title: DAMGO depresses inhibitory synaptic transmission via different downstream pathways of μ opioid receptors in ventral tegmental area and periaqueductal gray.
abstract: Opioid-induced rewarding and motorstimulant effects are mediated by an increased activity of the ventral tegmental area (VTA) dopamine (DA) neurons. The excitatory mechanism of opioids on VTA-DA neurons has been proposed to be due to the depression of GABAergic synaptic transmission in VTA-DA neurons. However, how opioids depress GABAergic synaptic transmission in VTA-DA neurons remain to be studied. In the present study, we explored the mechanism of the inhibitory effect of [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on GABAergic synaptic transmission in VTA-DA neurons using multiple approaches and techniques. Our results showed that (1) DAMGO inhibits GABAergic inputs in VTA-DA neurons at presynaptic sites; (2) effect of DAMGO on GABAergic inputs in VTA-DA neurons is inhibited by potassium channel blocker 4-aminopyridine (4-AP) and Gi protein inhibitor N-ethylmaleimide (NEM); (3) phospholipase A2 (PLA2) does not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons, but mediates it in the periaqueductal gray (PAG); (4) multiple downstream signaling molecules of μ receptors do not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons. These results suggest that DAMGO depresses inhibitory synaptic transmission via μ receptor-Gi protein-Kv channel pathway in VTA-DA neurons, but via μ receptor-PLA2 pathway in PAG neurons.
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: H L
authors.initials: HL
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: J J
authors.initials: JJ
authors.lastname: Song
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: B
authors.initials: B
authors.lastname: Lai
authors.affiliation: School of Life Sciences, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Y G
authors.initials: YG
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan University, Shanghai 200032, China. Electronic address: pzheng@shmu.edu.cn.
authors.forename: P
authors.initials: P
authors.lastname: Zheng
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology*; D054467:Phospholipases A2 / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology*
chemical_list: D015221:Potassium Channels; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D054467:Phospholipases A2
keywords: DAMGO; GABA release; PAG; PLA(2); VTA; μ receptors