Choline in tardive dyskinesia and Huntington's disease.

Eight men, 4 with tardive dyskinesia and 4 with Huntington's disease, were treated with oral doses of choline chloride up to 20 g daily for three to eight weeks. Prior to treatment, 7 of the 8 patients were tested with a graded dose of 3 mg of physostigmine salicylate, a cholinesterase inhibitor. Six of these 7 patients had a favorable acute response to physostigmine. The same six patients had a favorable response to chronic treatment with choline chloride. Relapses following a switch from active treatment to placebo were delayed, but this could not be explained on the basis of the rate of choline disappearance from plasma. Re-treatment with choline chloride reversed relapse in most instances. Choline chloride may ameliorate these movement disorders by increasing central cholinergic activity, but other mechanisms are possible. Its practical importance as a treatment needs further elucidation.     

Choline analogs as potential tools in developing selective animal models of central cholinergic hypofunction

A chronic deficiency in central cholinergic function has been implicated in a number of neuropsychiatric disease states. This deficiency most probably exists at the presynaptic nerve terminal in the brain, where acetylcholine metabolism is known to occur. To date there are no reports on animals that could simulate the neurochemical conditions which appear to cause these diseases in humans, as a result of a direct manipulation of the central cholinergic system. Several compounds related to choline have however been studied, which might be useful agents for developing such an animal model, through their specific action on the high-affinity choline transport system in the brain. This minireview presents an overview of results obtained with these potentially neurotoxic choline analogs, and provides a critical analysis of current knowledge in this area of investigation.     

Electrophysiological and pharmacological analysis of L-dopa-induced dyskinesia and tardive dyskinesia (author's transl)

Electrophysiological and pharmacological analysis of L-Dopa-induced dyskinesia and tardive dyskinesia (L.DD) due to neuroleptics was performed on 12 patients with Parkinson's disease and on 12 others with psychotic diseases. This analysis included the examination of spinal reflexes, monosynaptic H reflex, polysynaptic cutaneous reflex of the lower limb, muscular responses to passive movement [stretch reflex and shortening reaction (SR)] and the study of the motor response to a dopaminergic stimulus (I.V. injection of Piribedil (PBD), a dopamine agonist). There was no difference in EMG activity between L.DD and TD. Three EMG patterns can be distinguished: anarchic discharge pattern (ADA), tonic grouping discharge pattern (AST) and rhythmic burst pattern (ABR). PBD effects indicate a possible relationship between the EMG patterns and the sensitivity level of the motor dopamine receptors. During L-Dopa dyskinesia and tardive dyskinesia, the same changes in spinal reflexes were observed. Muscle tone tested by muscular responses to passive movement (shortening and myotatic reaction) was normal. Monosynaptic excitability explored by H/M ratio was within the normal range. In contrast, the polysynaptic nociceptive reflex was increased in every case. In Parkinsonian patients with L-Dopa dyskinesia, this pattern of the spinal reflexes was significantly different in comparison to the rigid phase. Intravenous infusion of PBD suppressed tremor and provoked the occurrence of dyskinetic activity in Parkinsonian patients with L-Dopa dyskinesia during the rigid phase. During the dyskinetic phase, as in tardive dyskinesia, PBD increases these phenomena and changes EMG activity in rhythmic pattern. It is suggested that L-Dopa dyskinesia and tardive dyskinesia can be determined by testing EMG activity, spinal reflexes and dopaminergic reactivity. There is evidence to suggest that the various types of involuntary abnormal movement represent a single entity, and that dopamine receptor supersensitivity may be involved.     

Choline chloride in methylphenidate- and apomorphine-induced stereotypy

The effect of choline chloride on apomorphine- and methylphenidate-induced stereotypy in rats was tested. Subcutaneous administration of a single dose of choline chloride significantly reduced apomorphine-induced stereotypy. These results could not be attributed to a nonspecific obtunding effect of choline chloride, and indicate that choline chloride may increase central cholinergic activity. However, neither acute nor chronic oral administration of choline chloride reversed apomorphine- or methylphenidate-induced stereotypy.     

Peripheral-type benzodiazepine-binding sites in platelets of schizophrenics with and without tardive dyskinesia

The density of peripheral-type benzodiazepine (BZ)-binding sites was studied in platelets of 10 medicated chronic schizophrenics with tardive dyskinesia (TD), 10 medicated chronic schizophrenics without TD, 7 drug-free schizophrenics, and 10 normal controls. The age range of the study population was 36-60 years. Age and sex distribution were similar in all 4 groups. The unmedicated schizophrenics did not differ in their maximal binding capacity from the healthy controls. A significant decrease in the density of peripheral-type BZ-binding sites in platelets was observed in treated schizophrenics both with and without TD in comparison to controls and untreated schizophrenics. The reduction in [3H]PK 11195 binding was more pronounced in TD patients (31.3% of controls) than in patients without TD (21.1% of controls). However, this parameter failed to discriminate statistically between TD and non-TD medicated schizophrenics.     

Mitochondrial ultrastructure and density in a primate model of persistent tardive dyskinesia

The use of neuroleptic drugs to treat schizophrenia is almost invariably associated with extrapyramidal movement disorders. One of these disorders, tardive dyskinesia (TD), can persist long after neuroleptic withdrawal suggesting that permanent neurological damage is produced. However, there appears to be no convincing pathology of TD and its pathogenesis remains unknown. Findings that neuroleptics interfere with normal mitochondrial function and produce mitochondrial ultrastructural changes in the basal ganglia of patients and animals suggest that mitochondrial dysfunction plays a role in TD. We have established a model for persistent TD in baboons that appears to involve compromised mitochondrial function. In this study, we evaluated two animals treated for 41 weeks with a derivative of haloperidol and two treated with vehicle only. Treatment was then withdrawn and the animals observed for a further 17-18 weeks. Treated animals developed abnormal orofacial signs that were consistent with TD. These symptoms persisted during the drug-free period. The animals were euthanased, the brains perfused-fixed then post-fixed in 4% paraformaldehyde and the caudate and putamen prepared for electron microscopy. Regardless of whether mitochondria were located in neural soma, excitatory terminals, glia or in non-somal neuropil there was no consistent difference either in size or number between treated and control animals. Thus, even if mitochondria in striatal neurons undergo ultrastructural alterations during neuroleptic therapy, these changes do not persist after drug withdrawal.     

Choline transport specificity in animal cells and tissues

1. Beta carbolines inhibit choline transport in rat brain. 2. The aziridinium ring on the nitrogen of mustard analogs of choline causes irreversible binding to the carrier in rat brain. 3. The uptake system in rat brain is stereoselective, requires a quaternary nitrogen, and prefers analogs with a nitrogen-oxygen distance of about 3.26 A. 4. In mouse brain troxonium derivatives inhibit choline transport. 5. In cuttlefish optic lobes and torpedo electric organ pyrene derivatives potently inhibit choline transport. 6. In guinea pig placenta, the affinity of the choline carrier remains high even when this molecule lacks one or two methyl groups.     

Use of gamma-linolenic acid in the treatment of schizophrenia and tardive dyskinesia.

There is good background evidence to suggest that essential fatty acids and their eicosanoid derivatives may play a role in schizophrenia and in with tardive dyskinesia. Trials involving treatment with essential fatty acids, or eicosanoids or drugs which stimulate eicosanoid synthesis have shown modestly promising results. Particularly favourable outcomes in both schizophrenia and tardive dyskinesia were associated with combined treatment using essential fatty acids and nutritional supplements.     

Effect of Emblica officinalis tannoids on a rat model of tardive dyskinesia

Effect of active tannoid principles of E. officinalis, comprising of emblicanin A (37%), emblicanin B (33%), punigluconin (12%) and pedunculagin (14%), was investigated on a rat model of tardive dyskinesia (TD) induced by once daily administration of haloperidol (1.5 mg/kg, ip) for 28 days. Involuntary orofacial movements (chewing movements, buccal tremors and tongue protusion) were assessed as TD parameters. The tannoid principles of E. officinalis (EOT) were administered concomitantly with haloperidol in the doses of 10, 20 and 50 mg/kg, po, for 28 days. Sodium valproate (200 mg/kg, po), a Gaba-mimetic agent, and vitamin E (400 mg/kg, po), an antioxidant, were used as the standard drugs and administered for the same period. EOT induced a dose-related inhibition of all the three TD parameters assessed, as did vitamin E. The effect of sodium valproate remained statistically insignificant. The results suggest that EOT exerts a prophylactive effect against neuroleptic-induced TD which is likely to be due to its earlier reported antioxidant effects in rat brain areas, including striatum.     

A comparison of two behavioral treatments in decreasing the orofacial movement of tardive dyskinesia

In a study with an elderly female subject, two behavioral treatments were evaluated in terms of their effectiveness in decreasing orofacial movement associated with tardive dyskinesia. Video feedback and discreet-discrete prompting, a self-control procedure using a portable audio signal generator, were compared by means of an alternating treatments experimental design. Video and instructional controls were included in the study. Results indicated that both procedures were effective in decreasing orofacial movement. In addition, during the concluding phase of the study, a prompting card was carried by the subject at all times as a reminder to control mouth movements on an ongoing basis. This concluding phase resulted in generalization of treatment effects to the nontreatment environment. Follow-up sessions indicated maintenance of treatment effects.     

Effect of Withania somnifera glycowithanolides on a rat model of tardive dyskinesia.

Withania somnifera glycowithanolides (WSG) were investigated for their preventive effect on the animal model of tardive dyskinesia (TD), induced by once daily administration of the neuroleptic, haloperidol (1.5 mg/kg, i.p.), for 28 days. Involuntary orofacial movements (chewing movements, tongue protusion and buccal tremors) were assessed as TD parameters. WSG (100 and 200 mg, p.o.), administered concomitantly with haloperidol for 28 days, inhibited the induction of the neuroleptic TD. Haloperidol-induced TD was also attenuated by the antioxidant, vitamin E (400 and 800 mg/kg, p.o.), but remained unaffected by the GABA-mimetic antiepileptic agent, sodium valproate (200 and 400 mg/kg, p.o.), both agents being administered for 28 days like WSG. The results indicate that the reported antioxidant effect of WSG, rather than its GABA-mimetic action, may be responsible for the prevention of haloperidol-induced TD.     

Striatal histone modifications in models of levodopa-induced dyskinesia

Despite recent advances in the treatment of Parkinson disease (PD), levodopa remains the most effective and widely used therapy. A major limitation to the use of levodopa is the development of abnormal involuntary movements, termed levodopa-induced dyskinesia (LDID), following chronic levodopa treatment. Since recent studies have suggested that modifications of chromatin structure may be responsible for many long-lasting changes in brain function, we have examined post-translational modifications of striatal histones in two models of LDID: an acute murine model and a chronic macaque monkey model, both exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the primate model, which closely resembles human LDID, we observed that chronic levodopa and the appearance of LDID was associated with marked deacetylation of histone H4, hyperacetylation and dephosphorylation of histone H3, and enhancement of the phosphorylation of extracellular signal-regulated kinase (ERK). In the murine model of acutely rather than chronically induced LDID, dopamine depletion and levodopa treatment also induced deacetylation of histone H4 and phosphorylation of ERK, but histone H3 exhibited decreased trimethylation and reduced rather than enhanced acetylation. These data demonstrate striking changes in striatal histones associated with the induction of LDID in both animal models. The pattern of changes observed, as well as the behavioral features, differed in the two models. However, both models exhibit marked deacetylation of histone H4, suggesting that inhibitors of H4 deacetylation may be useful in preventing or reversing LDID.     

Hypothesis: A nicotine-dopamine interaction linking smoking with Parkinson's disease and tardive dyskinesia

1. Nicotine, an important pharmacological component of cigarette smoke, is known to have significant effects on central nervous system (CNS) dopaminergic function. Although acute doses of nicotine have been shown to facilitate dopamine release, recent data indicate that chronic nicotine treatment may actually decrease CNS dopamine turnover in the striatum. 2. A number of epidemiological investigations have demonstrated that individuals who are or who have been smokers are less likely to develop idiopathic Parkinson's disease (a disorder involving a deficit in nigrostriatal dopaminergic neurotransmission). In addition, there is preliminary evidence that individuals with tardive dyskinesia (a hyperkinetic movement disorder observed in some cases of chronic neuroleptic treatment and thought by some to be associated with striatal dopamine receptor supersensitivity) are more likely to be smokers. 3. A unitary hypothesis is presented, proposing that smoking in early adult life may decrease CNS catecholamine turnover, thereby protecting against free radical formation from catecholamine oxidation that in turn damages striatal neurons. These individuals are thereby "protected" from the later development of Parkinson's disease. In this hypothetical scheme, individuals who are given neuroleptics and who also are smokers may develop a greater degree of dopamine receptor supersensitivity due to combined receptor blockade by neuroleptics and a decrease in CNS dopamine turnover caused by nicotine, resulting in an increased prevalence of tardive dyskinesia in this group.     

Successful treatment of one case of tardive dyskinesia with electromyographic feedback from the masseter muscle

Evidence from one case with a 15-month follow-up is presented to support the conclusion that electromyographic (EMG) feedback from the masseter was effective in controlling tardive dyskinesia, while a combination of EMG feedback from the frontalis and verbal muscle relaxation training were not.