Amisulpride the 'atypical' atypical antipsychotic--comparison to haloperidol, risperidone and clozapine.
BACKGROUND
Amisulpride's high and selective affinity for dopamine D2/3 (Ki 1.3/2.4 nM) receptors, lack of affinity for serotonin receptors, and its unusually high therapeutic doses (400-800 mg/day) makes it unique among atypical antipsychotics and prompted us to compare its actions with other antipsychotics in animal models.


METHODS
Amisulpride's effects on amphetamine and phencyclidine induced locomotor activity (AIL/PIL), conditioned avoidance response, catalepsy (CAT), subcortical Fos expression, and plasma prolactin was correlated to its time-course striatal D2/3 and prefrontal 5-HT2 receptor occupancy (D(2/3)/5-HT2RO); in comparison to haloperidol, clozapine, and risperidone.


RESULTS
Unlike the atypicals clozapine and risperidone, amisulpride lacked 5-HT2RO and showed a 'delayed' pattern of D2/3RO: 43, 60 and 88% after 1, 2 and 6 h (100 mg/kg), respectively, despite a quick onset (1 h) and decline (6 h) of prolactin elevation. While haloperidol and risperidone were effective at D2RO>60%, clozapine at D2/3RO<50%, amisulpride was effective only when its D2RO exceeded 60% with a delayed latency and lasted longer than other antipsychotics. CAT was observed for haloperidol and risperidone when D2RO exceeded 80%, while in the case of amisulpride, CAT was not observed even when doses exceeded 90% D2/3RO. Amisulpride also displayed functional limbic selectivity in Fos expression like the other atypicals.


CONCLUSIONS
Amisulpride's "delayed" functional profile on acute administration and the need for high doses is most likely due to its poor blood-brain-barrier penetration; however, it is distinct from other atypicals in showing low motor side-effects, activity against phencyclidine, and a mesolimbic preference, despite no action on serotonin receptors.
Natesan
Sridhar
S
Schizophrenia Program and the PET Centre, Centre for Addiction and Mental Health (CAMH), Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Reckless
Greg E
GE
Barlow
Karren B L
KB
Nobrega
José N
JN
Kapur
Shitij
S
D000077582:Amisulpride; D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000097:blood / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D018967:Risperidone / Q000378:metabolism / Q000494:pharmacology; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D013469:Sulpiride; D000077582:Amisulpride; D011388:Prolactin; D000661:Amphetamine; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone