Comorbid anxiety may predispose addicts to relapse secondary to the biological effects of stress and anxiety on the brain. Furthermore 'hyperexcitability'of the amygdala, as repeatedly seen during stress or fear and substance withdrawal, may contribute to anxiety responses and drug craving. Such increased excitability within the basolateral amygdala (BLA) may be due in part to decreased GABAA activation following stress or substance use. These studies will examine the molecular mechanisms of activity- dependent regulation of GABAA receptors by focusing on fear conditioning and benzodiazepine (BZD) dependence. Both of these manipulations lead to downregulation of GABAA receptors in the BLA. We will compare the molecular mechanisms of GABAA regulation following the stress of fear conditioning with acute, chronic, and withdrawal phases of BZD administration. We hypothesize that: 1) activity-dependent modulation of GABAA within the basolateral amygdala is a common mechanism of both substance dependence and stress response;and 2) GABAergic manipulations that affect BZD response will also affect acquisition and expression of conditioned fear. In this proposal, we will compare the molecular, behavioral, and electrophysiological mechanisms of GABAA regulation following conditioned fear stress with acute, chronic, and withdrawal phases of benzodiazepine administration. We propose that these pharmacological and behavioral events share similar mechanisms involving activity-dependent downregulation of the GABAA complex. A variety of molecular genetic approaches in mice will be used to test this hypothesis including: 1) examination of GABAA complex genes and proteins with in situ hybridization and immunoblotting;2) manipulation of GABAA receptor expression via amygdala-specific deletion of the GABAA alpha1 gene using the Cre/lox system;3) manipulation of post-synaptic GABAA alpha2 gene using Lentiviral-mediated gene silencing;4) manipulation of receptor clustering through silencing of the Gephyrin gene. These studies have direct implications for mechanisms of benzodiazepine dependence, withdrawal, and relapse. Given the role of amygdala GABAergic systems in modulating dopaminergic tone within the nucleus accumbens, amygdala GABAA regulation may have a more general role in addictive disorders. In fact, recent studies have suggested that morphine, alcohol, cocaine and nicotine may also alter GABAA functioning in amygdala, and acutely enhancing GABA levels blocks reinstatement by drug-associated cues or self-administration. This proposal represents a novel approach to understanding shared molecular and cellular mechanisms that may mediate comorbid anxiety and substance abuse disorders. Understanding the mechanisms shared by stress and drug response is critical for understanding pathophysiology and proposing new treatments for these highly comorbid disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019624-04
Application #
7675245
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pilotte, Nancy S
Project Start
2006-09-01
Project End
2011-08-30
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$361,839
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Gafford, Georgette M; Ressler, Kerry J (2015) GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis. Horm Behav 76:136-42
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Maguschak, Kimberly A; Ressler, Kerry J (2012) A role for WNT/?-catenin signaling in the neural mechanisms of behavior. J Neuroimmune Pharmacol 7:763-73
Gafford, Georgette M; Guo, Ji-Dong; Flandreau, Elizabeth I et al. (2012) Cell-type specific deletion of GABA(A)?1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction. Proc Natl Acad Sci U S A 109:16330-5
Andero, R; Ressler, K J (2012) Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav 11:503-12

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