Extrapyramidal side effects during chronic combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys. 1999

L Peacock, and G Jensen, and K Nicholson, and J Gerlach
Dept. P & Research Institute for Biological Psychiatry, Sct. Hans Hospital, DK-4000 Roskilde, Denmark. lis.nielsen@shh.hosp.dk

Previous studies in non-human primates have shown that tolerance to dystonia occurs during chronic dopamine D1 (D1) but not D2 antagonism and induction/aggravation of oral dyskinesia (TD) during D2 but not D1 antagonism. We were therefore interested in determining the effects of combined chronic D1 + D2 antagonism on dystonia and dyskinesia. To this intent, 8 male Cebus apella monkeys were treated 10 weeks with gradually increasing doses of D1 antagonist (NNC 112) + a D2 antagonist (raclopride), followed by 2 weeks of treatment with the D2 antagonist alone. Due to previous neuroleptic exposure, 5 monkeys had TD and all were sensitized to dystonia. During the combined antagonist treatment, tolerance to dystonia occurred; the tolerance disappearing upon discontinuation of the D1 antagonist and continuation of the D2 antagonist alone. Parallel to these results, improvement of TD was seen during the combined antagonist treatment with worsening during the D2 antagonist alone. Both the combined antagonists and the D2 antagonist alone resulted in moderate/severe bradykinesia, with no tolerance. These findings indicate that supplementation of traditional D2 antagonism with a D1 antagonist would lessen the risk of dystonia and allow alleviation of preexisting TD, though parkinsonian side effects might still occur. The findings further indicate that separate dopaminergic mechanisms control dystonia/dyskinesia and parkinsonism.

UI MeSH Term Description Entries
D008297 Male Males
D002428 Cebus A genus of the family CEBIDAE, subfamily CEBINAE, consisting of gracile or untufted capuchin species. Tufted capuchins belong to genus SAPAJUS. Members include C. capucinus, C. nigrivultatus, and C. albifrons. Cebus inhabits the forests of Central and South Americas. Cebu,Gracile Capuchins,Monkey, Capuchin,Monkey, Ring-Tail,Monkey, Ringtail,Monkey, Ringtailed,Untufted Capuchins,White-Fronted Capuchin,Monkey, Ring-Tailed,Capuchin Monkey,Capuchin Monkeys,Capuchin, Gracile,Capuchin, Untufted,Capuchin, White-Fronted,Gracile Capuchin,Monkey, Ring Tail,Monkey, Ring Tailed,Ring-Tail Monkey,Ring-Tail Monkeys,Ring-Tailed Monkey,Ring-Tailed Monkeys,Ringtail Monkey,Ringtail Monkeys,Ringtailed Monkey,Ringtailed Monkeys,Untufted Capuchin,White Fronted Capuchin,White-Fronted Capuchins
D004359 Drug Therapy, Combination Therapy with two or more separate preparations given for a combined effect. Combination Chemotherapy,Polychemotherapy,Chemotherapy, Combination,Combination Drug Therapy,Drug Polytherapy,Therapy, Combination Drug,Chemotherapies, Combination,Combination Chemotherapies,Combination Drug Therapies,Drug Polytherapies,Drug Therapies, Combination,Polychemotherapies,Polytherapies, Drug,Polytherapy, Drug,Therapies, Combination Drug
D004409 Dyskinesia, Drug-Induced Abnormal movements, including HYPERKINESIS; HYPOKINESIA; TREMOR; and DYSTONIA, associated with the use of certain medications or drugs. Muscles of the face, trunk, neck, and extremities are most commonly affected. Tardive dyskinesia refers to abnormal hyperkinetic movements of the muscles of the face, tongue, and neck associated with the use of neuroleptic agents (see ANTIPSYCHOTIC AGENTS). (Adams et al., Principles of Neurology, 6th ed, p1199) Dyskinesia, Medication-Induced,Medication-Induced Dyskinesia,Drug-Induced Dyskinesia,Drug-Induced Dyskinesias,Dyskinesia, Drug Induced,Dyskinesia, Medication Induced,Dyskinesias, Drug-Induced,Dyskinesias, Medication-Induced,Medication Induced Dyskinesia,Medication-Induced Dyskinesias
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001480 Basal Ganglia Diseases Diseases of the BASAL GANGLIA including the PUTAMEN; GLOBUS PALLIDUS; claustrum; AMYGDALA; and CAUDATE NUCLEUS. DYSKINESIAS (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include CEREBROVASCULAR DISORDERS; NEURODEGENERATIVE DISEASES; and CRANIOCEREBRAL TRAUMA. Extrapyramidal Disorders,Basal Ganglia Disorders,Lenticulostriate Disorders,Basal Ganglia Disease,Basal Ganglia Disorder,Extrapyramidal Disorder,Lenticulostriate Disorder
D001552 Benzazepines Compounds with BENZENE fused to AZEPINES.
D001572 Benzofurans Compounds that contain a BENZENE ring fused to a furan ring. Coumarones,Diphenylbenzofuran
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor
D017447 Receptors, Dopamine D1 A subfamily of G-PROTEIN-COUPLED RECEPTORS that bind the neurotransmitter DOPAMINE and modulate its effects. D1-class receptor genes lack INTRONS, and the receptors stimulate ADENYLYL CYCLASES. Dopamine D1 Receptors,Dopamine-D1 Receptor,D1 Receptors, Dopamine,Dopamine D1 Receptor,Receptor, Dopamine-D1

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