1. ¹Schizophrenia Program and the PET Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada
2. ²Neuroimaging Research Section, Centre for Addiction and Mental Health, Toronto, ON, Canada
3. ³Biopsychology Section, Centre for Addiction and Mental Health, Toronto, ON, Canada
4. ⁴Department of Pharmacology, University of Toronto, Toronto, ON, Canada
5. ⁵Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Correspondence: Dr S Kapur, Centre for Addiction and Mental Health, ARF Site, 33 Russell Street, Toronto, ON, Canada M5S2S1, Tel: +1 416 979 6890; Fax: +1 416 260 4206; E-mail: shitij_kapur@camh.net

Received 12 July 2005; Revised 6 October 2005; Accepted 14 October 2005; Published online 30 November 2005.

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 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.