title: Dissociation between in vivo occupancy and functional antagonism of dopamine D2 receptors: comparing aripiprazole to other antipsychotics in animal models.
abstract: The novel antipsychotic aripiprazole requires high (>90%) striatal D2 receptor occupancy (D2RO) to be clinically active, but despite its high D2RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D2RO, they show motor side effects when D2RO exceeds 80%. We investigated this discrepancy between D2RO, 5HT2 receptor occupancy (5-HT2RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D2RO. While risperidone clearly showed higher 5-HT2RO than D2RO, aripiprazole and haloperidol showed higher D2RO than 5-HT2RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing >80% D2RO, while aripiprazole despite higher D2RO (>90%) induced no catalepsy. Haloperidol and risperidone's ED50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to approximately 60% D2RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D2RO, a 23-fold higher dose (86% D2RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D2ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D2RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D2 agonist antipsychotics.
authors.affiliation: Schizophrenia Program and the PET Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Natesan
authors.forename: Greg E
authors.initials: GE
authors.lastname: Reckless
authors.forename: José N
authors.initials: JN
authors.lastname: Nobrega
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fletcher
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001362:Avoidance Learning / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016761:Oncogene Proteins v-fos / Q000096:biosynthesis; D010879:Piperazines / Q000494:pharmacology*; D011388:Prolactin / Q000097:blood; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018967:Risperidone / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D016761:Oncogene Proteins v-fos; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole; D011388:Prolactin; D006220:Haloperidol; D018967:Risperidone