Effect of olanzapine on functional responses from sensitized D1-dopamine receptors in rats with neonatal dopamine loss.
Previous work has suggested that the therapeutic efficacy of olanzapine might be partially dependent on action at the D(1)-dopamine (DA) receptor site. Because early DA loss can lead to supersensitive D(1)-DA receptors, effects of olanzapine were investigated in adult rats given lesions to DA-containing neurons as neonates. In these animals, locomotor effects of SKF-38393 (a D(1)-DA agonist) were attenuated by olanzapine, but at doses (5 and 10 mg/kg) that decreased activity when given alone. Olanzapine prevented induction of striatal Fos protein by SKF-38393 and partially attenuated the long-term "priming" effect of repeated SKF-38393 treatment. Olanzapine also antagonized the stimulant effects of quinpirole (a D(2)-type DA agonist) in animals lesioned as young adults, at doses lower than those necessary to antagonize SKF-38393-induced activity. In addition, olanzapine antagonized apomorphine-induced self-injurious behavior in neonate-lesioned rats in a dose-related fashion. Attenuation of self-injury in this animal model suggests that olanzapine should be tested against this symptom in patient populations.
Moy
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Department of Psychiatry, Skipper Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill 27599-7178, USA. sheryl.moy@css.unc.edu
Knapp
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Breese
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D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D018663:Adrenergic Agents; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001569:Benzodiazepines; D003342:Corpus Striatum / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D000077152:Olanzapine; D016627:Oxidopamine; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D018663:Adrenergic Agents; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D001569:Benzodiazepines; D010890:Pirenzepine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D001058:Apomorphine; D000077152:Olanzapine; D004298:Dopamine