Chronic dopamine D1, dopamine D2 and combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys: antiamphetamine effects and extrapyramidal side effects.
To determine: (1) whether the apparent lack of efficacy of dopamine D1 (D1) antagonists in the clinic might be attributable to development of 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 (NNC 756) ((+)-8-chloro-7-hydroxy-3-methyl-5-(7-(2,3- dihydrobenzofuranyl)-2,3,4,5-tetrahydro-1H-3-benzazepine), a D2 antagonist (raclopride) or a combination of the two antagonists. Prior neuroleptic exposure had resulted in oral dyskinesia in seven monkeys and sensitization to dystonia in all, yielding a model for acute and chronic extrapyramidal side effects (EPS). Dextroamphetamine-induced motoric unrest and stereotypies were used as a psychosis model. We found tolerance toward dystonic symptoms during D1 and D1 + D2 treatments but not during D2 treatment. D2 but not D1 or D1 + D2 antagonism caused exacerbation of dyskinesia. Both D1 and D1 + D2 antagonism were superior to D2 antagonism alone in counteracting the amphetamine-induced behaviors, with no tolerance to antiamphetamine effects. These findings suggest: (1) reasons other than tolerance (e.g., differences among antagonists) may explain the lack of efficacy in clinical trials with D1 antagonists; and (2) that D1 antagonism alone or combined and modest D1 and D2 antagonism offers the potential of antipsychotic efficacy with a lower risk of EPS than traditional D2 antagonism. Further clinical trials with D1 or combined D1 and D2 antagonists are, therefore, recommended.
Peacock
L
L
Research Institute for Biological Psychiatry, Sct. Hans Hospital, Roskilde, Denmark.
Hansen
L
L
Mørkeberg
F
F
Gerlach
J
J
D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001480:Basal Ganglia Diseases / Q000139:chemically induced*; D001552:Benzazepines / Q000009:adverse effects / Q000494:pharmacology; D001572:Benzofurans / Q000009:adverse effects / Q000494:pharmacology; D002428:Cebus; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced; D004421:Dystonia / Q000139:chemically induced; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020891:Raclopride; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012457:Salicylamides / Q000009:adverse effects / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects
D001552:Benzazepines; D001572:Benzofurans; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D020891:Raclopride; C075357:odapipam; D000661:Amphetamine