The long-term objective of the proposed research is to study the modulatory actions of endocannabinoids on synaptic transmission in the CNS. The experimental model involves identified mixed electrical and chemical, (glutamatergic) synapses between eighth nerve auditory primary afferents and the goldfish Mauthner (M-) cell and neighboring (GABA/Glycine) inhibitory terminals. While most studies describing the role of endocannabinoids on synaptic transmission have utilized in-vitro systems, this preparation uniquely allows continuous monitoring and quantification of changes in electrical and chemical transmission in-vivo. Sofar, endocannabinoids have been reported to depress chemical synaptic transmission via presynaptic activation of cannabinoid type 1 receptors (CBIRs). Contrasting this notion, our preliminary results show that activation ofCBIRs enhances synaptic transmission at these inputs on the M-cell. Intradendritic recordings, molecular biology techniques, and immunocytochemistry, will be used to test specific hypotheses and mechanisms underlying modifications of synaptic transmission induced by this agonist. Aim 1, explores the action of different cannabinoid agonists and endocannabinoids on the synaptic efficacy of mixed synapses and inhibitory terminals. It is based on data suggesting that activation of CB1R leads to long-lasting enhancement of both electrical and chemical transmission at mixed synapses. These changes also included nearby inhibitory terminals. I will explore the actions of locally applied cannabinoid agonists and endocannabinoids on unitary and population synaptic responses and membrane conductances that are relevant for the function of this auditory input. Aim 2 is to investigate the mechanisms underlying these long-term changes in synaptic transmission. It is based on the finding that dopamine receptor antagonists block the potentiation triggered by CB1R activation. We have previously reported the presence of a dopaminergic innervation and application of dopamine evoked lasting enhancements of the synaptic response. We will test the hypothesis that cannabinoid-evoked potentiation is mediated via dopamine release from neighboring varicosities. We will also ask under which physiological conditions and from which particular cell type endocannabinoids are released. The proposed research addresses the concept that modulation of intercellular communication by endocannabinoids is not restricted to chemical synapses but also include gap-junction mediated electrical synapses. Moreover, based on a functional interaction with the dopaminergic system, it can lead to long-term potentiation of synaptic responses. This modulatory action could constitute a widespread property, relevant not only to normal brain function in structures such as the basal ganglia, retina, and neocortex where both forms of transmission co-exist, but also to numerous health- related issues such as drug abuse.