title: Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction.
abstract: 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.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy; Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California.
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.forename: Sunmee
authors.initials: S
authors.lastname: Wee
authors.forename: Scott
authors.initials: S
authors.lastname: Edwards
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Whitfield
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Oleata
authors.forename: George
authors.initials: G
authors.lastname: Luu
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Schmeichel
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D012646:Self Administration; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D017473:Receptors, Opioid, kappa; D005680:gamma-Aminobutyric Acid; D003042:Cocaine
keywords: Addiction; GABA; anxiety; central amygdala; cocaine; kappa-opioid receptor