Although endogenous neuropeptide transmitters play critical roles in the reinforcing effects of ethanol consumption and the aversive effects of ethanol withdrawal, we have a poor understanding of mechanism(s) underlying central neuronal release of neuropeptides. This gap in our knowledge critically undermines our abilities to elucidate the biological effects of ethanol (EtOH), as 1) multiple studies have demonstrated that acute and chronic EtOH induces release of neuropeptides in brain regions associated with EtOH reinforcement and withdrawal-induced aversion, and 2) one of the very few medications (naltrexone) commonly used to treat EtOH craving is assumed to act by antagonizing effects of endogenously-released opioid peptides. Multiple behavioral studies document involvement of endogenous neuropeptides in response to stress, drugs and other behavioral states, but we still know very little about the physiological mechanisms underlying neuropeptide release. Howevever, this knowledge could significantly enhance our ability to create novel pharmacotherapies for alcohol dependence. Previous studies from our lab and others have shown enhanced release of neuropeptides in the central nucleus of the amygdala (CeA) by acute EtOH exposure. In addition, several studies have shown persistent release of specific peptides following withdrawal from chronic intermittent EtOH; these peptides may mediate the ?anxious-like? withdrawal behaviors. However, our current preliminary data suggest that many conventional notions of peptide release may be inaccurate or incomplete; specifically, high-frequency activity is neither sufficient nor necessary for peptide release. We have recently begun exploring potential cellular phenomena that could regulate peptide release and our preliminary data demonstrate that we can relatively selectively induce release of the neuropeptide corticotropin-releasing factor (CRF) using optogenetic methods. In addition, we have characterized the potential role of the BK potassium channel in mediating EtOH effects. Proteomic analysis has shown that the BK channel is linked to the intracellular enzyme dynamin-1, a protein essential for mediating peptide release. We hypothesize that in contrast to fast synaptic transmission at axonal terminals, central neuropeptide release is mediated by a mechanism dependent on both the BK channel and dynamin-1. Because of the wealth of preclinical data implicating endogenous neuropeptides in effects of ethanol consumption and the clinical experience with naltrexone (which acts by blocking effects of endogenous opioid peptides), we believe that mechanistic studies of the physiological and ethanol-induced release of peptides in the extended amygdala may facilitate development of novel pharmacotherapies for the treatment of alcoholism.

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 its 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 #
2I01BX001271-05
Application #
9241469
Study Section
Neurobiology A (NURA)
Project Start
2012-10-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Durham VA Medical Center
Department
Type
DUNS #
043241082
City
Durham
State
NC
Country
United States
Zip Code
27705
Kang-Park, Maenghee; Kieffer, Brigitte L; Roberts, Amanda J et al. (2015) Interaction of CRF and kappa opioid systems on GABAergic neurotransmission in the mouse central amygdala. J Pharmacol Exp Ther 355:206-11
Risher, Mary-Louise; Fleming, Rebekah L; Risher, W Christopher et al. (2015) Adolescent intermittent alcohol exposure: persistence of structural and functional hippocampal abnormalities into adulthood. Alcohol Clin Exp Res 39:989-97
Li, Qiang; Madison, Roger; Moore, Scott D (2014) Presynaptic BK channels modulate ethanol-induced enhancement of GABAergic transmission in the rat central amygdala nucleus. J Neurosci 34:13714-24
Klein, Rebecca C; Acheson, Shawn K; Mace, Brian E et al. (2014) Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice. Neurobiol Aging 35:2046-52
Klein, Rebecca C; Saini, Shyla; Risher, M-Louise et al. (2014) Regional-specific effects of ovarian hormone loss on synaptic plasticity in adult human APOE targeted replacement mice. PLoS One 9:e94071
Li, Qiang; Fleming, Rebekah L; Acheson, Shawn K et al. (2013) Long-term modulation of A-type K(+) conductances in hippocampal CA1 interneurons in rats after chronic intermittent ethanol exposure during adolescence or adulthood. Alcohol Clin Exp Res 37:2074-85
Wang, Hong-Gang; He, Xiao Ping; Li, Qiang et al. (2013) The auxiliary subunit KChIP2 is an essential regulator of homeostatic excitability. J Biol Chem 288:13258-68
Fleming, Rebekah L; Li, Qiang; Risher, Mary-Louise et al. (2013) Binge-pattern ethanol exposure during adolescence, but not adulthood, causes persistent changes in GABAA receptor-mediated tonic inhibition in dentate granule cells. Alcohol Clin Exp Res 37:1154-60
Kang-Park, Maenghee; Kieffer, Brigitte L; Roberts, Amanda J et al. (2013) ?-Opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites. J Pharmacol Exp Ther 346:130-7
Fleming, Rebekah L; Acheson, Shawn K; Moore, Scott D et al. (2012) In the rat, chronic intermittent ethanol exposure during adolescence alters the ethanol sensitivity of tonic inhibition in adulthood. Alcohol Clin Exp Res 36:279-85

Showing the most recent 10 out of 13 publications