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The effects of SM-3997 on central monoaminergic systems were evaluated by ex vivo measurement of monoamines and their metabolite levels in rat brain after intraperitoneal treatment of drugs and by in vitro measurement of monoamine uptake into rat brain slices. The effects of SM-3997 were also compared with those of other new nonbenzodiazepine anxiolytic compounds. SM-3997, buspirone, gepirone and ipsapirone showed no effects on serotonin uptake and dopamine uptake, and a weak inhibition of norepinephrine uptake at the concentration of 100 microM. SM-3997 decreased the serotonin metabolite (5-hydroxyindole-3-acetic acid) level without changing the serotonin level in hippocampus and increased dopamine metabolite (3,4-dihydroxyphenylacetic acid, homovanillic acid) level with no effect on the dopamine level in striatum. SM-3997 also produced an increase in the norepinephrine metabolite (3-methoxy-4-hydroxyphenylglycol) level with a decrease in the norepinephrine levels in hippocampus. Similar effects on serotonin metabolites and norepinephrine metabolites were observed in several other regions. Although the serotonergic effect of SM-3997 was similar to that of buspirone, gepirone and ipsapirone, the dopaminergic effect of SM-3997 was much weaker than that of buspirone.
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