Kappa Opioid Receptors Regulate Stress-Induced Cocaine Seeking and Synaptic Plasticity

Stress facilitates reinstatement of addictive drug seeking in animals and promotes relapse in humans. Acute stress has marked and long-lasting effects on plasticity at both inhibitory and excitatory synapses on dopamine neurons in the ventral tegmental area (VTA), a key region necessary for drug reinforcement. Stress blocks long-term potentiation at GABAergic synapses on dopamine neurons in the VTA (LTPGABA), potentially removing a normal brake on activity. Here we show that blocking kappa opioid receptors (KORs) prior to forced-swim stress rescues LTPGABA. In contrast, blocking KORs does not prevent stress-induced potentiation of excitatory synapses nor morphine-induced block of LTPGABA. Using a kappa receptor antagonist as a selective tool to test the role of LTPGABA in vivo, we find that blocking KORs within the VTA prior to forced-swim stress prevents reinstatement of cocaine seeking. These results suggest that KORs may represent a useful therapeutic target for treatment of stress-triggered relapse in substance abuse. ► Blocking kappa opioid receptors (KORs) rescues stress-induced block of LTPGABA ► KORs are not required for stress-induced potentiation of glutamatergic synapses ► Blocking KORs in the VTA prevents stress-induced reinstatement of cocaine-seeking Stress facilitates reinstatement of addictive drug-seeking in rats and promotes relapse in humans. Acute stress also prevents potentiation of ventral tegmental area GABAergic synapses. Graziane et al. report that blocking kappa opioid receptors rescues LTP and reduces cocaine-seeking in acutely stressed animals.