Abstract
Human and animal studies indicate that kappa opioid receptor (KOR) systems are involved in ethanol drinking and dependence (Xuei et al., 2006; Walker and Koob, 2008; Walker et al., 2011). The central amygdala (CeA) is a critical brain region mediating anxiety-related behavior and drug reward and is a likely site for the interaction of the KOR system and ethanol, although few studies have explored this interaction. Using in vitro single-cell recording techniques in mouse brain slices, we examined the physiological effects of KOR activation in 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) in the CeA, 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 in the CeA was further augmented by pharmacological blockade of KORs, from 14 % (n = 36) to 27% (n = 26; p < 0.01), or by genetic deletion of KORs, from 14 % in WT mice (n = 19) to 34 % in KOR knockout (KO) mice (n = 13, p < 0.01), suggesting that the KOR system regulates acute ethanol actions in the CeA. Subsequent experiments using tetrodotoxin to block activity-dependent neurotransmission suggest that KORs regulate GABA release at presynaptic sites. Thus, KOR activation modulates GABAergic neurotransmission and ethanol effects in CeA in a manner similar to other subtypes of opioid receptors, i.e., mu and delta opioid receptors (Kang-Park et al., 2007; Kang-Park et al., 2009). 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.
- The American Society for Pharmacology and Experimental Therapeutics