Opioid-Induced GABA potentiation after chronic morphine attenuates the rewarding effects of opioids in the ventral tegmental area.
GABA transmission in the ventral tegmental area (VTA) is critical for fine tuning the activity of dopamine neurons in response to opioids. However, the precise mechanism by which GABA input shapes opioid reward is poorly understood. We observed a reduction of conditioned place preference for low doses of the opioid [d-Ala2, N-MePhe4, Gly5-ol]-enkephalin (DAMGO) and a switch in the functional effects of μ-opioid receptor modulation of GABA postsynaptic currents in the mouse VTA 1 d after chronic morphine treatment. Specifically, whereas in naive mice DAMGO inhibits GABA postsynaptic currents, GABAergic currents are potentiated by DAMGO after chronic morphine treatment. Importantly, pretreatment with the cAMP signaling inhibitor (R)-adenosine, cyclic 3',5'-(hydrogenphosphorothioate) triethylammonium both restored DAMGO reward and reversed the DAMGO-mediated potentiation, thereby reestablishing the inhibitory effects of opioids on GABA currents. Thus, a paradoxical bidirectionality in μ-receptor-mediated control of GABA transmission following chronic morphine treatment is a critical mechanism that determines the expression of opioid reward in the VTA.
Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
Anuradha
A
Madhavan
Antonello
A
Bonci
Jennifer L
JL
Whistler
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007267:Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012201:Reward; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D013873:Thionucleotides; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C016957:adenosine-3',5'-cyclic phosphorothioate; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D000242:Cyclic AMP