Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress

Stressful experiences potently activate kappa opioid receptors (kORs). kORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of kORs. This is mediated by activation of the receptor during the stressor followed by a persistent, ligand-independent constitutive activation of the kOR itself. This lasting change in function is not seen at kORs at neighboring excitatory synapses, suggesting distinct time courses and mechanisms of regulation of different subsets of kORs. We also provide evidence that constitutive activity of kORs governs the prolonged reinstatement to cocaine-seeking observed after cold water swim stress. Together, our studies indicate that stress-induced constitutive activation is a novel mechanism of kOR regulation that plays a critical role in reinstatement of drug seeking.