Alcoholism and anxiety frequently co-occur in humans; however, it has been difficult to find a singletreatment which is effective against both conditions. Substantial evidence suggests that the motivationalaspects of alcohol withdrawal [e.g., increased anxiety and anhedonia] referred to as negative affective statesplay an important role in the maintenance of excessive alcohol drinking, and may also be associated withrelapse. Evidence also suggests a salient role for GABAergic mechanisms in regulating excessive alcoholdrinking and the negative affective states associated with abstinence. The initial objective of the presentproposal is to identify novel 1 GABAA subtype-preferring ligands at the preclinical level that may serve asprototypes for further evaluation of clinical efficacy in treating both excessive alcohol drinking and the negativeaffective states associated with abstinence. To accomplish this, Aim 1A will employ our establishedpharmacophore/receptor model of BDZ binding sites to synthesize novel 1 subtype-preferring ligands withreduced efficacies at diazepam sensitive [DS] subtypes [e.g., 1-3]. Once the three agents [e.g., CCt, 3-PBC,WYS8] have been synthesized, Aim 1B will test the hypothesis that their chronic oral administration for 30consecutive days can effectively attenuate excessive binge alcohol drinking in high alcohol drinking [HAD] rats.
Aim 1 C will test the hypothesis that a similar treatment will attenuate the negative affective states associatedwith abstinence. We hypothesize that chronic BDZ treatments will attenuate both binge dependence drinkingand the negative affective states associated with abstinence. The second objective will be to identify selectGABAA receptor subunits which may play a role in the regulation of excessive alcohol drinking and thenegative affective states associated with abstinence.
Aim 2 A will test the hypothesis that inhibition of the 1receptor subunits within the ventral pallidum [VP] will lead to selective time-dependent reductions in bingealcohol responding, while Aim 2B will evaluate the hypothesis that their inhibition within the lateral/basolateralamygdala [BLA] will lead to time-dependent reductions in negative affective states. To downregulate the 1subunit, a novel siRNA sequence will be delivered into the VP and BLA by bilateral microinfusion using aherpes simplex virus-1 [HSV-1] amplicon vector. These studies should identify novel pharmacotherapies forfurther evaluation of clinical efficacy in treating comorbid alcoholism and anxiety at the preclinical level. Inaddition, they should shed light on the salient neuronal mechanisms in the regulation of the comorbidcondition, which could be important in ultimately leading to a successful treatment for the comorbid condition.
Layman Summary [109 words] Alcoholism and anxiety frequently co-occur in humans;however, it has been difficult to find a single treatment which is effective against both conditions. In the present application, we propose to use novel benzodiazepine compounds to treat both alcohol dependence and the anxiety which is often seen following attempts to reduce chronic drinking. The second phase of the application will employ a gene reduction procedure referred to as RNAi to identify which GABA receptor may be important in regulating chronic alcohol drinking and anxiety. By identifying the receptors that play a role in regulating alcoholism and anxiety, it may be possible to develop more optimal treatments for the comorbid condition.
| Liu, Juan; Yang, Andrew R; Kelly, Timothy et al. (2011) Binge alcohol drinking is associated with GABAA alpha2-regulated Toll-like receptor 4 (TLR4) expression in the central amygdala. Proc Natl Acad Sci U S A 108:4465-70 |
