Research Component 8

pix_pair_comp8Genetic Interrelationships among Impulsivity, Ethanol Withdrawal and Withdrawal-induced Ethanol Consumption

Director: Suzanne Mitchell
Co-Directors: John Crabbe, Deborah Finn

In previous PARC-supported studies we discovered that measures of behavioral inhibition (anticipatory responding and responding during a cue signaling "don't respond") differ for different strains of mice, indicating that behavioral inhibition is influences by genes. Further, strains that showed the lowest levels of inhibition when ethanol-naïve were the strains that other studies showed had the highest levels of ethanol withdrawal after chronic exposure. This component includes experiments that will help us to understand the basis of this relationship, and how it relates to alcohol drinking.

If the relationship between inhibition and alcohol withdrawal severity is partly determined by the same genes, as suggested from our earlier studies, selectively breeding mice that differ for one characteristic should also produce a difference response in the other response. Mice selected for different levels of impulsivity are unavailable. However, we can examine mice selectively bred for severe (Withdrawal Seizure-Prone; WSP) versus mild (Withdrawal Seizure-Resistant; WSR) withdrawal severity after chronic exposure to ethanol. Our first study will do this and we predict that WSP mice will display higher levels of basal inhibition (anticipatory responding and responding during a "No-go" cue) on a Go/No-go task than WSR mice. Such a result would strongly imply that the association seen in the inbred strain panel is indeed due to shared genetic variance, and provide an additional behavioral target for research focused on the genetics of ethanol withdrawal.

Signs of alcohol withdrawal vary in severity after exposure ends, and different signs have different time courses. In our second study, WSP and WSR mice will be chronically exposed to ethanol and levels of inhibition will be tested after exposure has ended to establish when maximal disinhibition is seen, and for how long it persists. We expect that the WSR mice will show greater loss of inhibition than WSP mice, and that it will persist longer. Like the first study, this study will address the question of whether some of the same genes that affect withdrawal seizure severity differentially in WSP and WSR mice are the same as those affecting inhibition in these selected lines.

In our third study we will examine another consequence of alcohol abstinence, heightened alcohol consumption. Before and after chronic exposure to alcohol, alcohol drinking will be measured daily. We predict that mice selected for low levels of withdrawal (WSR mice) will show greater pre-alcohol exposure drinking than WSP and will show larger increases in post-alcohol exposure drinking. The effects of repeated cycles of alcohol exposure will be explored by exposing mice to three additional vapor exposure–drinking cycles. We expect that WSR mice will exhibit more drinking during withdrawal than WSPs over all cycles, and that the difference between the lines will be augmented by the repeated cycles.

These three experiments will enhance our understanding of the genetic interrelationships among impulsivity (behavioral inhibition/disinhibition), ethanol withdrawal severity and both pre-alcohol exposure and post-withdrawal increases in drinking. Each of these traits is a research focus in the PARC. Our studies examining these relationships will also provide exploratory data that will be used to identify the genes and/or gene networks that may underlie the genetic relationships among these processes, a major theme of the PARC

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