Tardive dyskinesia dopamine receptors

Specific cell injury or cell functional disorder occur with individual drugs or drug classes, e.g. tardive dyskinesia (dopamine receptor blockers), retinal damage (chloroquine, phenothiazines), retroperitoneal fibrosis (methysergide), NSAIDs (nephropathy). Cancer may occur, e.g. with oestrogens (endometrium) and with immunosuppressive (anticancer) drugs. 

Steen VM, Lovlie R, MacEwan T, McCreadie RG. Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. Mol Psychiatry 1997 2(2) 139—145. 

Segman R, Neeman T, Heresco-Levy U, Finkel B, Karagichev L, Schlafman M et al. Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. Mol Psychiatry 1999 4(3) 247-253. 

Rietschel M, Krauss H, Muller DJ, Schulze TG, Knapp M, Marwinski K et al. Dopamine D3 receptor variant and tardive dyskinesia. Eur Arch Psychiatry Clin Neurosci 2000 250(l) 31-35. 

Lerer B, Segman RH, Fangerau H, Daly AK, Basile VS, Aschauer HN et al. Pharmacogenetics of tardive dyskinesia Combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. 

Tardive dyskinesia from antipsychotic agents (dopamine D2 and D3 receptor variants)... 

Tardive dyskinesia is a condition that sometimes results from chronic neuroleptic treatment lasting from months to years (Baldessarini 1996 Stahl et al. 1982). It occurs in 15-25% of treated chronic psychotic patients and is characterized by repetitive, athetoid writhing and stereotyped choreiform movements of the face, eyes, mouth, extremities, and trunk. Discontinuation of neuroleptic medication allows the symptoms to gradually decline, but sometimes they can persist indefinitely. The pathophysiology of tardive dyskinesia is poorly understood, but it appears to involve supersensitive postsynaptic dopamine receptors in the basal ganglia. 

By contrast, studies of the dopamine D -like receptors have found evidence for the association of the receptor with disease (66) these studies have been replicated (41,42). From among the multitude of these studies, only selected examples are reviewed here. For example, evidence both for and against the association of the dopamine D -like receptors with schizophrenia has been reported. Polymorphisms of the dopamine receptor, including the third intracellular loop VNTR, alter dopamine receptor expression. In addition to association with schizophrenia (3,67-70), the dopamine polymorphisms have been associated with the genetic basis of the variable efficacy of antipsychotics such as clozapine (or neuromuscular toxicity—tardive dyskinesia) (69,71,72). Similarly, promoter SNPs have been associated with altered clozapine efficacy (67,68,73). 

Similar associations have been reported between dopamine D receptor variants with Tourette s syndrome, obesity (87-89), and alcohol dependence (90-93), although these findings are still the subject of debate in the literature. From the point of view of pharmacogenetics, the TaqlA polymorphism of the dopamine D receptor is associated with the development of tardive dyskinesia (88,94,95). While the results of these association studies vary (3,12), these data clarify our under-... 

Hori, H., Ohmori, O., Shinkai, T., Kojima, H., and Nakamura, J. (2001) Association between three functional polymorphisms of dopamine D receptor gene and tardive dyskinesia in schizophrenia. Am. J. Med. Genet. 105, llA-11. ... 

Some medication side effects also occur only after prolonged administration and, as such, are products of the adaptive response to the continued administration of the medication. For example, taking a so-called conventional or typical antipsychotic for a long period of time can cause involuntary movements called tardive dyskinesias. These dyskinesias are believed to occur after chronic administration of the antipsychotic has caused changes in the density and/or sensitivity of dopamine receptors in brain regions that coordinate movement. 

Acute dystonias occur immediately after neuroleptization and are manifested by motor impairments, particularly in the head, neck, and shoulder region. After several days to months, a parkinsonian syndrome (pseudoparkinsonism) or akathisia (motor restlessness) may develop. All these disturbances can be treated by administration of antiparkin-son drugs of the anticholinergic type, such as biperiden (i.e., in acute dystonia). As a rule, these disturbances disappear after withdrawal of neuroleptic medication. Tardive dyskinesia may become evident after chronic neuroleptization for several years, particularly when the drug is discontinued. It is due to hypersensitivity of the dopamine receptor system and can be exacerbated by administration of anticholinergics. 

Basile, V.S., Masellis, M., Badri, F, Paterson, A.D., Meltzer, H.Y., Lieberman, J.A., Potkin, S.G., Macciardi, F, and Kennedy, J.L. (1999). Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacology 21 17-27. 

Eichhammer, P., Albus, M., Borrmann-Hassenbach, M., Schoeler, A., Putzhammer, A., Frick, U., Klein, H.E., and Rohrmeier, T. (2000) Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients a generalization of Steen s study on DRD3 and tardive dyskinesia. Am J Med Genet 96 187-91. 

Rietschel, M., Krauss, H., Muller, D.J., Schulze, T.G., Knapp, M., Marwinski, K., Maroldt, A.O., Pans, S., Grunhage, R, Propping, P., Maier, W, Held, T., and Nothen, M.M. (2000) Dopamine D3 receptor variant and tardive dyskinesia. Eur Arch Psychiatry Clin Neurosci 250 31-35. 

Because the tardive syndromes that develop in adults are often irreversible and have no satisfactory treatment, care must be taken to reduce the likelihood of their occurrence. Antipsychotic medication should be prescribed only when necessary and should be withheld periodically to assess the need for continued treatment and to unmask incipient dyskinesia. Thioridazine, a phenothiazine with a piperidine side chain, is an effective antipsychotic agent that seems less likely than most to cause extrapyramidal reactions, perhaps because it has little effect on dopamine receptors in the striatal system. Finally, antimuscarinic drugs should not be prescribed routinely in patients receiving neuroleptics, because the combination may increase the likelihood of dyskinesia. 

FIGURE 11-5. Long-term blockade of dopamine 2 receptors by dopamine 2 antagonists in the nigrostriatal dopamine pathway may cause these receptors to up-regulate. A clinical consequence of this may be the hyperkinetic movement disorder known as tardive dyskinesia. This up regulation may be the consequence of the neuron s futile attempt to overcome drug-induced blockade of its dopamine receptors. 

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