Ethanol abuse and dependence causes significant morbidity and mortality within the veteran population. In an attempt to discern the neurophysiological basis of substance abuse disorders, the collection of brain nuclei referred to as the amygdala formation has become unequivocally linked to ethanol reinforcement, withdrawal and craving. Specific amygdaloid subnuclei, particularly the central amygdala nucleus (CeA) have been identified as part of a functional system essential to mediating the response to many drugs of abuse, including ethanol. The CeA modulates autonomic and emotional responses via efferent projections to hypothalamic and brainstem areas, and is activated during withdrawal from ethanol. Behaviors dependent on amygdala activity are strongly affected by several endogenous neurotransmitter systems: Corticotropinreleasing factor (CRF), opioid peptides (including enkephalin and dynorphin) and dopamine (DA). These transmitter systems also play powerful roles in mediating effects of ethanol. Drugs of abuse such as ethanol enhance release of DA in the nucleus accumbens (part of the "extended amygdala");this effect is associated with feelings of well-being and euphoria. Conversely, ethanol withdrawal is often accompanied by high levels of anxiety and is associated with a decrease in DA function and heightened CRF levels in CeA. In addition, manipulation of opioid peptide receptors (either pharmacologically or genetically) alters the amount of voluntary ethanol consumption in experimental animals. Recent anatomical research strongly suggests a role for DA in modulating these peptidergic systems in CeA. Surprisingly, little research has focused on direct physiological effects of these transmitter systems at the cellular and synaptic level in the CeA. Our recent collaborative work has determined that CRF enhances GABAergic mechanisms in the CeA. Furthermore, release of CRF is necessary for the effects of ethanol on GABAergic transmission in CeA. Using an in vitro rodent "brain slice" preparation, our laboratory has recently uncovered a novel local circuit CeA pathway that appears to be largely mediated by the release of endogenous CRF. The magnitude of the observed postsynaptic effect is extremely compelling because endogenous neuropeptide responses have rarely been observed, much less fully characterized. In addition, we now have evidence of tonic activity of opioids in the CeA. These actions tend to oppose the actions of CRF. By characterizing these endogenous peptidergic responses in CeA, we have a unique model system to study effects of applied ethanol in a brain region considered critical to the reinforcing effects of ethanol consumpion. A full investigation of these endogenous peptidergic systems, and their regulation by DA, could help elucidate role of the amygdala in ethanol dependence. This proposed investigation of direct effects of ethanol, CRF, opioid peptides, and DA in the central amygdala may provide significant direction for future clinical studies of the neurobiological substrates of drug dependence and drug withdrawal.

Public Health Relevance

The Veterans Administration currently treats a substantial number of veterans with alcohol-related disorders, accounting for a large portion of services received on medical, surgical, and psychiatric units. Since individuals with anxiety disorder diagnoses also have high rates of co-morbid alcoholism, it is imperative to examine the effects of alcohol use from the standpoint of it anxiolytic and anxiogenic actions. Current available pharmacological interventions have limited beneficial effects. As an on-going search for better pharmacological therapeutics, this study aims to investigate candidate mechanisms mediating alcohol dependence. Specifically, we will examine the role of stress-related neuropeptides in the amygdala, a key brain region mediating stress and anxiety. This proposed study should contribute to the development of more effective pharmacological therapeutics to ameliorate and/or treat alcohol dependence.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001271-02
Application #
8597920
Study Section
Neurobiology A (NURA)
Project Start
2012-10-01
Project End
2016-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Durham VA Medical Center
Department
Type
DUNS #
043241082
City
Durham
State
NC
Country
United States
Zip Code
27705