Effects of 1,2-benzisoxazole-3-acetamidoxime on central monoamine neurons in the rat.

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Abstract
The effects of 1,2-benzisoxazole-3-acetamidoxime HCl (PF-257), a novel psychotropic agent possessing the pharmacological properties similar to those of tricyclic antidepressants or monoamine oxidase [MAO] inhibitors, on the metabolism of brain monoamines were studied in rats. A single large dose or repeated doses of PF-257 caused a slight but significant increase in brain norepinephrine [NE] level without affecting the contents of dopamine [DA] and serotonin [5-hydroxytryptamine, 5-HT]. Like MAO inhibitors, PF-257 prevented and reversed the decrease in brain NE induced by reserpine but it lacked the property to inhibit MAO in the brain. Unlike tricyclic antidepressants, the compound was devoid of the capacity to inhibit NE uptake in vitro. Administration of PF-257 in combination with L-dopa enhanced the increase in brain DA without influencing the amount of the amino acid incorporated into the brain. At relatively small doses, PF-257 reduced the rate of decline of brain NE and DA levels following .alpha.-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, and also decreased the levels of brain 3-methoxy-4-hydroxy-phenylethyleneglycol sulfate and homovanillic acid, major metabolites of brain NE and DA, respectively. The fundamental mechanisms underlying the pharmacological and biochemical effects of PF-257 may be its activity to decelerate catecholamine metabolism in the brain without inhibiting the enzymes participating in the metabolic degradation of the amines.

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