Prepublication Article Abstract

Kappa Opioid Receptor-Mediated Dysregulation of GABAergic Transmission in the Central Amygdala in Cocaine Addiction

Marsida Kallupi, Sunmee Wee, Scott Edwards, Tim W. Whitfield Jr., Christopher S. Oleata, George Luu, Brooke E. Schmeichel, George F. Koob, and Marisa Roberto
Accepted: May 01, 2013


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 1h (short access, ShA) or 6h (long access, LgA) sessions induced plasticity at CeA GABAergic synapses, or altered the sensitivity of these synapses to KOR agonism (U50488) or antagonism (nor-BNI). 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 to cocaine-naïve rats. Acute cocaine (1 uM) application significantly decreased GABA release in all groups (naïve, ShA, and LgA rats). Application of U50488 (1 uM) significantly decreased GABAergic transmission in the CeA from naïve rats, but increased it in LgA rats. Conversely, nor-BNI (200 nM) significantly increased GABAergic transmission in the CeA from naïve rats, but decreased it in LgA rats. Nor-BNI did not alter the acute cocaine-induced inhibition of GABAergic responses. Finally, CeA microinfusion of nor-BNI 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.

© 2013 Society of Biological Psychiatry