title: Cerebral activating properties of indeloxazine HCl and its optical isomers.
abstract: The cerebral activating actions of indeloxazine HCl and its optical isomers were evaluated in comparison with those of several selective monoamine uptake inhibitors. The effects of indeloxazine and its optical isomers on monoamine uptake were also determined. Indeloxazine was equipotent to the (-)-isomer in desynchronizing the spontaneous electroencephalogram (EEG) in both mature and aged rats and in accelerating recovery of consciousness induced by concussive head trauma in mice, whereas the (+)-isomer showed about 3 times less potent activity than indeloxazine and the (-)-isomer. The potency of indeloxazine and the (-)-isomer in inhibiting [14C]norepinephrine (14C-NE) uptake was approximately 25-30 times more potent than that of the (+)-isomer. Maprotiline and viloxazine, selective NE uptake inhibitors, also showed facilitatory actions in concussed mice. Selective 5-hydroxytryptamine (5-HT) uptake inhibitors such as citalopram, alaproclate, and zimeldine showed little effect. Indeloxazine, the (-)-, and the (+)-isomers facilitated passive avoidance learning behavior with a bell-shaped response curve in normal rats. The potency of the (+)-isomer in inhibiting [14C]5-HT uptake was equipotent to those of both indeloxazine and the (-)-isomer. While citalopram, alaproclate, and zimeldine also facilitated the acquisition of learning behavior, maprotiline and viloxazine, as well as the dopamine uptake inhibitor amantadine, showed little influence on the latency of step-through behavior. Amitriptyline, with anticholinergic activity, impaired learning behavior. Indeloxazine, its optical isomers, citalopram, alaproclate, and zimeldine also ameliorated cycloheximide-induced disturbance of learning behavior in mice, while maprotiline and viloxazine showed little effect.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shimizu-Sasamata
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Harada
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D004569:Electroencephalography; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000928:Antidepressive Agents; D009025:Morpholines; D012701:Serotonin; C020852:indeloxazine; D003513:Cycloheximide; D009638:Norepinephrine