Alcoholism and anxiety frequently co-occur in humans;however, it has been difficult to find a single treatment which is effective against both conditions. Substantial evidence suggests that the motivational aspects of alcohol withdrawal (e.g., increased anxiety and anhedonia) referred to as negative affective states play an important role in the maintenance of excessive alcohol drinking, and may also be associated with relapse. Evidence also suggests a salient role for GASAergic mechanisms in regulating excessive alcohol drinking and the negative affective states associated with abstinence. The initial objective of the present proposal is to identify novel a1 GASAA subtype-preferring ligands at the preclinical level that may serve as prototypes for further evaluation of clinical efficacy in treating both excessive alcohol drinking and the negative affective states associated with abstinence. To accomplish this, Aim 1 will employ our established pharmacophore/receptor model of SDl binding sites to synthesize novel a1 subtype-preferring ligands with reduced efficacies at diazepam sensitive (DS) subtypes (e.g., a1,2,3,5)'Once the two agents (e.g., I3CCt, 3-PSC) have been synthesized, Aim 2 will test the hypothesis that their chronic oral administration for 30 consecutive days can effectively attenuate excessive binge alcohol drinking in the high alcohol drinking (HAD) rats using the drinking-in-the-dark-multiple-scheduled-access [DIDMSA] model. We hypothesize that chronic SDl treatments will attenuate excessive binge drinking.
Aim 3 will test the hypothesis that chronic SDl treatment will attenuate negative affective states (e.g., increased anxiety and anhedonia) associated with abstinence. The second objective will be to identify select GASAA receptor subunits which may playa role in the regulation of excessive alcohol drinking and the negative affective states associated with abstinence.
Aim 4 will test the hypothesis that inhibition of the a1 receptor subunits within the ventral' pallidum (VP) will lead to selective time-dependent reductions in binge alcohol responding. To down regulate the a1 subunit, a novel siRNA sequence will be delivered into the VP by bilateral microinfusion using a herpes simplex virus-1 (HSV-1) amplicon vector. These studies should identify novel pharmacotherapies for further evaluation of clinical efficacy in treating comorbid alcoholism and anxiety at the preclinical level. In addition, they should shed light on the salient neuronal mechanisms in the regulation of comorbid alcoh.olism and anxiety, which could be important inultimately leading to a successful treatment for the comorbid condition.
Alcoholism and anxiety frequently co-occur in humans;however, it hasbeen difficult to find a single treatment which is effective against both conditions. In the presElnt 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 wilJemploy a gene reduction procedure referred to as RNAi to identify which GAB A receptors may be important in regulating chronic alcohol drinking and anxiety. By Identifying the receptors that playa 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 |
