The effects of D1 (NNC 22-0215) and D2 (haloperidol) antagonists in a chronic double-blind placebo controlled trial in cebus monkeys.
The effects of chronic treatment for 28 days with the oral D1 (NNC 22-0215) or D2 (haloperidol) antagonist were evaluated in nonhuman primates in a double blind, placebo controlled crossover trial. Cebus monkeys, 10-18 years old, which were previously sensitized to neuroleptics, were treated in three different groups with NNC 22-0215 2-3 mg/kg PO (n = 6), haloperidol 2-3 mg/kg PO (n = 5), or lactose placebo (n = 7) each day in a banana slice. At the end of 28 days the NNC 22-0215 group crossed over to haloperidol and the haloperidol group crossed over to NNC 22-0215 for 28 more days. The lactose group continued on lactose. Extrapyramidal symptoms (EPS) of dystonia and sedation were scored daily. Initially both NNC 22-0215 and haloperidol produced equal rates of dystonia. However, the NNC 22-0215 group demonstrated nearly full desensitization by day 2 and showed no EPS by day 6, whereas the haloperidol group had increased EPS during the first week, followed by moderate desensitization to EPS, but continued to have symptoms on each of the 28 days of treatment. At crossover, the previously treated haloperidol group rapidly desensitized with NNC 22-0215 by day 4 to show no EPS, whereas the previously treated NNC 22-0215 group showed full EPS on the first day of haloperidol and had EPS continue over the next 28 days of treatment. Sedation from NNC 22-0215 also desensitized within the first week of treatment. Haloperidol produced minimal sedation that did not change. The profound difference in rates of desensitization between repeated D1 and D2 antagonist treatment suggests that D1 antagonists in the clinic may produce EPS side effects for only the first few days, in contrast to the continuous acute EPS associated with chronic neuroleptic treatment.
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Psychiatry Service (116A), VA Medical Center, Portland, OR 97207, USA.
D000284:Administration, Oral; D000818:Animals; D002428:Cebus; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004421:Dystonia / Q000139:chemically induced; D006220:Haloperidol / Q000494:pharmacology*; D007785:Lactose / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013997:Time Factors
D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007785:Lactose; D006220:Haloperidol