The antipsychotic potential of l-stepholidine--a naturally occurring dopamine receptor D1 agonist and D2 antagonist.
BACKGROUND
l-Stepholidine, a dopamine D(2) antagonist with D(1) 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.


METHODS
We examined its in vitro interaction with dopamine D(2) and D(1) 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 D(1) and D(2) receptors (D(1) 9-77%, 0.3-30 mg/kg; D(2) 44-94%, 1-30 mg/kg), though it showed a rather rapid decline of D(2) 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 D(2)RO (>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 D(1) agonism in vitro, and then using D(2) receptor, knockout mice showed that l-stepholidine shows D(1) 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 D(1) agonism, and, if its rapid elimination does not limit its actions, it could provide a unique therapeutic approach to schizophrenia.
Natesan
Sridhar
S
Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London, UK.
Reckless
Greg E
GE
Barlow
Karen B L
KB
Odontiadis
John
J
Nobrega
José N
JN
Baker
Glen B
GB
George
Susan R
SR
Mamo
David
D
Kapur
Shitij
S
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001599:Berberine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016762:Genes, fos / Q000187:drug effects; D006213:Hallucinogens / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D011388:Prolactin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D065127:Dopamine D2 Receptor Antagonists; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D001599:Berberine; C010513:stepholidine; D011388:Prolactin; D000661:Amphetamine; D010622:Phencyclidine