Effect of the selective D1 antagonists SCH 23390 and NNC 01-0112 on the delay, duration, and improvement of behavioral responses to dopaminergic agents in MPTP-treated monkeys.
We assessed the antiparkinsonian response in MPTP-treated monkeys after acute or repeated treatment with oral L-Dopa, subcutaneous administration of L-Dopa methyl ester (LDME) or apomorphine, alone and in combination with D1 antagonists SCH 23390 (SCH) or NNC 01-0112 (NNC). When given alone, the L-Dopa effect occurred within the first hour after treatment. Coadministration of SCH or NNC with L-Dopa significantly delayed the onset of action. The response duration remained unchanged, as did the extent of the antiparkinsonian effect, after SCH, whereas the former became shorter at the higher doses of NNC tested. Bypass of the gastrointestinal tract using parenteral injections of LDME and apomorphine allowed the rapid turning "on" of the animals. Both D1 antagonists administered with LDME delayed the onset and shortened the duration of the therapeutic effect as the dose increased. Pretreatment with SCH failed to block the antiparkinsonian effect induced by apomorphine, but reduced the response duration markedly in a dose-related fashion. Repeated treatment of one monkey with SCH combined with the same dopaminergic drugs produced results similar to those obtained after acute treatment in four animals. The results obtained with parenteral administration of LDME and apomorphine most probably involve pharmacodynamic actions resulting in increased threshold of response. The delay observed with L-Dopa suggests pharmacokinetic interference possibly mediated via dopamine receptors located at the level of the gut.
Doan
V D
VD
Neurobiology Research Center, Enfant-Jesus Hospital, Québec, Canada.
Grondin
R
R
Hadj Tahar
A
A
Grégoire
L
L
Bédard
P J
PJ
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001058:Apomorphine / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D004064:Digestive System / Q000187:drug effects; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000627:therapeutic use*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D007980:Levodopa / Q000031:analogs & derivatives / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology; D008252:Macaca fascicularis; D013997:Time Factors
D000978:Antiparkinson Agents; D001552:Benzazepines; D015259:Dopamine Agents; D018492:Dopamine Antagonists; C114704:NNC 01-0012; D007980:Levodopa; C035420:levodopa methyl ester; D001058:Apomorphine