[Pharmacological effects of the novel dopamine uptake inhibitor 1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride (I-893) on the central nervous system].
The effects of 1-[2-[bis (4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl) piperazine dihydrochloride (I-893) on the central nervous system were behaviorally and electroencephalographically investigated. Intraperitoneally injected I-893 (5-10 mg/kg) dose-dependently increased spontaneous motor activity in mice, but repeated injections did not affect the increase in the locomotor activity. In reserpinized mice, spontaneous motor activity was not increased by oral I-893. In alpha-MPT-treated mice, the motor activity was lower than that in vehicle-treated animals with intermediate doses (10-40 mg/kg, p.o.) of I-893, but there was no difference between the two groups with high doses. In rats with unilaterally 6-OHDA-induced lesion of the nigrostriatal pathway, I-893 induced circling behavior toward the lesioned side. Haloperidol-induced catalepsy in rats was reduced by I-893. Tremorine-induced tremor in mice was inhibited by I-893. The effect was not altered in the mice treated with I-893 for 10 days. Oral I-893 induced stereotypy in rats, but it did not affect methamphetamine-induced stereotypy. Hypnosis induced by barbiturates was antagonized by I-893. In rats treated with I-893 for 6 days, pentobarbital-induced sleep was not different from that in vehicle-treated animals on the day after the final treatment. Intravenous I-893 altered EEGs in the cerebral cortex and amygdala nucleus to low voltage and fast waves and altered hippocampal EEG to theta waves in immobilized rabbits. These results suggest that I-893 inhibits re-uptake of dopamine released by exocytosis and indirectly has dopaminergic effects.
Nagase
T
T
Marion Merrell Dow K.K., Development Laboratories, Osaka, Japan.
Hotta
K
K
Morita
S
S
Sakai
K
K
Yamane
M
M
Omote
M
M
Mizusawa
H
H
D000818:Animals; D001463:Barbiturates / Q000037:antagonists & inhibitors; D001831:Body Temperature / Q000187:drug effects; D002375:Catalepsy; D004285:Dogs; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D006220:Haloperidol / Q000037:antagonists & inhibitors; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012890:Sleep / Q000187:drug effects; D014202:Tremor; D014203:Tremorine / Q000037:antagonists & inhibitors
D001463:Barbiturates; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D008694:Methamphetamine; D007980:Levodopa; C043425:vanoxerine; D006220:Haloperidol; D014203:Tremorine; D004298:Dopamine; C032232:barbituric acid