4.7 Article

Kappa Opioid Receptor-Mediated Dysregulation of Gamma-Aminobutyric Acidergic Transmission in the Central Amygdala in Cocaine Addiction

Journal

BIOLOGICAL PSYCHIATRY
Volume 74, Issue 7, Pages 520-528

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2013.04.028

Keywords

Addiction; anxiety; central amygdala; cocaine; GABA; kappa-opioid receptor

Funding

  1. National Institute on Alcohol Abuse and Alcoholism
  2. National Institute on Drug Abuse [DA025785, AA020839, DA033726, DA004398, AA016895]
  3. Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute

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Background: Studies have demonstrated an enhanced dynorphin/kappa-opioid receptor (KOR) system following repeated cocaine exposure, but few reports have focused on neuroadaptations within the central amygdala (CeA). Methods: We identified KOR-related physiological changes in the CeA following escalation of cocaine self-administration in rats. We used in vitro slice electrophysiological (intracellular and whole-cell recordings) methods to assess whether differential cocaine access in either 1-hour (short access [ShA]) or 6-hour (long access [LgA]) sessions induced plasticity at CeA gamma-aminobutyric acid (GABA)ergic synapses or altered the sensitivity of these synapses to KOR agonism (U50488) or antagonism (norbinaltorphimine [norBNI]). We then determined the functional effects of CeA KOR blockade in cocaine-related behaviors. Results: Baseline evoked GABAergic transmission was enhanced in the CeA from ShA and LgA rats compared with cocaine-naive rats. Acute cocaine (1 mu mol/L) application significantly decreased GABA release in all groups (naive, ShA, and LgA rats). Application of U50488 (1 mu mol/L) significantly decreased GABAergic transmission in the CeA from naive rats but increased it in LgA rats. Conversely, norBNI (200 nmol/L) significantly increased GABAergic transmission in the CeA from naive rats but decreased it in LgA rats. Norbinaltorphimine did not alter the acute cocaine-induced inhibition of GABAergic responses. Finally, CeA microinfusion of norBNI blocked cocaine-induced locomotor sensitization and attenuated the heightened anxiety-like behavior observed during withdrawal from chronic cocaine exposure in the defensive burying paradigm. Conclusions: Together these data demonstrate that CeA dynorphin/KOR systems are dysregulated following excessive cocaine exposure and suggest KOR antagonism as a viable therapeutic strategy for cocaine addiction.

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