Ongoing ETOH Research

Allyson Bennett
“Adolescent Alcohol Consumption: Developmental & Long-term Risks” Our research interests center on the interplay between genetic and environmental factors that contribute to individual differences in vulnerability and resilience to psychopathology. In this research, monkeys are used to model aspects of complex disorders in order to study genetic and early experiential risk factors that influence their development and expression. Our approach is comparative and integrative. A major component of the research includes the development and use of multiple test strategies to assess cognitive, affective, and behavioral function in monkeys. These measures facilitate translational studies and strengthen the use of nonhuman primates as models for complex disorders. One primary focus of our laboratory is on early risk factors for excessive, entrenched patterns of alcohol consumption in adulthood. Risk factors under investigation include adolescent alcohol consumption, early childhood stress, and temperament. We have also initiated a longitudinal project with comprehensive behavioral and physiological measurements that will document the effects of controlled adolescent alcohol exposure. While alcoholism is a primary focus of study, the research approach and techniques that we use translate to other disorders with behavioral, cognitive, and affective components that can be modeled in primates. Thus, another project uses similar measurements with monkeys derived from a large pedigreed population in a new initiative to develop a nonhuman primate model of autism. Taken together, by moving from phenotype development with basic descriptive work to identification of associated candidate genes, our broad goal is to develop productive behavioral pharmacogenetic approaches in nonhuman primates and thus contribute to the development of animal models in research on targeted therapeutics for complex disorders.

James Daunais
“Imaging Stress and Alcohol in Monkeys”  The focus of my research is the assessment of the neurobiological and behavioral consequences of exposure to abused substances, in particular, cocaine. Brain imaging methods such as quantitative receptor, transporter G-protein autoradiography and in situ hybridization histochemistry techniques, are combined with hybrid array analysis to determine the mechanisms of action of abused drugs at various transporter and receptor systems. The noninvasive positron emission tomography (PET) method is also applied in parallel studies to identify the biological and functional correlates that result from repeated drug use.

Donald Dougherty
Dr. Dougherty currently conducts his research at the NRLC and is broadly interested in aggressive and impulsive behaviors.  In particular, in his research he examines the effects of drugs, medications, and neurotransmitter manipulations on behavior measured in the laboratory, as well as determining biological markers that may predict these behaviors.

David Friedman
“Early Stress and Alcoholism: Neurobiological Analysis”  This project will study the interaction of childhood stress and ethanol by comparing mother-reared to nursery-reared rhesus monkeys.  It will study drinking behavior, endocrine status, the serotonin transporter and receptors, and gene expression in the serotonin systems.

Dwayne Godwin
"A New Model Systems for the Study of Ethanol's Influence on Sleep" Drinking alcohol makes you sleepy.  For some insomniacs, this effect is the pathway to bedtime alcohol consumption and eventual abuse. Sleep disturbances are common in alcoholic patients, with a number of serious health consequences. Among these are cardiovascular abnormalities, breathing difficulties, and memory impairment. Ethanol also influences the clinical course of psychiatric and sleep disorders by a number of mechanisms which have as a common basis perturbations in the balance of central nervous system neurotransmitter systems. The net effect is a disruption in clinical outcomes, including medication strategies. Research within Dr. Godwin's laboratory examines the influence of ethanol on the intrinsic membrane properties and synaptic interactions of neurons at known sites of sleep generation and maintenance. A current focus is the effect of ethanol on the spindle generating circuitry of the thalamus, where many of the classical targets of ethanol play important roles in the initiation and propagation of spindle oscillations.

Scott Hemby
My general research interest is in the elucidation of the neurobiological substrates of complex mammalian behaviors. Currently, my research focuses on the dysregulation of neurobiological mechanisms in neuropsychiatric disorders, principally drug addiction and schizophrenia, with specific attention to limbic circuits and cell types within these circuits. Ongoing projects in the lab include the following:

Neurochemical and molecular plasticity of GABAergic medium spiny neurons in the nucleus accumbens following opiate self-administration in rodents

Identification of gene and protein expression profiles of cocaine addiction using rat and rhesus monkey models as well as brain tissue from cocaine overdose victims and controls. Currently, we are focusing on alterations in ionotropic glutamate receptor function as a function of cocaine abuse.

Determination of cortical and subcortical molecular pathology associated with schizophrenia using post-mortem brain tissue from individuals diagnosed with schizophrenia. Gene and protein expression patterns are compared with analogous brain regions in rhesus monkeys treated with antipsychotics. Rodent studies include determination of neuroadaptive changes associated with the delay of onset of antipsychotic administration.

Experimental approaches include gene profiling of brain regions and individual neurons using microarray technology, protein profiling of brain regions using 2DIGE technology, intravenous self-administration, in vivo microdialysis and capillary electrophoresis with laser induced fluorescence, immunohistochemistry and Western blotting.

Results from these projects will further our understanding of the biological basis of addictive disorders and schizophrenia and provide preliminary molecular "fingerprint" of these disorders which could provide novel targets for pharmacotherapeutic intervention. Current and future research will focus on the molecular phenotype of the targeted neurons, how complex cellular mechanisms are disrupted in disease states and how behavior modulates gene expression.

Sara Jones
"Ethanol Effects on Dopamine and Serotonin Dynamics in Mouse Brain" Ethanol shares with all major dependence-producing drugs the ability to activate the mesolimbic dopamine system, as important part of the brain reward system.  The mechanisms of action of neurons directly or acts through intermediate neurotransmitter systems is an open question.  Ethanol has been shown repeatedly to elevate extracellular dopamine levels in the nucleus accumbens (NAC) in vivo.  This elevation is likely due to an increase in dopamine neuron firing rate in the ventral tegmental area (VTA), but several studies have also reported direct effects of ethanol on dopamine from nerve terminals.  We are working to determine exactly how ethanol affects release and uptake of dopamine from nerve terminals in the NAC and also, the exact effects of acute ethanol exposure on the release and uptake of dopamine and 5-HT in nerve terminal fields using cyclic voltammetry.

Anthony Liguori
"Behavioral Effects of Marijuana/ Alcohol/Sleep-Deprivation Combinations" Marijuana smoking has frequently been associated with automobile accidents. Many marijuana users simultaneously use other drugs, with alcohol most frequently paired. Alcohol use and marijuana use have been associated respectively with nearly 50% of traffic fatalities in the United States and 33% of reckless drivers. Additionally, sleep deprivation has been associated with half of all long distance driving trips. The goal of this series of studies is to quantify how these factors, alone and in combination, affect mood, body sway, and simulated driving.

"Behavioral Effects of Alprazolam-Alcohol Combinations" Alprazolam (Xanax) is a widely prescribed sedative used for short-term relief of anxiety. Although the combined use of alcohol and sedatives is widely discouraged, millions of Americans use both drugs on the same occasion. This is very likely dangerous, as alcohol and alprazolam separately and together have been shown to impair mental activity and motor action. This study will determine whether commonly used alcohol doses increase alprazolam-induced impairment of simulated driving, memory, attention, and balance.

Charles Mathias
Dr. Mathias currently conducts his research at the NRLC and is broadly interested in psychophysiological mechanisms involved in aggressive and impulsive behaviors.

Brian McCool
Our lab is currently focused on understanding the cellular and molecular mechanisms governing the interaction between anxiety and drugs of abuse. We are especially interested in the chronic effects of ethanol on excitatory and inhibitory neurotransmitter systems in brain areas regulating such behaviors. We utilize patch clamp electrophysiology and isolated cell preparations from these areas to investigate alterations in receptor pharmacology and function. We also utilize molecular biological approaches like single-cell RT-PCR and real-time RT-PCR to understand the contribution of gene expression.

Linda Porrino
"Neural Substrates for the Acute Effects of Alcohol" Our laboratory combines the use of animal models of alcohol use and abuse with neuroimaging methods to investigate the effects of alcohol in a variety of situations. The purpose of the studies proposed in this application is to identify the circuits in the brain that are involved when larger and larger amounts of alcohol are consumed by rats.  We will also see if the effects of alcohol vary with the length of time since ingestion.  In other studies we will try to identify the circuits in the brain that are activated during craving for alcohol.  Finally, we will investigate the contribution of the neurotransmitter dopamine to these processes.

James Smith
"Neurobiological Mechanisms of Alcohol Drinking" This research project will investigate the brain systems responsible for alcohol drinking using a rat model.  Measures of brain cell activity will be assessed in small regions by measuring the rates of synthesis and degradation of six different chemicals that different brain cell types use to transfer information to other brain cells. The rate of synthesis and degradation of these six neurochemicals will be measured in 28 different brain regions of rats drinking either sweetened alcohol, the sweetener itself, water or with a history of drinking sweetened alcohol but not drinking on that day.  These data will be used to identify the brain cell circuits involved in alcohol drinking.

Jeff Weiner
"Ethanol and Synaptic GABAa Receptors" The overall aim of this research project is to characterize the synaptic mechanisms underlying alcohol potentiation of GABAA receptor-gated inhibitory synaptic transmission.  The GABAA receptor mediates the majority of fast inhibitory synaptic transmission in the mammalian CNS, and a considerable volume of evidence suggests that these receptors may be one of the major CNS mediators of alcohol intoxication.  In this project, we will use the whole cell patch clamp technique to record from hippocampal CA1 pyramidal neurons in brain slices from mature rats.  By characterizing the effects of alcohol on spontaneous and miniature GABAA receptor-mediated synaptic currents and currents evoked by somatic application of low concentrations of GABA, the specific mechanisms through which alcohol enhances pre- and postsynaptic components of GABAA receptor-gated synaptic transmission at a central mammalian synapse will be elucidated.  The results of these experiments will clarify the pharmacological relevance of presynaptic and postsynaptic alcohol actions to its facilitatory effect on GABAA receptor-gated synaptic transmission and identify mechanisms underlying the physiological regulation of alcohol sensitivity at these sites.