Our results reveal an important role for the dynorphin/KOR system to regulate synaptic transmission and alcohol effects in the CeA, a brain nucleus implicated in the etiology of drug and alcohol dependence. Activation of KOR with its natural ligand dynorphin or with the synthetic selective agonist U69 decreased inhibitory transmission and diminished the effect of ethanol by acting on GABA release. Blockade of KOR unmasked a tonic activity at KOR by dynorphin and also prevented the ethanol effect at a presynaptic site. Because dynorphin may affect other opioid receptors such as MOR and the synthetic agonist U69 is highly selective for KORs (Raynor et al., 1994), we used the selective U69 to verify the involvement of KOR and eliminate the participation of endogenous degradation mechanisms. Conversely, we used dynorphin throughout this study to ensure that the endogenous form of the KOR ligand reproduced effects obtained with the synthetic ligand.
