(Fadel/Wilson): Anxiety and affective disorders represent an important clinical problem, yet our understanding of the disorders and the drugs used to treat them remains limited. Brain imaging studies show amygdala changes in patients with these disorders. The present studies use a multifaceted approach to elucidate how amygdalar opioid systems regulate anxiety and fear-related processes. These studies will enhance our understanding of amygdala circuits that control distinct aspects of anxiety and fear by comparing several anxiety-evoking stimuli, and elucidate the specific role of mu opioid receptors (MOR) in these different responses. Since our previous studies suggested that mu opioid receptors (MOR) and enkephalin in the amygdala can modulate basal anxiety responses and the actions of benzodiazepine anxiolytic drugs, the proposed studies will examine how MOR receptors modulate amygdalar circuitry to alter these anxiety-related responses. We hypothesize that distinct neuronal circuits are activated by different conditioned and unconditioned anxiety-evoking situations, and that presynaptic MOR receptors localized in specific amygdalar neurocircuits regulate changes in amygdala glutamate and GABA release to shift anxiety-related responses in a context-dependent manner. Four anxiety-evoking tests, including the elevated plus maze (unpredictable threat), predator odor-induced defensive burying (specific threat), restraint stress (psychogenic stimulus) and cue- conditioned freezing (learned fear), will be compared in these studies.
Aim 1 uses virus-mediated gene transfer to examine if decreasing the expression of MOR in the amygdala alters anxiety-related behaviors and/or endocrine responses to restraint stress, and if selectively targeting these decreases to pyramidal neurons of the basolateral amygdala produces the same effects.
Aim 2 uses cFos immunoreactivity to compare the cellular phenotype(s) activated by distinct anxiety-evoking situations, the localization of MOR in these activated neuron populations, and if activation patterns are altered by decreasing amygdala MOR expression.
Aim 3 uses in vivo microdialysis in the amygdala to assess 1) if MOR activation alters GABA or glutamate efflux, 2) if anxiety-evoking situations induce release of enkephalin, GABA, or glutamate, and 3) if decreasing MOR expression modifies MOR-induced or anxiety-induced release of GABA or glutamate. The studies will enhance our understanding of how the amygdala and the opioid system regulate anxiety responses, and could provide novel therapeutic strategies for treating affective and anxiety-related disorders. Since opioid systems in the amygdala are modified during chronic pain states and altered by drugs of abuse, the results of these studies will also enhance our understanding of the neural basis of heightened anxiety states seen in chronic pain patients or during withdrawal from opiates, benzodiazepines, and alcohol. Relevance: Anxiety disorders are the most common mental illness and affect more than19 million US adults, yet our understanding of these disorders and the drugs used to treat them remains limited. The present studies use animal models to elucidate how the circuitry in the brain region underlying emotional behaviors, namely the amygdala, controls responses in three different anxiety-evoking situations. The focus on endogenous morphine-like chemicals (opioids) could lead to new treatment strategies for anxiety disorders, and increase our understanding of why chronic pain states or withdrawal from prescribed or abused opioid drugs lead to increased anxiety.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Winsky, Lois M
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University of South Carolina at Columbia
Schools of Medicine
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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
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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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