l-Stepholidine-induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5-HT(1A) receptor partial agonistic activity.
BACKGROUND
l-Stepholidine (l-SPD), a tetrahydroprotoberberine alkaloid, possesses a pharmacological profile of a D₁/5-HT(1A) agonist and a D₂ 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.


RESULTS
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 D₂-like receptors antagonist raclopride. Collectively, these results indicate that l-SPD excited VTA DA neurons requiring its D₂-like receptors antagonistic activity and 5-HT(1A) receptor agonistic activity.


CONCLUSIONS
The present data demonstrate that D₂ 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.
Gao
Ming
M
State Key Laboratory of Drug Research and Department of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Chu
Hong-Yuan
HY
Jin
Guo-Zhang
GZ
Zhang
Zhang-Jin
ZJ
Wu
Jie
J
Zhen
Xue-Chu
XC
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology*
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D001599:Berberine; C010513:stepholidine; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003913:Dextroamphetamine; D004298:Dopamine