title: κ-Opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites.
abstract: Human and animal studies indicate that κ-opioid receptors (KORs) are involved in ethanol drinking and dependence (Xuei et al., 2006; Walker and Koob, 2008; Walker et al., 2011). Using in vitro single-cell recording techniques in mouse brain slices, we examined the physiologic effects of KOR activation in the central amygdala (CeA) on GABAergic neurotransmission and its interaction with acute ethanol. A selective KOR agonist (U69593, 1 μM) diminished evoked GABAergic inhibitory postsynaptic currents (IPSCs) by 18% (n = 10), whereas blockade of KORs with a selective antagonist (nor-binaltorphimine, 1 μM) augmented the baseline evoked GABAergic IPSCs by 14% (P < 0.01; n = 34), suggesting that the KOR system contributes to tonic inhibition of GABAergic neurotransmission in the CeA. In addition, the enhancement by acute ethanol of GABAergic IPSC amplitudes was further augmented by pharmacologic blockade of KORs, from 14% (n = 36) to 27% (n = 26; P < 0.01), or by genetic deletion of KORs, from 14% in wild-type mice (n = 19) to 34% in KOR knockout mice (n = 13; P < 0.01). Subsequent experiments using tetrodotoxin to block activity-dependent neurotransmission suggest that KORs regulate GABA release at presynaptic sites. Our data support the idea that KORs modulate GABAergic synaptic responses and ethanol effects as one of multiple opioid system-dependent actions of ethanol in the CeA, possibly in a circuit-specific manner.
authors.affiliation: Department of Psychiatry, Duke University Medical Center, and Research Service, Veterans Administration Medical Center, Durham, North Carolina 27705, USA.
authors.forename: Maenghee
authors.initials: M
authors.lastname: Kang-Park
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Roberts
authors.forename: George R
authors.initials: GR
authors.lastname: Siggins
authors.forename: Scott D
authors.initials: SD
authors.lastname: Moore
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059010:Single-Cell Analysis; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000700:Analgesics; D014151:Anti-Anxiety Agents; D002492:Central Nervous System Depressants; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; D017473:Receptors, Opioid, kappa; D026941:Sodium Channel Blockers; C116587:kappa(1) opioid receptor; D000431:Ethanol