CHRONIC DOPAMINE D1, DOPAMINE D2 AND COMBINED DOPAMINE D1 AND D2 ANTAGONIST TREATMENT IN CEBUS-APELLA MONKEYS - ANTIAMPHETAMINE EFFECTS ANDEXTRAPYRAMIDAL SIDE-EFFECTS

To determine: (1) whether the apparent lack of efficacy of dopamine D1 (D1) antagonists in the clinic might be attributable to development o f tolerance to antipsychotic effects; and (2) whether combined D1 and D2 antagonism might contribute to clozapine's clinical profile, eight Cebus apella monkeys were chronically treated with a D1 antagonist (NN C 756) nzofurnanyl)-2,3,4,5-tetrahydro-1H-3-benzazepine), a D2 antagon ist (raclopride) or a combination of the two antagonists. Prior neurol eptic exposure had resulted in oral dyskinesia in seven monkeys and se nsitization to dystonia in all, yielding a model for acute and chronic extrapyramidal side effects (EPS). Dextroamphetamine-induced mo toric unrest and stereotypies were used as a psychosis model. We found tole rance toward dystonic symptoms during D1 and D1 + D2 treatments but no t during D2 treatment. D2 but not D1 or D1 + D2 antagonism caused exac erbation of dyskinesia. Both D1 and D1 + D2 antagonism were superior t o D2 antagonism alone in counteracting the amphetamine-induced behavio rs, with no tolerance to antiamphetamine effects. These findings sugge st: (1) reasons other than tolerance (e.g., differences among antagoni sts) may explain the lack of efficacy in clinical trials with D1 antag onists; and (2) that D1 antagonism alone or combined and modest D1 and D2 antagonism offers the potential of antipsychotic efficacy with a l ower risk of EPS than traditional D2 antagonism. Further clinical tria ls with D1 or combined D1 and D2 antagonists are, therefore, recommend ed. [Neuropsychopharmacology 20:35-43, 1999] (C) 1998 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.