Alcohol and inhibition in the prefrontal cortex

描述(申请人提供)：酗酒对美国公众的影响是深远的，无论是在个人福祉和对家庭结构的影响方面，还是在生产力损失和相关的医疗费用方面给社会带来的巨大代价。尽管我们做出了越来越多的努力，但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了解仍然不完整。流行病学研究指出，青春期是酒精障碍发展的关键时期。大脑的一个区域似乎特别容易受到酒精的影响，那就是前额叶皮质(PFC)，它在青春期开始时仍然不成熟。PFC参与决策、记忆和冲动控制，这些行为在饮酒后经常被扰乱，被认为是长期成瘾的基础。在PFC中，已知药理上相关剂量的酒精会抑制神经元活动(Tu等人。2007年)，但对其与PFC内的抑制受体GABA和甘氨酸的相互作用知之甚少。这是尽管GABA-A受体亚型在PFC中的表达(Hoestgaard-Jensen等人。在其他脑区调节紧张性抑制，并表现出对酒精的高度敏感性(魏等人。2004年，Jia et al.2008年)。 此外，我们注意到功能性甘氨酸受体也存在于PFC中(Ye等人。2011年)，但几乎没有受到关注。这项研究的目的是研究酒精对青少年PFC神经元兴奋性以及对GABA和甘氨酸介导的突触和紧张性抑制的药理作用，并确定青春期长期饮酒是否会导致抑制的特定变化，从而影响神经元的兴奋性。TIS信息可以增强我们对青春期饮酒的负面影响的理解，对相关细胞机制的更多关注有助于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.