Glutamatergic synaptic transmission in the nucleus accumbens (NAc) has been implicated in neuroadaptive alterations which underlie the development of addiction to alcohol. In an animal model adopted by the INIA-West consortium (Withdrawal-induced drinking mouse model, hereafter termed WID experience), C57/BL6J mice that experienced 3 intermittent 16 hrethanol vapor exposures displayed a 2-3 fold enhancement in both shell and core NAc cFos expression and a marked increase in their ethanol intake over mice that experienced constant ethanol exposure. Our preliminary data indicate conditioning stimuli which normally induces NMDA-receptor dependent synaptic depression in wild-type mouse shell Nac medium spiny neurons (MSNs) instead induces a remarkable conversion to synaptic potentiation in nondrinking mice that had undergone a single bout of WID experience. This form of synaptic plasticity in shell NAc MSNs has also been implicated in the expression of behavioral sensitization to cocaine and therefore may represent a fundamental cellular process involved in neuroadaptation to ethanol and other reinforcers. Changes in the level of excitatory drive onto MSNs have been implicated in sustained upstates of the membrane potential or bistability recorded under current clamp conditions. Such shifts in excitability of these neurons are thought to be critically involved in information processing in mesolimbic structures and thus we propose that MSN bistability is an important electrophysiological process altered by WID experience and therefore important to the development of ethanol dependence. Finally, alterations in AMPA and NMDA receptor synaptic drive are implicated in ethanol dependence, synaptic plasticity as well as membrane potential bistability. Therefore, our overarching hypothesis is that WID experience induces alterations in excitatory synaptic drive mediated by aberrant plasticity of AMPA/NMDA receptors and that these changes in plasticity impact MSN function (bistability). Thus, we propose to perform a comprehensive analysis of the alterations in synaptic plasticity, membrane potential bistability and AMPA/NMDA receptor mediated synaptic transmission and receptor levels induced by WID experience in medium spiny neurons of the shell of the NAc. This project uses electrophysiological, immunofluorescent, confocal microscopy and co-localization image analysis to investigate these hypotheses.
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