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-naïve rats. Acute cocaine (1 µmol/L) application significantly decreased GABA release in all groups (naïve, ShA, and LgA rats). Application of U50488 (1 µmol/L) significantly decreased GABAergic transmission in the CeA from naïve rats but increased it in LgA rats. Conversely, norBNI (200 nmol/L) significantly increased GABAergic transmission in the CeA from naïve 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.
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-naïve rats. Acute cocaine (1 µmol/L) application significantly decreased GABA release in all groups (naïve, ShA, and LgA rats). Application of U50488 (1 µmol/L) significantly decreased GABAergic transmission in the CeA from naïve rats but increased it in LgA rats. Conversely, norBNI (200 nmol/L) significantly increased GABAergic transmission in the CeA from naïve 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.
Authors: W A Carlezon; J Thome; V G Olson; S B Lane-Ladd; E S Brodkin; N Hiroi; R S Duman; R L Neve; E J Nestler Journal: Science Date: 1998-12-18 Impact factor: 47.728
Authors: Marisa Roberto; Maureen T Cruz; Nicholas W Gilpin; Valentina Sabino; Paul Schweitzer; Michal Bajo; Pietro Cottone; Samuel G Madamba; David G Stouffer; Eric P Zorrilla; George F Koob; George R Siggins; Loren H Parsons Journal: Biol Psychiatry Date: 2010-01-08 Impact factor: 13.382
Authors: Marisa Roberto; Samuel G Madamba; Scott D Moore; Melanie K Tallent; George R Siggins Journal: Proc Natl Acad Sci U S A Date: 2003-02-03 Impact factor: 11.205
Authors: Marsida Kallupi; Lieselot L G Carrette; Jenni Kononoff; Leah C Solberg Woods; Abraham A Palmer; Paul Schweitzer; Olivier George; Giordano de Guglielmo Journal: Proc Natl Acad Sci U S A Date: 2020-01-13 Impact factor: 11.205