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
- "Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal." Psychopharmacology In: , 29.06.2017, p. 1-19.
- "Tigecycline Reduces Ethanol Intake in Dependent and Nondependent Male and Female C57BL/6J Mice." Alcoholism: Clinical and Experimental Research In: , Vol. 40, No. 12, 01.12.2016, p. 2491-2498.
- "Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice." Alcoholism: Clinical and Experimental Research In: , Vol. 40, No. 12, 01.12.2016, p. 2499-2505.
- "Pharmacologically counteracting a phenotypic difference in cerebellar GABA receptor response to alcohol prevents excessive alcohol consumption in a high alcohol-consuming rodent genotype." Journal of Neuroscience In: , Vol. 36, No. 35, 31.08.2016, p. 9019-9025.
- "Alcohol Suppresses Tonic GABA Receptor Currents in Cerebellar Granule Cells in the Prairie Vole : A Neural Signature of High-Alcohol-Consuming Genotypes." Alcoholism: Clinical and Experimental Research In: , Vol. 40, No. 8, 01.08.2016, p. 1617-1626.
- "Functional regulation of PI3K-associated signaling in the accumbens by binge alcohol drinking in male but not female mice." Neuropharmacology In: , Vol. 105, 01.06.2016, p. 164-174.
- "Sex and the Lab : An Alcohol-Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies." Alcoholism: Clinical and Experimental Research In: , Vol. 40, No. 6, 01.06.2016, p. 1182-1191.
- "Protein kinase C epsilon activity in the nucleus accumbens and central nucleus of the amygdala mediates binge alcohol consumption." Biological Psychiatry In: , Vol. 79, No. 6, 15.03.2016, p. 443-451.
- "Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence." Neuropharmacology In: , Vol. 97, 27.06.2015, p. 182-193.
- "Null Mutation of 5α-Reductase Type I Gene Alters Ethanol Consumption Patterns in a Sex-Dependent Manner." Behavior Genetics In: , Vol. 45, No. 3, 01.05.2015, p. 341-353.
- "Sex Differences in Ethanol’s Anxiolytic Effect and Chronic Ethanol Withdrawal Severity in Mice with a Null Mutation of the 5α-Reductase Type 1 Gene." Behavior Genetics In: , Vol. 45, No. 3, 01.05.2015, p. 354-367.
- "Effect of nucleus accumbens shell infusions of ganaxolone or gaboxadol on ethanol consumption in mice." Psychopharmacology In: , Vol. 232, No. 8, 01.04.2015, p. 1415-1426.
- "Environmental stressors influence limited-access ethanol consumption by C57BL/6J mice in a sex-dependent manner." Alcohol In: , Vol. 48, No. 8, 01.12.2014, p. 741-754.
- "Quantification of ten neuroactive steroids in plasma in Withdrawal Seizure-Prone and -Resistant mice during chronic ethanol withdrawal." Psychopharmacology In: , Vol. 231, No. 17, 01.09.2014, p. 3401-3414.
- "Differences in the reinstatement of ethanol seeking with ganaxolone and gaboxadol." Neuroscience In: , Vol. 272, 11.07.2014, p. 180-187.
- "Binge alcohol drinking by mice requires intact group1 metabotropic glutamate receptor signaling within the Central nucleus of the Amygdale." Neuropsychopharmacology In: , Vol. 39, No. 2, 01.2014, p. 435-444.
- "The neurosteroid allopregnanolone impairs object memory and contextual fear memory in male C57BL/6J mice." Hormones and Behavior In: , Vol. 66, No. 2, 2014, p. 238-246.
- "Contribution of P2X4 receptors to ethanol intake in male C57BL/6 mice." Neurochemical Research In: , Vol. 39, No. 6, 2014, p. 1127-1139.
- "The effect of mGluR5 antagonism during binge drinking on subsequent ethanol intake in C57BL/6J mice : Sex- and age-induced differences." Alcoholism: Clinical and Experimental Research In: , Vol. 38, No. 3, 2014, p. 730-738.
- "The relationship between adjunctive drinking, blood ethanol concentration and plasma corticosterone across fixed-time intervals of food delivery in two inbred mouse strains." Psychoneuroendocrinology In: , Vol. 38, No. 11, 11.2013, p. 2598-2610.
- "Pharmacological insights into the role of P2X4 receptors in behavioural regulation : Lessons from ivermectin." International Journal of Neuropsychopharmacology In: , Vol. 16, No. 5, 06.2013, p. 1059-1070.
- "Local Changes in Neurosteroid Levels in the Substantia Nigra Reticulata and the Ventral Tegmental Area Alter Chronic Ethanol Withdrawal Severity in Male Withdrawal Seizure-Prone Mice." Alcoholism: Clinical and Experimental Research In: , Vol. 37, No. 5, 05.2013, p. 784-793.
- "Recent Advances in the Discovery and Preclinical Testing of Novel Compounds for the Prevention and/or Treatment of Alcohol Use Disorders." Alcoholism: Clinical and Experimental Research In: , Vol. 37, No. 1, 01.2013, p. 8-15.
- "Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration." Neuropharmacology In: , Vol. 63, No. 4, 09.2012, p. 555-564.
- "Ivermectin reduces alcohol intake and preference in mice." Neuropharmacology In: , Vol. 63, No. 2, 08.2012, p. 190-201.
- "Ethanol up-regulates nucleus accumbens neuronal activity dependent pentraxin (Narp) : Implications for alcohol-induced behavioral plasticity." Alcohol In: , Vol. 46, No. 4, 06.2012, p. 377-387.
- "A genetic animal model of differential sensitivity to methamphetamine reinforcement." Neuropharmacology In: , Vol. 62, No. 7, 06.2012, p. 2168-2176.
- "A genetic animal model of differential sensitivity to methamphetamine reinforcement." Neuropharmacology In: , Vol. 62, No. 7, 06.2012, p. 2169-2177.
- "Localization of brain 5α-reductase messenger RNA in mice selectively bred for high chronic alcohol withdrawal severity." Alcohol In: , Vol. 45, No. 8, 12.2011, p. 763-772.
- "Alteration of ethanol drinking in mice via modulation of the GABA A receptor with ganaxolone, finasteride, and gaboxadol." Alcoholism: Clinical and Experimental Research In: , Vol. 35, No. 11, 11.2011, p. 1994-2007.