G protein-gated inwardly-rectifying potassium ion channels (GIRK) mediate the postsynaptic inhibitory effect of many neurotransmitters and related drugs of abuse. The long-term goal of my research is to understand how GIRK channels influence behaviors associated with the modulation of inhibitory neuretransmitter signaling pathways. Recent findings from both forward and reverse genetic studies have suggested that the GIRK3 subunit influences the sensitivity of mice to key behavioral effects of opiates, including analgesia, reward, and dependence. Though the GIRK3 cDNA was cloned more than a decade ago, the precise function of this subunit remains controversial. The goal of this proposal is to understand how and where GIRK3 influences the sensitivity of mice to the behavioral effects of opiates. Our current working hypothesis is that GIRK3 assembles with other GIRK subunits to form functional channels that are relatively insensitive to GABA(B)-dependent inhibition. Indeed, preliminary studies show the loss of GIRK3 renders dopamine neurons of the VTA more sensitive to GABA(B) receptor activation. The observed decreased sensitivity of mice lacking GIRK3 to the behavioral effects of opiates could reflect, therefore, an increased sensitivity of VTA dopamine neurons to the tonic GABA(B)-dependent inhibition provided by local GABAergic interneurons. Consequently, relatively high levels of opiates would be required to disinhibit VTA dopamine neurons, a process thought to underlie the motor stimulatory and reinforcing effects of opiates such as morphine. This working hypothesis and conceptual framework will be tested using multi-disciplinary approaches described in two specific aims: #1) To measure the contribution of GIRK3 to GABA(B)- dependent inhibition in neurons. The function of GIRK3 will be evaluated by measuring GABA(B)-dependent GIRK currents in cultured neurons following multiple genetic manipulations designed to perturb the level and/or function of GIRK3. #2) To probe the contribution of GIRK3 and the VTA to opiate-induced behaviors. Stereotaxic methods to deliver drugs and genetic reagents to the mouse VTA will be employed, followed by assessments of opiate-induced behavior in an established testing paradigm.
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