Mixed agonist-antagonist properties of umespirone at neostriatal dopamine receptors in relation to its behavioral effects in the rat.
In normal rats treated with the inhibitor of cerebral decarboxylase, NSD-1015 (100 mg kg-1 i.p.), umespirone (1.9-30.0 mumol kg-1 s.c.) produced an increase in neostriatal DOPA (dihydroxyphenylalanine) accumulation, whereas decreased DOPA accumulation was obtained in reserpine-pretreated (5 mg kg-1 s.c., -18 h) animals. The latter effect was statistically significant only in the ventral, limbic, portion of the neostriatum. Neostriatal 5-hydroxytryptophan (5-HTP) accumulation was decreased in the reserpine-treated animals but not in normal controls. DOPA accumulation in the neocortex was not affected by umespirone treatment in either preparation, whereas 5-HTP accumulation was decreased in the reserpine-treated animals. Spontaneous locomotor activity was suppressed by umespirone at doses that did not affect treadmill locomotion (7.9-31.2 mumol kg-1 s.c., -30 min), and there were no signs of catalepsy at doses ranging from 31.2-249.6 mumol kg-1 s.c. up to 2 h after injection. Thus, umespirone behaves as a mixed dopamine receptor agonist/antagonist and also displays 5-HT receptor agonist properties. This biochemical profile was associated with sedation, as observed in the open-field, at doses which did not affect treadmill locomotion or induced catalepsy.
Department of Behavioral Pharmacology, Astra Arcus AB, Södertälje, Sweden.
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Ahlenius
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Wijkström
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002375:Catalepsy / Q000139:chemically induced; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology
D015306:Biogenic Monoamines; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004295:Dihydroxyphenylalanine; D012110:Reserpine; D006916:5-Hydroxytryptophan; C059363:umespirone