The long term objective of this component is to understand genetic interrelationships among ethanol withdrawal severity and both basal levels and post-withdrawal escalations in ethanol consumption and impulsivity (behavioral inhibition/disinhibition). Data from a panel of eight inbred strains indicate that indices of behavioral inhibition (anticipatory responding and responding during a No-go cue) are influenced by genotype and that this genetic influence is correlated with genetic contributions to both acute and chronic ethanol withdrawal severity, assessed using the handling-induced convulsion (HIC). Other data indicate a negative genetic relationship between chronic ethanol withdrawal and alcohol intake. The proposed studies will assess these genetic interrelationships by performing in three studies. Study 1 examines whether levels of inhibition in ethanol-naive animals and ethanol withdrawal severity are influenced by some of the same genes by assessing basal inhibition on a Go/No-go task in mice selectively bred for severe (inbred Withdrawal Seizure-Prone;iWSP) versus mild (inbred Withdrawal Seizure-Resistant;iWSR) withdrawal HIC severity after chronic exposure to ethanol vapor. Study 2 examines levels of inhibition following chronic ethanol exposure (72 hrs of continuous ethanol inhalation) to establish when maximal disinhibition is seen and for how long it persists. Like Study 1, Study 2 will address the question of whether some of the same genes that affect withdrawal HIC severity differentially in iWSP and iWSR mice are the same as those affecting inhibition and withdrawal-induced inhibition in these selected lines. Study 3 will examine whether ethanol drinking in alcohol-nondependent animals and ethanol withdrawal severity are influenced by some of the same genes using the iWSP and iWSP mice. The study will also assess genotypic differences in the effects of withdrawal on ethanol drinking following four cycles of chronic intermittent ethanol exposure (each cycle = 16 hours ethanol: 8 hours air for 4 days). Taken together these three studies will permit the development of a broader-based description of ethanol withdrawal that encompasses changes in impulsivity/inhibition and ethanol drinking, as well as provide critical information for future genetic mapping studies to identify the precise genes involved in these processes.
The studies in this component will extend our understanding of the behavioral consequences of withdrawal in alcohol-dependent individuals, and the extent to which these are genetically determined. This information will be useful in individualizing withdrawal treatments, and will enable us to predict and manage alcohol withdrawal more effectively.
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