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l ‐Stepholidine‐induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5‐HT 1A receptor partial agonistic activity
Author(s) -
Gao Ming,
Chu HongYuan,
Jin GuoZhang,
Zhang ZhangJin,
Wu Jie,
Zhen XueChu
Publication year - 2011
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20855
Subject(s) - ventral tegmental area , chemistry , agonist , raclopride , pharmacology , dopamine , partial agonist , receptor antagonist , excitatory postsynaptic potential , receptor , neuroscience , dopamine receptor d2 , antagonist , biology , dopaminergic , biochemistry
Rationale: l ‐Stepholidine ( l‐ SPD), a tetrahydroprotoberberine alkaloid, possesses a pharmacological profile of a D 1 /5‐HT 1A agonist and a D 2 antagonist. This unique pharmacological profile makes it a promising novel antipsychotic candidate. Preliminary clinical trials and animal experiments suggest that l ‐SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. To further explore the antipsychotic mechanisms of the drug, we studied the effects of l ‐SPD on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) using in vivo single‐unit recording technique in rats. Result: We found that l ‐SPD increased VTA DA neurons firing rate and induced slow oscillation in firing pattern. Moreover, l ‐SPD, not clozapine, reversed d‐amphetamine‐induced inhibition which induced an excitation of VTA DA neurons. Furthermore, our data indicated that the excitatory effect of l ‐SPD is associated with its partial agonistic action for the 5‐HT 1A receptor since the 5‐HT 1A receptor antagonist WAY100635 could block the l ‐SPD‐induced excitatory effect. However, activation of 5‐HT 1A receptor alone by specific agonist (±)‐8‐Hydroxy‐2‐(dipropylamino) tetralin (8‐OH‐DPAT) was insufficient to elicit excitation of VTA DA neurons, but the excitation of 8‐OH‐DPAT on VTA DA neurons was elicited in the presence of D 2 ‐like receptors antagonist raclopride. Collectively, these results indicate that l ‐SPD excited VTA DA neurons requiring its D 2 ‐like receptors antagonistic activity and 5‐HT 1A receptor agonistic activity. Conclusion : The present data demonstrate that D 2 receptor antagonist/5‐HT 1A receptor agonistic dual properties modulate dopaminergic transmission in a unique pattern that may underlie the different therapeutic responses between l ‐SPD and other atypical antipsychotic drugs. Synapse, 2010. © 2010 Wiley‐Liss, Inc.