1. ¹Department of Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
2. ²Department of Pharmacology, College of Pharmacy, Fudan University, Shanghai, China
3. ³Department of Anatomy, Xuzhou Medical College, Xuzhou, China
4. ⁴Neuropsychopharmacological Research Unit, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

Correspondence: Professor W-X Shi, Department of Psychiatry, Neuropsychopharmacological Research Unit, Yale University School of Medicine, 300 George Street, Room 8300C, New Haven, CT 06511, USA. Tel: +1 203 785 4507; Fax: +1 203 785 4510; E-mail: wei-xing.shi@yale.edu

Received 1 June 2004; Revised 5 October 2004; Accepted 21 October 2004; Published online 1 December 2004.

Abstract

l-Stepholidine (SPD) is a tetrahydroprotoberberine alkaloid and a mixed dopamine D1 agonist/D2 antagonist. Preliminary clinical trials suggest that SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. Here, we report that SPD mimics the effect of the atypical antipsychotic drug clozapine, preferentially increasing Fos expression in corticolimbic areas. Thus, at 10 mg/kg (i.p.), SPD induced Fos expression in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral septal nucleus (LSN) without significantly affecting the dorsolateral striatum (DLSt). At higher doses (20–40 mg/kg), SPD also increased Fos expression in the DLSt. The increase, however, was less pronounced than the increase seen in the NAc. Within the NAc, SPD also induced more Fos expression in the shell than in the core. In all subcortical areas examined, the Fos expression induced by SPD was mimicked by the D2 antagonist sulpiride and reversed by the D2 agonist quinpirole, suggesting that the effect is due to blockade of D2-like receptors by SPD. In the mPFC, however, the effect was not mimicked by sulpride or reversed by quinpirole. It was also not mimicked by the D1 agonist SKF38393 or SKF38393 plus sulpride, and not reversed by the D1 antagonist SCH23390. These results suggest that, in the mPFC, SPD may induce Fos expression through a non-DA mechanism. Whether the mechanism involves an interaction of SPD with other neurotransmitters such as 5-HT and norepinephrine remains to be determined.