The amygdala is a brain structure that plays a crucial role in fear and anxiety, and the actions of anxiety-reducing compounds. The opioid peptide has also been shown to modulate anxiety-related responses within the amygdala. Using herpes virus-mediated gene transfer, we have demonstrated that overexpression of enkephalin in the amygdala enhances the anxiety-reducing influences of the benzodiazepine diazepam (Valium) in rats. These initial results demonstrate that herpes virus-mediated gene transfer can transiently alter expression of neuropeptides in confined brain sites of adult rats, and that these changes can modify behavioral responses. The present studies continue to utilize this powerful technique to examine the role of amygdalar enkephalin in regulating anxiety-related behaviors and the actions of anxiolytic drugs. Both decreases and cell-targeted increases in peptide expression will be examined in several animal models of anxiety.
Aim 1 will verify the ability of virus-mediated gene transfer to decrease and cell-specifically increase expression of enkephalin in select areas of amygdala. Anatomical and quantitative methods will assess changes in mRNA expression, while peptide changes will be assessed with immunohistochemistry and radioimmunoassay.
AIM 2 examines if altered enkephalin expression in central amygdala modifies anxiety-related behaviors in additional animal tests of anxiety behaviors and/or the effectiveness of other anxiolytics in these tests. These studies 1) compare decreases with cell-specific increases in enkephalin expression, 2) test the activity of other anxiolytics (alcohol, the serotonergic compound buspirone), and 3) tests effects in several models of anxiety.
AIM 3 assesses the effects of pharmacological modulation of enkephalin activity in amygdala. Using more traditional techniques selective opioid receptor (mu, delta) agonists and antagonists will be locally applied in amygdala, and the effect of these compounds on responses to anxiolytic drugs will be tested. These studies will lead to a better understanding of the role of amygdala and enkephalin in anxiety and anxiolytic responses, as well as elucidate the differences between animal models of anxiety. This understanding may also suggest novel, avenues for development of treatments for anxiety or affective disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063344-02
Application #
6660761
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Winsky, Lois M
Project Start
2002-09-15
Project End
2007-08-31
Budget Start
2003-09-15
Budget End
2004-09-14
Support Year
2
Fiscal Year
2003
Total Cost
$291,000
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
Butler, Ryan K; Oliver, Elisabeth M; Fadel, Jim R et al. (2018) Hemispheric differences in the number of parvalbumin-positive neurons in subdivisions of the rat basolateral amygdala complex. Brain Res 1678:214-219
Wilson, Marlene A; Fadel, Jim R (2017) Cholinergic regulation of fear learning and extinction. J Neurosci Res 95:836-852
Sharko, Amanda C; Kaigler, Kris F; Fadel, Jim R et al. (2016) Ethanol-induced anxiolysis and neuronal activation in the amygdala and bed nucleus of the stria terminalis. Alcohol 50:19-25
Butler, Ryan K; Oliver, Elisabeth M; Sharko, Amanda C et al. (2016) Activation of corticotropin releasing factor-containing neurons in the rat central amygdala and bed nucleus of the stria terminalis following exposure to two different anxiogenic stressors. Behav Brain Res 304:92-101
Grillo, Claudia A; Mulder, Petra; Macht, Victoria A et al. (2014) Dietary restriction reverses obesity-induced anhedonia. Physiol Behav 128:126-32
Sharko, Amanda C; Kaigler, Kris F; Fadel, Jim R et al. (2013) Individual differences in voluntary ethanol consumption lead to differential activation of the central amygdala in rats: relationship to the anxiolytic and stimulant effects of low dose ethanol. Alcohol Clin Exp Res 37 Suppl 1:E172-80
Butler, Ryan K; White, L Casey; Frederick-Duus, Dani et al. (2012) Comparison of the activation of somatostatin- and neuropeptide Y-containing neuronal populations of the rat amygdala following two different anxiogenic stressors. Exp Neurol 238:52-63
Grillo, Claudia A; Piroli, Gerardo G; Kaigler, Kris F et al. (2011) Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats. Behav Brain Res 222:230-5
Butler, R K; Sharko, A C; Oliver, E M et al. (2011) Activation of phenotypically-distinct neuronal subpopulations of the rat amygdala following exposure to predator odor. Neuroscience 175:133-44
Grillo, Claudia A; Piroli, Gerardo G; Junor, Lorain et al. (2011) Obesity/hyperleptinemic phenotype impairs structural and functional plasticity in the rat hippocampus. Physiol Behav 105:138-44

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