Neuroendocrine evidence that tetrabenazine is a dopamine antagonist.

Tetrabenazine is considered to be a reserpine-like drug because of its ability to block dopamine storage in presynaptic vesicles. We used two methods to determine that tetrabenazine is also a dopamine antagonist. Tetrabenazine displaced the specific [3H]spiperone binding to the dopamine receptors of the anterior pituitary, the corpus striatum, and a transplantable rat pituitary tumor with values for 50% displacement (IC50) of about 15 microM. Under in vitro conditions, 0.5 to 10 microM tetrabenazine blocked dopaminergic inhibition of prolactin secretion from rat anterior pituitary glands. One, four, and twenty-four hours after a single tetrabenazine injection (30 mg/kg, ip), the serum prolactin changed from 22 +/- 9 ng/ml initially, to 450 +/- 52, 254.7 +/- 10.4, and 9.3 +/- 1.1 ng/ml, respectively. Pituitary glands of the treated rats incubated in vitro were refractory to dopaminergic inhibition of prolactin release to an extent that was maximal at one hour but inapparent by 24 hours after injection. In vivo and in vitro, tetrabenazine induces biological responses characteristic of a dopamine antagonist. These actions are independent of the reserpine-like properties of tetrabenazine. The unusual ability of tetrabenazine both to antagonize dopamine and to block presynaptic dopamine storage may provide a new tool for understanding the physiology of dopaminergic systems.