TETRABENAZINE, AN AMINE-DEPLETING DRUG, ALSO BLOCKS DOPAMINE-RECEPTORS IN RAT-BRAIN

  • 1 January 1983
    • journal article
    • research article
    • Vol. 225  (3) , 515-521
Abstract
Tetrabenazine (TBZ) is used in the treatment of hyperkinetic movement disorders. Its effect is thought to be mediated by depletion of dopamine (DA) stores. Other possible mechanisms of action of this drug were studied. TBZ decreased DA concentration in rat striatum and nucleus accumbens in a dose-dependent manner with an IC50 [medium inhibitory concentration] of approximately 1.2 mg .cntdot. kg-1. Maximal depletion was obtained within 30 min with only partial recovery at 8 h. TBZ induced (at 40 mg .cntdot. kg-1) 5- to 8-fold increases in 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations in both brain regions. Unlike reserpine, TBZ completely abolished the apomorphine-induced inhibition of DA synthesis under conditions in which this effect is mediated by presynaptic DA receptors. Both TBZ (5 mg .cntdot. kg-1) and reserpine (5 mg .cntdot. kg-1) depleted, at 1 h, striatal DA content by approximately 90%. TBZ, but not reserpine, significantly stimulated in vivo tyrosine hydroxylase activity. TBZ inhibited [3H]spiperone binding in the striatum with Ki [inhibition constant] = 2.1 .times. 10-6 M. In rats, with unilateral destruction of the nigrostriatal pathway with 6-hydroxydopamine, pretreatment with TBZ significantly reduced the number of rotatins induced by apomorphine. In rats treated with either TBZ (5 mg .cntdot. kg-1) or reserpine (5 mg .cntdot. kg-1), prolactin levels significantly increased as compared to control values. TBZ, but not reserpine, blocked apomorphine inhibition of prolactin secretion. In addition to depleting monoamines, TBZ blocks both presynaptic and postsynaptic DA receptors in rat brain.