Tetrabenazine has properties of a dopamine receptor antagonist

Abstract

Tetrabenazine is considered to act in a manner similar to reserpine to reduce the involuntary movements of tardive dyskinesia or Huntington's disease and to improve psychoses. We determined that tetrabenazine also has properties of a dopamine receptor antagonist by testing the ability of tetrabenazine to block the inhibitory effect of dopamine on prolactin secretion from rat anterior pituitary glands in vitro and to displace 3H-spiperone binding to dopamine receptors in the pituitary, corpus striatum, and a rat transplantable prolactin-secreting tumor. Under in vitro conditions, 0.5 to 10 microM tetrabenazine directly blocked dopaminergic inhibition of prolactin secretion. Furthermore, 1 hour after tetrabenazine injection (30 mg/kg intraperitoneally) in vivo, when the serum prolactin had increased from 22 +/- 9 to 450 +/- 52 ng/ml (p less than 0.01), pituitary glands of the treated rats examined in vitro were refractory to dopaminergic inhibition of prolactin release. Tetrabenazine apparently interacts with the dopamine receptor because this drug displaced the dopamine antagonist 3H-spiperone from dopamine receptors of the three different tissues with an apparent inhibitory constant of about 5 microM. We conclude that tetrabenazine has biological and pharmacological properties typical of a dopamine receptor antagonist. These observations should stimulate a reevaluation of the mechanisms for the actions of tetrabenazine previously attributed exclusively to a "reserpine-like" effect.

Tetrabenazine in the treatment of hyperkinetic movement disorders

“…Although in vitro studies have shown that TBZ blocks dopamine D 2 receptors, as suggested by its ability to inhibit [ 3 H]spiperone binding to striatal membranes with a K i of approximately 2.1 × 10 -6 M, this affinity is 1000-fold lower than its affinity for VMAT2 [50,51]. Therefore, it is unlikely that the weak D 2 receptor antagonism is responsible for TBZ clinical effects, although it may be possibly involved in acute dystonic reactions rarely reported with TBZ [52].…”

Dopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease

“…This mode of action was confirmed in our studies, because tetrabenazine prevented an increase in striatal dopamine content resulting from L-DOPA feeding to mice in our in vivo experiments (Table 2). Tetrabenazine also directly binds to and inhibits dopamine receptors in the brain (Login et al, 1982(Login et al, , 1983Reches et al, 1983). The brain concentrations of tetrabenazine achieved in our experiments were in the range 30 -60 nM (Table 2), which is sufficient to block VMAT-2 but not likely to inhibit striatal dopamine receptors in vivo [for related discussion, see Savani and Login (2007)].…”

Rapid improvement of tardive dyskinesia with tetrabenazine, clonazepam and clozapine combined: a naturalistic long-term follow-up study

“…TBA, a synthetic benzoquinoline, depletes presynaptic storage of monoamines [20] and block post synaptic dopamine receptors [21]. Although it has been described as causing a dystonic reaction in very rare cases [22], the fact that it may produce TD has never been documented.…”