Cocaine addiction remains among the most significant health concerns in the United States. Understanding the mechanisms by which recreational use of cocaine leads to compulsive drug abuse is certain to enhance our ability to design better treatment strategies for cocaine addiction. The forebrain nucleus accumbens (NAc) has long been recognized as a critical structure involved in motivated behavior, including drug seeking and the reinforcing effects of drugs and other """"""""natural rewards"""""""". This nucleus is comprised primarily of medium spiny neurons (MSNs) which serve as its only output source and are regulated by both afferent inputs and voltage-gated ion channels (VGICs). The present application seeks to continue studies designed to determine how DA and other neurotransmitters specifically modulate VGICs and how both channel activity and neurotransmitter modulation are altered by repeated cocaine administration and withdrawal. For all studies, we will use primarily whole-cell patch clamp recordings from acutely dissociated rat NAc neurons. The first specific aim will characterize further the modulation of whole-cell sodium current and alterations produced by repeated cocaine administration. Experiments will determine whether other drugs of abuse, like cocaine, decrease basal whole-cell sodium current density, whether DA modulates persistent Na+ currents and whether such currents and modulation are altered by repeated cocaine administration. Finally, we will determine whether metabotropic glutamate receptors (mGluRs), which have recently been found to be necessary for cocaine self-administration, might also modulate whole-cell Na+ currents. The second specific aim will determine the mechanisms by which repeated cocaine administration reduces basal whole-cell Ca2 current in NAc neurons and whether DA D2Rs and mGluR receptors alter Ca2+ currents, and if so, whether repeated cocaine treatment alters such modulation. The third specific aim will initiate studies designed to determine whether DA receptors modulate specific K+ conductances in NAc neurons and whether such modulation is altered by repeated cocaine treatment. We anticipate that delineation of the roles of DA-Rs and mGluRs in modulating specific VGICs and how such modulation is altered by repeated cocaine treatment will greatly advance our understanding of potential molecular targets for pharmacotherapy.
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