Neuropharmacology; neuroendocrinology of ethanol intake and withdrawal
Summary of Current Research
Several research projects focus on the physiological significance of neurosteroid action. These endogenous modulators alter brain function by enhancing GABAergic neurotransmission via potent and selective interactions with GABA-A receptors. In a broad sense, studies are investigating whether drugs or physiological states which produce alterations in endogenous neurosteroids such as allopregnanolone (ALLO) influence seizure susceptibility, anxiety levels, drug withdrawal hyperexcitability or dysphoria, or patterns of drug intake and the response to drug intake. One neurosteroid project is using gas chromatography-mass spectrometry to simultaneously analyze 10 neurosteroids in discrete brain regions and electrophysiological characterization of GABA-A receptor-mediated currents to test the hypothesis that a reduction in hippocampal GABAergic function, due to decreased GABA-A receptor sensitivity to neurosteroids and a concomitant imbalance in ALLO and related neurosteroids, represents a neurochemical substrate for enhanced susceptibility to high ethanol withdrawal. Long term goals of this research are to gain information that will aid in our understanding of the mechanisms underlying ethanol withdrawal as well as the therapeutic potential of neurosteroid treatment during ethanol withdrawal. A second neurosteroid project is manipulating endogenous GABAergic neurosteroid levels or administering synthetic neurosteroids and determining the influence on the appetitive and consummatory processes involved in ethanol self-administration in male and female mice. One long term goal of this research is to evaluate the influence of neurosteroids on gender differences in human patterns of alcohol intake and the response to alcohol, since males and females differ in endogenous neurosteroid levels.
A second research focus is using models of high ethanol intake to examine changes in neurochemical systems following binge drinking in dependent and non-dependent mice as well as following binge drinking and intermittent stress exposure. The first binge project is pursuing a model whereby chronic intermittent ethanol vapor exposure and withdrawal produces high alcohol intake (termed "withdrawal-induced drinking" or WID). These studies utilize a brain site-specific microinjection technique to manipulate the GABAergic, glutamatergic, and CRF peptide environment of brain regions important in the intoxication circuit and in the dependence and stress circuit. The goal of these studies is to determine whether the neurochemical systems and adaptations in discrete neural sites that are important for the expression of WID differ from those underlying high ethanol intake in non-dependent animals. This information should aid in the development of new strategies for the treatmen of alcohol use disorders and alcoholism. A second binge project is examining the relationship between binge drinking and stress in adolescent and adult male and female mice on subsequent ethanol intake. We observed marked sex differences in adaptations in the glutamatergic system and in several biological pathways following binge drinking that may confer susceptibility for a later increase in drinking behavior. Additionally, evidence indicates that early environmental stress can be a risk factor for alcoholism, but few studies have examined the possibility that binge ethanol exposure could accentuate the physiological and behavioral effects of stress. Current studies are using exposure to predator odor stress, as a model of post-traumatic stress disorder, and are characterizing age and sex differences in the ability of predator odor stress to escalate ethanol intake in mice with prior binge alcohol experience. The goal of these studies is to gain information that can guide the development of new pharmacological strategies, that may differ in males and females, and that can be used to reduce binge consumption and the transition to dependence.
NINDS Postdoctoral Research Fellow, University of California, Irvine
Areas of interest
- GABAergic neurosteroid modulation of ethanol drinking and ethanol withdrawal
- The influence of steroid levels on brain function and behavior, with behavioral assessments using animal models of anxiety, depression, and seizure susceptibility
- Neurochemical substrates underlying binge drinking and interaction with stress with a focus on sex differences
- Use of genetic animal models to examine alcohol-related behaviors
- B.S., Loyola Marymount University 1978
- Ph.D., University of Southern California 1989