Kappa opioid receptors control a stress-sensitive brain circuit and drive cocaine seeking.

Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. Kappa opioid receptors (kORs) play a critical role in mediating stress responses. Our previous studies in the ventral tegmental area (VTA) demonstrated that acute stress activates kORs to block long-term potentiation at GABA_A synapses on dopamine neurons (LTP_GABA) and triggers stress-induced reinstatement of cocaine seeking. Here we identify the specific GABAergic afferents affected by stress, the precise localization of kORs within the VTA, and show that VTA kOR activation is sufficient to drive reinstatement. In male and female mice we optogenetically activated specific GABAergic afferents and found that nucleus accumbens (NAc)-to-VTA, but not lateral hypothalamus (LH)-to-VTA projections, exhibit stress-sensitive LTP_GABA Using a conditional knock-out approach, we found that selectively deleting kORs from NAc neurons but not from dopamine cells prevents stress-induced block of LTP_GABA Selectively activating dynorphin-containing NAc neurons with an excitatory DREADD mimics acute stress, preventing LTP_GABA at VTA synapses. We furthermore demonstrated that without acute stress, microinjection of a selective kOR agonist directly into the VTA of male rats facilitates cocaine reinstatement without similarly affecting sucrose-motivated responding, demonstrating the critical role of kORs in stress-induced cocaine reinstatement. Our results show that kORs on GABAergic NAc nerve terminals in the VTA underlie loss of LTP_GABA that may drive stress-induced addiction-related behaviors. Our work highlights the importance of inhibitory inputs for controlling dopamine neuron excitability in the context of addiction and contributes to defining the circuit involved in stress-induced drug reinstatement.Significance statement Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. The VTA is a key brain area for processing aversive and rewarding stimuli. Inhibitory synapses that control the activity of dopamine neurons in this area display plasticity, strengthening or weakening the inhibitory control of dopamine neuron firing. We previously characterized a form of long-term plasticity at GABA_A synapses on dopamine neurons (LTP_GABA). Acute stress activates kappa opioid receptors (kORs) to block LTP_GABA and also triggers kOR-dependent reinstatement of cocaine-seeking. Here we identified specific GABAergic afferents affected by stress, the location of relevant kORs in VTA, and show that VTA kOR activation by itself is sufficient to drive reinstatement of cocaine seeking.