The antipsychotic potential of l-stepholidine—a naturally occurring dopamine receptor D1 agonist and D2 antagonist
- 407 Downloads
l-Stepholidine, a dopamine D2 antagonist with D1 agonist activity, should in theory control psychosis and treat cognitive symptoms by enhancing cortical dopamine transmission. Though several articles describe its impact on the dopamine system, it has not been systematically evaluated and compared to available antipsychotics.
Materials and methods
We examined its in vitro interaction with dopamine D2 and D1 receptors and compared its in vivo pharmacokinetic profile to haloperidol (typical) and clozapine (atypical) in animal models predictive of antipsychotic activity.
In vitro, l-stepholidine showed significant activity on dopamine receptors, and in vivo, l-stepholidine demonstrated a dose-dependent striatal receptor occupancy (RO) at D1 and D2 receptors (D1 9–77%, 0.3–30 mg/kg; D2 44–94%, 1–30 mg/kg), though it showed a rather rapid decline of D2 occupancy related to its quick elimination. In tests of antipsychotic efficacy, it was effective in reducing amphetamine- and phencyclidine-induced locomotion as well as conditioned avoidance response, whereas catalepsy and prolactin elevation, the main side effects, appeared only at high D2RO (>80%). This preferential therapeutic profile was supported by a preferential immediate early gene (Fos) induction in the nucleus accumbens over dorsolateral striatum. We confirmed its D1 agonism in vitro, and then using D2 receptor, knockout mice showed that l-stepholidine shows D1 agonism in the therapeutic dose range.
Thus, l-stepholidine shows efficacy like an “atypical” antipsychotic in traditional animal models predictive of antipsychotic activity and shows in vitro and in vivo D1 agonism, and, if its rapid elimination does not limit its actions, it could provide a unique therapeutic approach to schizophrenia.
Keywordsl-Stepholidine Antipsychotic D1 and D2 receptor occupancy Schizophrenia Animal models
This study was funded by a Stanley Medical Research Institute grant (#04R-826) to Shitij Kapur. Susan R. George was supported by a grant from the National Institute on Drug Abuse. The authors would like to thank Jun Parkes of the PET group, Roger Raymond of the Neuroimaging Section of CAMH, and George Varghese from the Department of Pharmacology, University of Toronto for their technical assistance.
- Chen LJ, Guo X, Wang QM, Jin GZ (1992) Feed-back regulation of presynaptic D2 receptors blockaded by l-stepholidine and l-tetrahydropalmatine. Acta Pharmacol Sin 13:442–445Google Scholar
- Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, Chen C, Chen X, Choo E, Cianfrogna J, Cox LM, Gibbs JP, Gibbs MA, Hatch H, Hop CE, Kasman IN, Laperle J, Liu J, Liu X, Logman M, Maclin D, Nedza FM, Nelson F, Olson E, Rahematpura S, Raunig D, Rogers S, Schmidt K, Spracklin DK, Szewc M, Troutman M, Tseng E, Tu M, Van Deusen JW, Venkatakrishnan K, Walens G, Wang EQ, Wong D, Yasgar AS, Zhang C (2005) The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 33:165–174PubMedCrossRefGoogle Scholar
- Finney DJ (1971) Probit analysis. Cambridge University Press, LondonGoogle Scholar
- Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic, San DiegoGoogle Scholar
- Huang KX, Sun BC, Gonon FG, Jin GZ (1991) Effects of tetrahydroprotoberberines on dopamine release and 3,4-dihydroxyphenylacetic acid level in corpus striatum measured by in vivo voltammetry. Acta Pharmacol Sin 12:32–36Google Scholar
- McNamara FN, Clifford JJ, Tighe O, Kinsella A, Drago J, Fuchs S, Croke DT, Waddington JL (2002) Phenotypic, ethologically based resolution of spontaneous and D2-like vs D1-like agonist-induced behavioural topography in mice with congenic D(3) dopamine receptor “knockout”. Synapse 46:19–31PubMedCrossRefGoogle Scholar
- O’Sullivan GJ, Kinsella A, Sibley DR, Tighe O, Croke DT, Waddington JL (2005) Ethological resolution of behavioural topography and D1-like versus D2-like agonist responses in congenic D5 dopamine receptor mutants: identification of D5:D2-like interactions. Synapse 55:201–211PubMedCrossRefGoogle Scholar
- O’Sullivan GJ, Kinsella A, Grandy DK, Tighe O, Croke DT, Waddington JL (2006) Ethological resolution of behavioral topography and D2-like vs. D1-like agonist responses in congenic D4 dopamine receptor “knockouts”: identification of D4:D1-like interactions. Synapse 59:107–118PubMedCrossRefGoogle Scholar
- Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
- Zhang ZD, Zhou CM, Jin GZ, Zhang X, Yang L (1990) Pharmacokinetics and autoradiography of [3H] or [14C]stepholidine. Acta Pharmacol Sin 11:289–292Google Scholar
- Zhang X, Sun BC, Jin GZ (1997) Atypical neuroleptic properties of l-stepholidine. Science in China (Series C) 40:532–538Google Scholar
- Zou LL, Chen Y, Song YY, Jin GZ (1996) Effect of (−)-stepholidine on serum prolactin level of female rats. Acta Pharmacol Sin 17:311–314Google Scholar