Tetrabenazine, an amine-depleting drug, also blocks dopamine receptors in rat brain.

Tetrabenazine (TBZ) is used in the treatment of hyperkinetic movement disorders. Its effect is thought to be mediated by depletion of dopamine (DA) stores. We studied other possible mechanisms of action of this drug.

Lithium interferes with reserpine-induced dopamine depletion.

Long-term lithium treatment attenuated the hypokinetic effect of reserpine in a patient with tardive dyskinesia. In rats, prophylactic lithium administration inhibits reserpine-induced dopamine depletion in the brain. These data indicate that lithium may limit the therapeutic efficacy of reserpine in tardive dyskinesia.

Normal erythrocyte uptake of L-DOPA in Parkinson's, Huntington's, and related diseases.

We measured the kinetic constants for the unidirectional influx of L-DOPA into red blood cells of patients with Parkinson's disease (seven patients), Huntington's disease (seven patients), and other extrapyramidal diseases (11 patients), and in five controls. Influx consisted of two components with low affinity and high exchange capacity. In individual subjects, the L-DOPA concentration giving half-maximal influx (Km) varied between 0.

Treatment of tardive dyskinesia: use of dopamine-depleting agents.

Four different clinical syndromes encompassing the TD spectrum are described: (a) classical TD, which is choreatic in speed of movement and stereotypic in pattern; (b) tardive akathisia; (c) withdrawal emergent syndrome, which presents as true chorea; and (d) tardive dystonia, which presents with dystonic movements and postures. All are made worse or are unmasked by withdrawal of the antipsychotic drugs, and all tend to be reduced in severity by increasing the dosage of the antipsychotic drugs (dopamine-receptor blockers) or utilizing presynaptically acting dopamine-depleting drugs. Treatment depends on discontinuing the causative agent, i.

Electroencephalographic studies of chlorpromazine methiodide and somatostatin-induced barrel rotation in rats.

It has been reported that intraventricular injection of chlorpromazine methiodide (CPZMI), a quaternary ammonium derivative of chlorpromazine, in rats induces abnormal, twisting postures which may serve as an experimental model of the human movement disorder dystonia. We have shown elsewhere that the behavior induced by intraventricular CPMZI is identical to what has been called "barrel rotation," first observed to follow intraventricular injection of somatostatin (SRIF), which consists of twisting about the long axis, with repetitive lateral rolling. The suitability of barrel rotation, induced by CPZMI or SRIF, as an experimental model for dystonia depends on its physiologic basis.

Neurotensin interacts with dopaminergic neurons in rat brain.

Neurotensin (NT) injected intracerebroventricularly in rat increases dopamine (DA) turnover in the corpus striatum and nucleus accumbens. Significant increases in 3,4-dihydroxyphenylacetic acid (DOPAC) levels occurred within 15 minutes after injection with peak levels at 60 minutes. The effect on NT on DOPAC and homovanillic acid (HVA) accumulation was dose-dependent at 3-100 micrograms.

Long-term treatment of tardive dyskinesia with presynaptically acting dopamine-depleting agents.

Fourteen patients with TD, all but one also having tardive akathisia, were evaluated on presynaptically acting dopamine-depleting drugs, reserpine, TBZ, and AMT. Initially, the drugs were evaluated individually, but later AMT was used in combination with reserpine and with TBZ, since their different mechanisms of action allowed for increased potency when they were used in this combination. All but one patient responded to this therapeutic approach.

Normal pressure hydrocephalus and Parkinson's disease.

Three patients with normal pressure hydrocephalus and Parkinson's disease are reported. The recognition of this association is important because these two entities require specific therapeutic approaches. The presence of Parkinson's disease does not preclude an excellent response of the hydrocephalus to a shunting procedure.

High-dosage anticholinergic therapy in dystonia.

Twenty-three children and 52 adults with torsion dystonia of various etiologies and distribution patterns of the involuntary movements were treated in an open-label study with anticholinergic medication. The dosage was build up gradually until there was either benefit or tolerable adverse effect. Trihexyphenidyl was used initially, but beginning in 1979, ethopropazine was utilized in the adult subjects.

Tardive dystonia: late-onset and persistent dystonia caused by antipsychotic drugs.

It is not widely recognized that antipsychotic drugs can cause late-onset and persistent dystonia. This dystonia, which we call tardive dystonia, is to be distinguished from acute dystonic reactions, which are transient, and from classic tardive dyskinesia, which is a choreic disorder that predominantly affects the oral region. We present 42 patients with tardive dystonia.

Effect of 3',4'-dihydroxy-2-methyl-propriophenone (U-0521) on catechol-O-methyltransferase activity and on DOPA accumulation in rat red blood cells and corpus striatum.

The effects of the catechol-O-methyltransferase (COMT) inhibitor 3',4'-dihydroxy-2-methyl-propriophenone (U-0521) were studied in red blood cells (RBC) and corpus striatum in the rat. In vitro U-0521 inhibited RBC COMT activity in a dose-dependent manner with an IC50 of 6 x 10(-6)M. In vivo maximum inhibition (90%) of enzyme activity in RBC was obtained with 250 mg/kg with a peak effect at 5 min and enzyme recovery within 90 min.

Chlorpromazine methiodide-induced barrel rotation: an antimuscarinic effect.

Barrel rotation is a motor response observed in rats in which the animal twists about its long axis and rolls laterally. This response was first described following intracerebroventricular injection of somatostatin. The pharmacologic specificity of the response has been questioned, and its physiologic basis is unknown.

Paroxysmal dystonic choreoathetosis in a patient with familial ataxia.

A patient with paroxysmal dystonic choreoathetosis also had familial ataxia. His brother was similarly affected but had rare paroxysmal episodes. No secondary or symptomatic forms of this type of paroxysmal dyskinesia have ever been reported.

3-O-methyldopa blocks dopa metabolism in rat corpus striatum.

3-O-Methyldopa (OMD) given to rats inhibits striatal uptake and utilization of L-dopa. Thus, the accumulation of L-dopa, dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in OMD-pretreated rats after L-dopa injection is significantly lower compared with control rats. This effect of OMD is dose-dependent.

The effect of chronic L-dopa administration on supersensitive pre- and postsynaptic dopaminergic receptors in rat brain.

Chronic administration of haloperidol induced supersensitivity of the pre- and postsynaptic dopaminergic receptors in rat brain. The response of the presynaptic receptors was determined by an enhanced inhibitory effect of apomorphine on dopamine synthesis after gamma-butyrolactone injection. This change in the receptor function was detected both in the nigrostriatal and mesolimbic pathways.

Catechol-O-methyltransferase inhibition by U-0521 increases striatal utilization of levodopa.

The effects of U-0521, a catechol-O-methyltransferase (COMT) inhibitor, were studied on this enzyme activity and on Dopa metabolism in rat striatum. In vivo maximal inhibition (95%) of COMT activity was obtained at 5 min with enzyme recovery to 64% of basal activity at 120 min. When injected in increasing doses U-0521 (200 mg .