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Amphetamine's locomotor-stimulant and norepinephrine-releasing effects: Evidence for selective antagonism by nisoxetine

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Abstract

A new procedure that allows simultaneous and objective measurement of both locomotor activity and stereotypy in individual mice was used to determine the effects of the selective noradrenergic uptake inhibitor, nisoxetine (Lilly 94939), on amphetamine-induced changes in these behaviors. Amphetamine markedly increased locomotor activity at a dose of 3 mg/kg, while stereotypy was significantly increased at doses of 5.6 mg/kg and above. After nisoxetine (20 mg/kg, 30 min pretreatment), the locomotor-stimulant effect of amphetamine was abolished and its actions on stereotypy were potentiated. The action of nisoxetine was selective in that it did not significantly affect the locomotor activity induced by a moderate dose (56 mg/kg) of morphine. In addition, nisoxetine pretreatment had little affect on the accumulation of 3H-amphetamine in the mouse brain. Biochemically, nisoxetine (10-6 M) antagonized amphetamine-induced release of 3H-norepinephrine from the mouse cerebral cortex, but not that of 3H-dopamine or 3H-5-hydroxytryptamine from the mouse corpus striatum. The data indicate that nisoxetine selectively antagonizes certain of amphetamine's behavioral and biochemical actions. They are also consistent with the suggestion that amphetamine-induced release of nor-epinephrine is causally related to the locomotor-stimulant action of amphetamine and may inhibit stereotypy produced by the drug.

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  1. Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas, U.S.A.

    Thomas D. Tyler & Richard E. Tessel

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  1. Thomas D. Tyler
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  2. Richard E. Tessel
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Tyler, T.D., Tessel, R.E. Amphetamine's locomotor-stimulant and norepinephrine-releasing effects: Evidence for selective antagonism by nisoxetine. Psychopharmacology 64, 291–296 (1979). https://doi.org/10.1007/BF00427512

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