adolescence as a critical period in the development of alcohol disorders. One area of the brain that appears especially vulnerable to the effects of alcohol is the prefrontal cortex (PFC), which remains immature at the onset of adolescence. The PFC is involved in decision- making, memory and impulse control, behaviors that are often disrupted following consumption of alcohol and are believed to underlie long-term addiction. In the PFC, pharmacologically relevant doses of alcohol are known to depress neuronal activity (Tu et al. 2007), but very little is known of its interactions with the inhibitor receptors, GABA and glycine, within the PFC. This is despite the expression of GABA-A receptor subtypes in the PFC (Hoestgaard-Jensen et al. 2010) that mediate tonic inhibition in other brain regions and demonstrate high sensitivity to alcohol (Wei et al. 2004, Jia et al. 2008). In addition, we note that functional glycine receptors are also present in PFC (Ye et al. 2011) but have received little to no attention. The goal of this research proposal is to examine the pharmacological actions of alcohol on neuronal excitability and on GABA and glycine-mediated synaptic and tonic inhibition in the adolescent PFC, and to determine if chronic alcohol drinking during adolescence leads to specific alterations of inhibition that affect neuronal excitability. Tis information could enhance our understanding of the negative effects of alcohol drinking during adolescence and an increased focus on cellular mechanisms involved can help lead to the development of therapeutic strategies to treat alcohol use disorders.