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Component #3

Effects of Acute and Chronic Alcohol on Orbitofrontal Cortex Function

Principal Investigator: John Woodward, Ph.D.
Co-Investigator: Heather Trantham-Davidson, Ph.D.

Alcoholism is characterized by a loss of control over drinking, suggesting that there are long-lasting changes in higher cortical brain areas that normally control compulsive behaviors. Despite this general understanding, there is little known about the specific actions of alcohol on neurons within these cortical circuits.

In prior animal studies, we addressed this shortcoming and completed a series of electrophysiological studies that examined the effects of ethanol on “persistent” activity in the medial prefrontal cortex (PFC). This activity is characterized by spontaneous and rhythmic transitions between quiescent down-states and depolarized up-states that generate relevant patterns of firing. Persistent activity may allow PFC neurons to integrate and process sensory information derived from internal and external cues and to use this information to control sub-cortical circuits. The results from these pioneering studies showed that prefrontal up-states and associated firing are inhibited by concentrations of alcohol associated with mild to moderate intoxication. They also demonstrated that this effect resulted from inhibition of synaptic NMDA receptors and that PFC AMPA receptors and GABAA receptors are largely insensitive to behaviorally relevant concentrations of alcohol.

In this component, we will extend these studies and investigate the effects of chronic alcohol on prefrontal cortex function. These studies use a well-established animal model of chronic intermittent ethanol (CIE) exposure that increases levels of drinking as compared to non-dependent animals.

We hypothesize that repeated cycles of CIE exposure will produce long-lasting changes in the excitability and plasticity of neurons within the orbitofrontal region (OFC) of the prefrontal cortex, an area known to be dysfunctional in human alcoholics. This hypothesis will be tested using four specific aims that will 1) Assess the effect of chronic alcohol exposure on behaviors that require a functional OFC network; 2) Determine the acute ethanol sensitivity of glutamatergic and GABAergic transmission in OFC neurons; 3) Monitor changes in glutamatergic and GABAergic synaptic transmission in OFC neurons from control and ethanol dependent animals; and 4) Determine the effects of chronic ethanol exposure on plasticity mechanisms of OFC neurons. The results from these studies will be critical in advancing our understanding of the effects of chronic alcohol on higher cortical function.


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