title: The differential behavioural effects of benzazepine D1 dopamine agonists with varying efficacies, co-administered with quinpirole in primate and rodent models of Parkinson's disease.
abstract: The effects of co-administration of quinpirole with benzazepine D1 dopamine (DA) agonists possessing full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393 and SKF 75670) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) were investigated in rodent and primate models of Parkinson's disease (PD). In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, co-administration of SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) strongly potentiated the contralateral circling induced by quinpirole. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of quinpirole alone increased locomotor activity and reversed motor deficits. Grooming and oral activity were unaltered. Co-administration of SKF 38393 and SKF 75670 inhibited the quinpirole-induced changes in locomotor activity and motor disability. The combined treatment of SKF 80723 or SKF 82958 with quinpirole had no overall effect on locomotor activity or motor disability. In contrast, SKF 83959 extended the duration of the quinpirole-induced increase in locomotor activity with corresponding decreases in motor disability. Co-administration of high doses of SKF 82958 and more especially SKF 83959 and SKF 80723, with quinpirole induced hyperexcitability and seizures. Oral activity and grooming were unaltered following the co-administration of benzazepine derivatives with quinpirole. The ability of some benzazepine D1 DA agonists to prolong the antiparkinsonian effects of quinpirole in the MPTP-treated marmoset may indicate a role for certain D1 DA agonists in the clinical treatment of PD. In general, the behavioural responses to the combined administration of benzazepines with quinpirole in the 6-OHDA lesioned rat and more especially the MPTP-treated marmoset failed to correlate with their ability to stimulate AC. These observations further implicate a behavioural role for D1 DA receptors not linked to AC.
authors.affiliation: Parkinson's Disease Society, Experimental Research Laboratories, King's College, London, U.K.
authors.forename: K K
authors.initials: KK
authors.lastname: Gnanalingham
authors.forename: A J
authors.initials: AJ
authors.lastname: Hunter
authors.forename: P
authors.initials: P
authors.lastname: Jenner
authors.forename: C D
authors.initials: CD
authors.lastname: Marsden
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002144:Callithrix; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004873:Ergolines / Q000627:therapeutic use*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D019257:Quinpirole; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D013045:Species Specificity
chemical_list: D018491:Dopamine Agonists; D004873:Ergolines; D017447:Receptors, Dopamine D1; D019257:Quinpirole; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000262:Adenylyl Cyclases