Differential interaction of neuroleptics with apomorphine-induced behavior in rats as a function of changing levels of dopamine receptor stimulation.
Twenty-two neuroleptic drugs were studied for interaction with the behavior induced by intravenous injection of apomorphine in rats. All compounds dose-dependently shortened the duration of the apomorphine-induced agitation and-with the exception of clozapine-shortened the onset of the de-arousal grooming that typically occurs immediately after the agitation phase has been terminated. Progressively higher doses were required to antagonize higher levels of apomorphine at earlier time intervals after the intravenous injection. The compounds also decreased palpebral opening, and most of them suppressed grooming behavior at higher doses. Compounds differed considerably in dose increments required for: 1) suppression of grooming, from 0.33 for clozapine to >600 for remoxipride, raclopride, and droperidol; 2) blockade of agitation at 5 minutes after apomorphine, from 2.6 for pimozide to 165 for chlorprothixene and 254 for remoxipride; 3) mild decrease of palpebral opening, from 0.21 for sertindole to 191 for remoxipride; and 4) pronounced decrease of palpebral opening, from 10 for melperone to >820 for raclopride. Only four compounds were able to advance grooming to 15 minutes postapomorphine, but again dose increments varied considerably: droperidol (3.4), pimozide (9.1), raclopride (42), and remoxipride (383). Based on these results obtained in a single animal model, compounds were differentiated in terms of behavioral specificity, incisiveness (the power to counteract the effects of progressively higher apomorphine concentrations), and sedative side-effect liability. Possible explanations for the observed differences and clinical relevance are discussed.
Department of Neurosciences, Janssen Research and Development, a Division of Janssen Pharmaceutica, Beerse, Belgium.
Anton A H P
AA
Megens
Herman M R
HM
Hendrickx
Hilde
H
Lavreysen
Xavier
X
Langlois
D000316:Adrenergic alpha-Agonists / Q000633:toxicity; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D003228:Conjunctiva / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006120:Grooming / Q000187:drug effects; D006993:Hypnotics and Sedatives; D016014:Linear Models; D008297:Male; D009638:Norepinephrine / Q000633:toxicity; D011595:Psychomotor Agitation / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D013268:Stimulation, Chemical
D000316:Adrenergic alpha-Agonists; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D006993:Hypnotics and Sedatives; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D001058:Apomorphine; D009638:Norepinephrine