l-Stepholidine-induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5-HT(1A) receptor partial agonistic activity

Synapse. 2011 May;65(5):379-87. doi: 10.1002/syn.20855. Epub 2010 Sep 24.


Rationale: 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.

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 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Action Potentials / drug effects
  • Animals
  • Berberine / analogs & derivatives*
  • Berberine / pharmacology
  • Dextroamphetamine / pharmacology
  • Dopamine / metabolism*
  • Dopamine Agonists / pharmacology*
  • Dopamine Uptake Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Male
  • Neural Inhibition / drug effects
  • Neurons / drug effects*
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Ventral Tegmental Area / cytology*


  • Dopamine Agonists
  • Dopamine Uptake Inhibitors
  • Piperazines
  • Pyridines
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Berberine
  • stepholidine
  • Receptor, Serotonin, 5-HT1A
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Dextroamphetamine
  • Dopamine