, Volume 199, Issue 2, pp 275-289
Date: 03 Jun 2008

The antipsychotic potential of l-stepholidine—a naturally occurring dopamine receptor D1 agonist and D2 antagonist

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Abstract

Rationale

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.

Results

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.

Conclusions

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.