TETRABENAZINE (NITOMAN) IN THE TREATMENT OF PSYCHOSES. WITH A DISCUSSION ON THE CENTRAL MODE OF ACTION OF TETRABENAZINE AND RESERPINE.
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Behavior, Animal↗
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[MECHANISM OF ACTION OF TETRABENAZINE AS A MORPHINE ANTAGONIST. 1. THE EFFECTS OF TETRABENAZINE ON THE BRAIN NORADRENALINE AND SEROTONIN LEVELS AND MORPHINE ANTAGONISM].
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Animals↗
Effects of imipramine on behavior and brain norepinephrine metabolism in tetrabenazine treated rats: comparative study of a single administration with repeated administrations of imipramine.
The effects of a single and repeated administrations of imipramine on the tetrabenazine-induced sedation in rats were studied. The 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO4) level in the brain was measured. A single administration of imipramine of 20 mg/kg had no significant effect on the rats' locomotor activity and the brain MHPG-SO4. The administration of 30 mg/kg of tetrabenazine produced marked sedation and significantly increased the brain MHPG-SO4. The imipramine pretreatment reversed the tetrabenazine-induced sedation. The brain MHPG-SO4 in the rats treated with a single administration of imipramine along with tetrabenazine decreased significantly, compared with that in the rats treated with tetrabenazine only. The administration of alpha-methyl-para-tyrosine (alpha-MT) of 250 mg/kg suppressed the reversal of the tetrabenazine-induced sedation. The administration of Ro4-4602 of 50 mg/kg and L-3,4-dihydroxyphenylalanine (L-DOPA) of 100 mg/kg had no significant effect on the reversal. The repeated daily administrations of imipramine of 20 mg/kg reversed the tetrabenazine-induced sedation and produced the locomotor hyperactivity. When the rats were treated with the repeated administrations of imipramine for five days and had tetrabenazine administered on the last day, the brain MHPG-SO4 increased significantly as compared with that in the rats treated with a single administration of imipramine and tetrabenazine. There was no difference in the amount of locomotor activity between the rats administered imipramine of 20 mg/kg and tetrabenazine and those administered imipramine of 40 mg/kg and tetrabenazine. Several considerations were given to the above-mentioned results.
Animals↗
Tetrabenazine has properties of a dopamine receptor antagonist.
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.
Animals↗
Differential interactions of phencyclidine with tetrabenazine and reserpine affecting intraneuronal dopamine.
This study has examined the effects on synaptosomal (P2) dopamine of interactions of phencyclidine and some other stimulants with tetrabenazine and reserpine. Tetrabenazine and reserpine both enhanced the spontaneous synaptosomal release of [14C]dopamine and inhibited its formation from [14C]phenylalanine. The [14C]dopamine formation increases induced by phencyclidine and amfonelic acid, however, were affected differentially by coadditions of tetrabenazine and reserpine. At the lower concentrations, tetrabenazine either did not affect or augmented the dopamine formation enhancements by the stimulants. Reserpine at all levels blocked the synthesis enhancements and revealed inhibitory effects of phencyclidine and amfonelic acid upon dopamine formation; only at the highest concentration did the action of tetrabenazine mimick that of reserpine. Amphetamine stimulation of dopamine formation was affected by tetrabenazine and reserpine alike; the stimulation was either maintained or enhanced. Ketamine did not affect dopamine formation either by itself, with tetrabenazine, or with reserpine. In summary, tetrabenazine and reserpine affected synaptosomal dopamine formation and release in a comparable manner, but intraneuronal dopaminergic actions of phencyclidine and also of amfonelic acid may be influenced differentially by these two releasing agents.
Animals↗
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.
Animals↗
Chimeric vesicular monoamine transporters identify structural domains that influence substrate affinity and sensitivity to tetrabenazine.
The vesicular monoamine transporters (VMATs) 1 and 2 show close sequence similarity but substantial differences in apparent substrate affinity and drug sensitivity. To identify structural domains that determine these functional characteristics, chimeric transporters were constructed and their properties were analyzed in a heterologous expression system. The results implicate multiple regions in the recognition of serotonin and histamine and the sensitivity to tetrabenazine. Two domains of VMAT2, one extending from transmembrane domain (TMD) 5 to the beginning of TMD8 and the other from the end of TMD9 through TMD12, increase the affinity for serotonin and histamine as well as the sensitivity to tetrabenazine but only in the context of more C-terminal and more N-terminal VMAT2 sequences, respectively. In addition, the extreme N terminus of VMAT2 alone suffices to confer a partial increase in substrate affinity and tetrabenazine sensitivity. Despite these similarities among the interactions with serotonin, histamine, and tetrabenazine, the region of VMAT2 from TMD3 through TMD4 increases serotonin affinity but not histamine affinity or tetrabenazine sensitivity, and whereas the region from TMD5 to TMD8 of VMAT2 increases serotonin affinity in the context of more C-terminal VMAT2 sequences, the region encompassing TMD5 through TMD7 reduces serotonin but not histamine affinity or tetrabenazine sensitivity in the context of more N-terminal VMAT2 sequences. Thus, the chimeric analysis also reveals differences between serotonin recognition and the recognition of both histamine and tetrabenazine that may account for the observed differences in their interaction with the transport protein.
Animals↗
Tetrabenazine treatment for tardive dyskinesia: assessment by randomized videotape protocol.
OBJECTIVE: Tetrabenazine, a monoamine depleter and dopamine receptor blocker, is used to treat several hyperkinetic movement disorders. The authors studied the use of tetrabenazine for tardive dyskinesia. METHOD: Twenty patients with tardive dyskinesia (mean duration = 43.7 months) were videotaped before and after tetrabenazine treatment. Randomized videotapes were scored with the motor subset of the modified Abnormal Involuntary Movement Scale (AIMS) by raters blind to pre- or posttreatment status. RESULTS: One patient did not tolerate tetrabenazine owing to sedation. The remaining 19 were rated after a mean of 20.3 weeks at a mean tetrabenazine dose of 57.9 mg/day. There were significant improvements in mean scores on both the patient AIMS self-rating and the AIMS motor subset evaluated by the blind videotape raters. All 19 patients continued to take tetrabenazine after the study. CONCLUSIONS: Tetrabenazine was well tolerated and resulted in significant improvements in AIMS scores for patients with refractory tardive dyskinesia.
Adult↗
Imipramine and tetrabenazine: effects on monoamine receptor binding sites and phosphoinositide hydrolysis.
Treatment of rats for 21 days with tetrabenazine, a drug which depletes monoamines and is used behaviorally to screen for antidepressants, significantly decreased 5-HT2 receptor density, increased alpha 1-adrenoceptor density but did not alter beta-adrenoceptor density in homogenates of frontal cortices labeled with [3H]ketanserin, [3H]prazosin and [3H]dihydroalprenolol, respectively. These effects were not opposite to those of the antidepressant drug imipramine which decreased both 5-HT2 and beta-adrenoceptor density and did not alter alpha 1-adrenoceptor density. Some evidence for antagonistic interactions between the two drugs was found in that imipramine partially prevented the tetrabenazine-induced increase in alpha 1-adrenoceptor density and tetrabenazine partially prevented the imipramine-induced decrease in beta-adrenoceptor density. Neither drug altered phosphoinositide hydrolysis coupled to alpha 1-adrenoceptors. While the effects of tetrabenazine are frequently attributed to its reserpine-like action of depleting monoamines, these results provide the first indication that tetrabenazine alters 5-HT2 and beta-adrenoceptor density in a manner different from that of reserpine.
Animals↗
Tetrabenazine fails to antagonize a behavioral effect of cocaine in rhesus monkeys.
For research and therapeutic purposes, a cocaine antagonist is an important drug development goal. The vesicular monoamine transport inhibitor tetrabenazine was tested for interaction with cocaine using food-reinforced responding in rhesus monkeys as an assay. Both tetrabenazine and cocaine suppressed food-maintained behavior individually. However, a low-dose tetrabenazine pretreatment did not alter the rate-suppressing effects of cocaine and cocaine did not alter the rate-suppressing effects of a high dose tetrabenazine pretreatment. Because tetrabenazine interacts with the monoamine oxidase inhibitor deprenyl in this assay, we conclude that cocaine does not produce an effect through vesicular catecholamines in this assay.
Adrenergic Uptake Inhibitors↗
The mode of action of tetrabenazine on peripheral noradrenergic nerves.
1. Tetrabenazine (100 mg/kg i.p. in rats) greatly decreased catecholamine-induced histofluorescence in the iris, hepatic portal vein, inferior vena cava and mesenteric blood vessels 4 h after injection. Fluorescence returned to normal by 24 h after injection. 2. The extent of this depletion (4 h after tetrabenazine) was similar to that seen 18 h after reserpine (0.5 mg/kg i.p.). 3. Incubation of tissues taken from rats 4 h after this dose of tetrabenazine with noradrenaline 5 X 10(-6)M restored the intraneuronal fluorescence as well as the electron density of noradrenergic vesicle cores viewed with the electron microscope. No such repletion was seen on incubation of tissues from reserpine-treated rats with noradrenaline under the same conditions. 4. Incubation of tetrabenazine-treated hepatic portal veins with noradrenaline also reinstated the normal response to electrical stimulation of the intramural nerves. This did not occur with reserpine-treated veins. 5. The interpretation that tetrabenazine exerts a reversible depleting effect on the noradrenergic vesicle is supported by the demonstration that it exerts no monoamine oxidase inhibiton.
Animals↗
Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias.
Dopamine receptor blocking drugs, commonly used in the treatment of involuntary movements, may cause potentially serious adverse effects, including tardive dyskinesia. Tardive dyskinesia has not been reported with tetrabenazine, a dopamine-depleting drug. We report a follow-up in 217 patients treated with tetrabenazine for about 18 months (range, 1 to 80). The response was rated on a scale of 0 to 5 (1 = marked improvement, 4 = no response, 5 = worsening). The mean effect from tetrabenazine was rated as follows: 2.3 in 44 patients with tardive dyskinesia, 2.6 in 15 with tardive dystonia, 2.6 in 10 with Huntington's disease, 2.7 in 17 with Gilles de la Tourette's syndrome, 2.8 in 19 with generalized dystonia, 2.8 in 57 with Meige's syndrome, and 3.4 in 25 with other focal dystonias. Twenty-two patients with a variety of unusual movement disorders had a mean effect of 2.9. Parkinsonism occurred as a side effect in 53 patients, sedation in 28, depression in 23, anxiety in 16, insomnia in 11, and akathisia in 10. The choreatic movement disorders are most amenable to tetrabenazine therapy, but tardive and idiopathic dystonia may also be responsive. Tetrabenazine is an effective and relatively safe drug for a variety of hyperkinetic movement disorders.
Chorea↗
Modifications by lithium of behavioral responses to methamphetamine and tetrabenazine.
Different groups of mice were injected s.c. daily with lithium chloride in three doses(0.52, 1.58 and 4.72meg/kg) or with saline for a period of 3 weeks. Lithium administered acutely or chronically did not affect spontaneous locomotor activities. However, methamphetamine-induced hyper-locomotor activities were inhibited in the lithium groups as compared with those in the saline group, while the hyper-locomotor activities induced by tetrabenazine in the nialamide-pretreated animals were reduced to some extent but not significantly by lithium. Tetrabenazine brought about an initial transient increase followed by a decrease of spontaneous locomotor activities in the lithium groups, whereas it induced only a decrease of the activities in the saline group. In addition, jumping and vertical jumping behaviors, which were not observed in the saline group, occurred 30-60 min after tetrabenazine in the lithium groups. These effects of lithium tended to increase with an increase of the doses administered and with a prolongation of its daily administration. The results demonstrate that lithium modifies behavioral responses to methamphetamine and tetrabenazine.
Animals↗
Circadian susceptibility rhythm to neuroleptics: tetrabenazine.
In order to clarify the influences of situational factors on the effects of psychotropic drugs, the sedative effects of tetrabenazine after injection at various times of the day were studied. When 50 mg/kg body weight of tetrabenazine was injected into rats at eight different times of the day (07:30-19:30 dark, 19:30-07:30 light), a circadian rhythm of sedative effect was observed with a peak sedative time of 1490 min at 10:30 and a nadir of 736 min at 07:30. With 10 mg/kg body weight of tetrabenazine a similar circadian rhythm of sedative effect was observed. This rhythm did not appear to be due to differences of metabolism of tetrabenazine in the tissues, but rather to be closely related to daily fluctuation of serotonin synthesis and release in the brain.
Animals↗
Determination of therapeutic plasma concentrations of tetrabenazine and an active metabolite by high-performance liquid chromatography.
A reversed-phase high-performance liquid chromatographic method for the determination of tetrabenazine and a hydroxy metabolite in plasma is described. Tetrabenazine and the hydroxy metabolite are quantified as their dehydro derivatives using fluorescence detection. This method has been applied to the analysis of plasma samples from patients with Huntington's chorea and has been found to be sensitive, reliable and specific for tetrabenazine and the hydroxy metabolite. The plasma concentrations of tetrabenazine found in patients were lower than could be detected using previously published methods.
Chromatography, High Pressure Liquid↗
Neuroleptic malignant syndrome related to tetrabenazine introduction and haloperidol discontinuation in Huntington's disease.
We describe the second reported case of neuroleptic malignant syndrome (NMS) related to tetrabenazine therapy in Huntington's disease. In the previously reported case, factors capable of potentiating NMS included a high dosage of tetrabenazine exceeding the accepted therapeutic range, and co-medication with the dopamine-synthesis inhibitor alpha-methylparatyrosine, while in the present case abrupt introduction of the drug and discontinuation of concomitant neuroleptics may have contributed to this important adverse reaction. Uneventful recovery occurred in both cases without the need for drugs specifically enhancing dopaminergic transmission, while rechallenge by tetrabenazine with conventional doses and slow upward titration was not followed by recurrence of the NMS. Tetrabenazine has proved to be a safe and frequently useful drug in the long-term treatment of approximately 400 dyskinetic patients. We believe that NMS related to this drug is rare, provided that it is properly administered.
Female↗
Treatment of involuntary movement disorders with tetrabenazine.
Seventeen patients with choreiform, athetoid, or ballistic involuntary movements, or with spasmodic torticollis, were treated with tetrabenazine in doses of 25 to 200 mg daily for periods varying from two weeks to more than six months. Randomized ciné film of the patients' involuntary movements, taken before, during, and after treatment was assessed individually by seven `blind' observers. Eight patients were judged improved; two had Huntington's chorea, two athetosis, two dystonia musculorum deformans, one hemiballismus, and one spasmodic torticollis. Four of the eight improved patients have continued taking the drug for longer than six months. In a second study seven patients with Huntington's chorea were treated for two weeks each with tetrabenazine (50 mg t.d.s.) and with amantadine (100 mg t.d.s.) and the results assessed by the same method. The choreiform movements of six of these patients were strikingly improved with tetrabenazine therapy, but amantadine had no effect. Tetrabenazine is an effective agent for the suppression of choreiform and ballistic involuntary movements. It is only slightly effective in the treatment of athetosis and spasmodic torticollis. Drowsiness, insomnia, and depression were the most conspicuous unwanted effects, and these may limit the clinical usefulness of the drug.
Adolescent↗
Reversal by L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), a L-norepinephrine precursor of reserpine- or tetrabenazine-induced hypothermia.
The effects of L-threo-DOPS on the hypothermia and the decrease of brain norepinephrine (NE) concentration in the mouse pretreated with reserpine or tetrabenazine were studied. Reserpine (5 mg/kg, i.p.) or tetrabenazine (40 mg/kg, i.p.) produced a significant decrease in body temperature. The i.p. injection of L-threo-DOPS (100, 200 and 400 mg/kg) reversed these hypothermia in a dose-dependent manner. These hypothermia were also antagonized by the i.c. injection of NE (5 micrograms/mouse). Both reserpine and tetrabenazine markedly decreased the brain content of NE, and L-threo-DOPS (400 mg/kg, i.p.) recovered it. These results suggested that L-threo-DOPS would reverse the reserpine- or tetrabenazine-induced hypothermia at least in part by the formation of NE in the central nervous system.
Animals↗