A confound of these observations in humans is that deficits could reflect a preexisting phenotype and may not be a direct result of alcohol exposure. Therefore, controlled studies in animal models are needed to better understand how excessive and repeated episodes of alcohol exposure alter PFC function and behavioral control. NMDA receptor -mediated glutamatergic neurotransmission is required for several forms of neuronal plasticity. Alterations in glutamate neurotransmission in prefrontal-limbic circuits have been implicated in the development of addiction to psychostimulants and may play a similar role in the development of alcohol dependence. Acute alcohol exposure inhibits NMDARs at pharmacological concentrations associated with intoxication. In contrast, chronic alcohol exposure has been reported to increase the synaptic expression of NR2B subunit-containing NMDARs. This increase presumably occurs as a homeostatic adaptive response to the prolonged reduction of NMDAR activity in the presence of alcohol. NMDARs containing the NR2B subunit have been especially implicated in synaptic plasticity and alterations in learning and memory. Using a mouse model of alcohol dependence that involves repeated Butenafine hydrochloride cycles of alcohol exposure, the goal of the present study was to determine whether the plasticity of medial PFC is Cinoxacin altered in response to chronic alcohol exposure. Specifically, we hypothesized that CIE exposure increases the synaptic expression of NR2B receptors in mPFC pyramidal neurons that in turn promotes persistent alterations in synaptic plasticity. In acute brain slices from adult animals, we found that CIE exposure resulted in an increase in the NMDA/AMPA current ratio that was still present 1-week after the last episode of ethanol exposure. Consistent with a selective increase in synaptic NMDA currents, Western blot analysis of the insoluble PSD containing membrane fraction revealed increases in NR1 and NR2B subunits but no change in GluR1 subunits in tissue examined immediately after the last episode of alcohol exposure. However, the increase in NR1 and NR2B was no longer present when examined 1-week after the last episode of ethanol exposure. At the structural level, analysis of dendritic spines revealed a selective increase in the density of mature spines that persisted throughout 1 week of withdrawal. CIE exposure and withdrawal was also associated with aberrant expression of NMDAR-mediated STDP. Lastly, behavioral studies using a mPFC-dependent task showed that CIE exposure was associated with deficits in behavioral flexibility that persisted up to 1-week after the last period of ethanol exposure. These results indicate that chronic ethanol exposure induces changes in PFC plasticity, which may contribute to a loss of appropriate attentional control over behavior. At the structural level, we have previously shown that chronic ethanol exposure of primary hippocampal neuronal cultures results in increases in the size of dendritic spines. These in-vitro observations are supported by in-vivo chronic ethanol studies of changes in the density and/or morphology of dendritic spines. Using diolistic labeling procedures coupled with 3D image analysis, we compared CIE-induced neuroadaptations of dendritic spine density and morphology of basal dendrites of layer V mPFC pyramidal neurons. CIE exposure did not alter the total spine density measured either immediately after the last episode of alcohol exposure or following 1-week of withdrawal. However, there was a small but significant increase in the density of mature, 
mushroom-type spines.