Role of Endocannabinoid Signaling in Alcoholism

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Alcohol (EtOH) suppress the excitatory neurotransmission and potentiate the inhibitory neurotransmission whereas AEA released by postsynaptic neurons is shown to inhibit neurotransmitter release by activating CB1 receptors (CB1 R) at presynaptic neurons. The purpose of this project is to gain a better understanding of anandamide (AEA) and CB1Rs role in the action of EtOH on neurotransmission at synapses between granular neurons, interneuron, Purkinje cells. In our approach we use cerebellar mixed neurons in culture. This preparation offers the unique possibility that granular cells and interneurons establish synaptic contacts with Purkinje cells as they do in the intact cerebellum and are known to use glutamate or GABA as a neurotransmitter. Our researches will focus on the role of AEA and CB1Rs in the action of EtOH on the spontaneous and evoked excitatory and inhibitory synaptic transmission. Additional experiments will also test whether or not novel AEA receptors are involved in the action of EtOH on the spontaneous and evoked synaptic transmission using cells from CB1R knockout mice pups. In the first specific aim, we will test whether or not AEA and CB1Rs are involved in the action of EtOH on the spontaneous and evoked excitatory and inhibitory synaptic transmission. We will measure the EPSC and IPSC amplitude and mEPSC and mlPSC frequency and amplitude in acute EtOH exposed cells in the presence or absence of receptor modulators. In specific aim 2, we will measure the chronic EtOH-induced changes in CB1R and FAAH immunoreactivity and the role of AEA and CB1Rs in the effects of chronic EtOH on IPSC and EPSC amplitudes and mlPSC and mEPSC frequency and amplitude. In aim 3, we will study how the lack of CB1Rs influences the effects of acute and chronic EtOH on IPSC and EPSC amplitudes and mlPSC and mEPSC frequency and amplitude. The better understanding of these mechanisms will yield new drug therapies with potential in treatment of alcoholism.