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Transcript
Association of the MscI Polymorphism of the Dopamine D3 Receptor Gene with Tardive Dyskinesia in Schizophrenia Basile et al (1999) NEUROPSYCHOPHARMACOLOG Y. 21 (1): 17 The Nature of Schizophrenia • Effects 1% of the population • One of the most important forms of psychiatric illness as it affects people from an early age • Often chronic and usually highly disabling • Associated with a neurodevelopment disorder affecting mainly the cerebral cortex, and occuring in the first few months of prenatal development. • Strong hereditary factor (twin studies) • Combination of Genetic and Environmental factors (complex trait) Clinical features Positive Symptoms Delusions ( often paranoid in nature). Negative Symptoms Hallucinations, usually in the form of voices. Withdrawal from social contacts Thought disorder, comprising wild trains of thought and irrational conclusions, often associated with the feeling that thoughts are inserted or withdrawn by an outside agency. Flattening of emotional responses Causes Large portion of dopamine content of the brain is found in • Pharmacological evidence is the corpus striatum, a part of the generally consistent with dopamine extrapyramidal system over activitymotor hypothesis concerned with the coordination of movement. Dopamine Receptors G-protein-coupled transmembrane receptors D1 family D1 & D5 D2 family D2, D3 & D4 Hypothalmus Corpus striatum MESOCORTICAL PATHWAY Pituitary gland Nucleus accumbens Tuberohypophyseal pathway Mesolimbic/mesocortical Substantia Short neurons pathway nigrarunning from Cellarcuate bodies nucleus occur inof groups in midbrain with the hypothalamus to fibres projecting, via the Nigrostriatal pathway the pituitary gland medial forebrain bundle, 75% dopaminergic to parts of the limbic neurons ie abundant system, and to the in the striatum cortex Fibres run in the medial forebrain bundle. MESOLIMBIC Hippocampus Amygdaloid nucleus Location of the main groups of cell bodies and fibre tracts Drug therapy Although there are no cures, neuroleptic medications aredrugs Neuroleptic medications = antipychotic frequently used to alleviate the typical neuroleptic drugs = psychosis. classical antipychotic drugs pre-1980 drugs which are very similar in their properties. produce motor disturbances collectively termed Extra-pyramidal sideESP can occur within the first few days(EPS) or effects weeks of treatment, or it can appear after Dopamine months and years of antipsychotic Antagonist medication use. Accumulation More than 60% of the people who take of dopamine conventional antipsychotic medications metabolites experience some form of EPS. Dopamine EPS can cause a variety of symptoms, e.g. involuntary movements, tremors and Dopamine D rigidity, body restlessness, muscle 2 synthesis contractions and changes in breathing and Receptor & heart rate. release Tardive dyskinesia (TD). • motor disorderthe characterized by abnormal Although mechanism of TD involuntary movements of the orofacial remains unknown, has musculature, particularly initthe jaw,been lips, and tongue. Choreoathetoid movements postulated that an over activityofof the extremities and/or trunk involvement dopaminergic may occur as well. neurotransmission • in the basal ganglia may play a occurs in predisposed individuals during or crucial role in the manifestation following cessation of prolonged typical of TD. neuroleptic treatment. Group of nuclei lying deep in the white matter of the frontal lobes that organizes motor behavior. Basal Ganglia http://www.driesen.com/basal_ganglia.htm The dopamine overactivity hypothesis for TD dopamine agonists increase TD severity, It has been suggested the neurolepticwhereas, dopamine that antagonists reduce induced increase the in dopamine symptomsreceptor density eventually results in an overactivity of the Corpus Substanti striatum TD results from chronic neuroleptic blockade a nigra tract nigrostriatal dopaminergic of dopamine D2-like receptors in the basal ganglia long-term blockade results in an upregulation of dopamine receptors on postsynaptic membranes 20–30% of patients suffer from neuroleptic-induced TD - implying variable susceptibility susceptibility and/or protection, predisposing only certain patients to TD Evidence form animal models Example Cebus monkey, even after several years of neuroleptic administration, only some develop this disorder Genetic Predisposition Studies family studies localized dopamine D3 mRNA -and protein to the ventral side of the striatum and the ventral putamen in the basal ganglia. human postmortem study illustrated a 45 to 56% increase in Candidate Genes the number of D3 receptors in the basal ganglia of neuroleptic-treated schizophrenics - initially D2 receptor gene was thought to be the most likely candidate. study revealed a twofold increase in the number of D3 receptors in the basal ganglia of long-term hospitalized patients with schizophrenia. dopamine D3 receptors provide an inhibitory effect on locomotor activity. - Dopamine D3 receptor dopamine receptor D3 (DRD3) 3q13.3 This gene encodes the D3 subtype of the dopamine receptor. The D3 subtype inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is expressed in phylogenetically older regions of the brain, suggesting that this receptor plays a role in cognitive and emotional functions. It is a target for drugs which treat schizophrenia and Parkinson disease. Alternative splicing of this gene results in five transcript variants encoding different isoforms. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1814 Predisposing Polymorphism The Ser9Gly polymorphism denotes a serine to glycine amino acid substitution in the N-terminal extracellular domain of the D3 receptor additionally allelic differences in affinity for dopamine have been shown Table 1. Demographic Distributions of the Sample • Patients received at least three periods of treatment in the preceding 5 years at doses equivalent to or greater than 1000 mg/d of chlorpromazine for a period of at least 6 weeks. • None of the patients had ever been treated with atypical neuroleptics. • Patients underwent a washout period of 2–4 weeks which allows the TD phenotype to be expressed more fully if they carry a predisposing factor. • TD severity measured using either the Abnormal Involuntary Movement Scale (AIMS) or a modified Hillside Simpson Dyskinesia scale. • Genotyping Table 1. Demographic Distributions of the Sample Interesting Observations • African Americans in the sample had higher mean AIMS scores than the other patients of different ethnic origins • Significant linear relationship was found between age and TD severity. More specifically, as age increased, patients were more likely to exhibit higher AIMS scores • Statistically significant difference between genotype frequency and ethnic status. African Americans had a significantly higher occurrence of the glycine allele of the Ser9Gly polymorphism than did the Caucasians. • serine to glycine polymorphism in the DRD3 receptor was significantly associated with typical neuroleptic-induced TD. • higher mean AIMS scores in patients homozygous for the glycine allele of the DRD3 gene when compared to heterozygous patients and patients homozygous for the serine allele. Figure 1. Mean corrected AIMS scores for each of the genotypic classes. The variances(s2) for each of the genotypic classes were as follows: (s2 for Ser/Ser genotype was 18.8; s2 for Ser/Gly genotype was 28.4; and s2 for Gly/Gly genotype was 156.1). The Levene Test for homogeneity of variances revealed a significant difference in the variances among the genotypic classes, thus violating one of the assumptions of the ANCOVA model. However, a nonparametric alternative, the Kruskal–Wallis Test, illustrated similar results ( 2 = 13.6644, df = 2, p = .0011, p = 0.0033 Bonferroni corrected) To test for effects of ethnic stratification, we conducted an analysis that separated Caucasians and African Americans. It was found that in both Caucasians (n = 85, F[2,75] = 3.85, p = .026) and African Americans (n = 25, F[1,23] = 8.10, p = .0091), patients homozygous for the glycine allele were more likely to exhibit higher AIMS scores. Figure 2. Ethnically stratified analysis. To address the issue of population stratification, an analysis separating Caucasians from African Americans was conducted. It was found that in both ethnic samples, patients with Gly/Gly genotypes were more likely to exhibit larger AIMS scores, thus reducing the possibility of a false positive attributable to ethnic stratification. Figure 2A illustrates the Caucasian results, and Figure 2B gives the African American results Conclusion • observed a statistically significant association between the glycine variant of DRD3 and TD. • mean AIMS scores for individuals homozygous for the glycine variant were significantly higher than individuals who were either serine/serine homozygotes or serine/glycine heterozygotes. Parallels The substitution of a polar serine residue to a nonpolar glycine residue may alter the tertiary structure of the D3 receptor. The functional differences in dopamine affinity for each of these receptor alleles as expressed in CHO cell lines have been identified There is a higher dopamine affinity for the glycine homozygote cells, as compared to both heterozygote binding and serine/serine homozygotesin these cells. Problems • Factors examined D3 genotype age totalsex neuroleptic phenotypic histories for ethnicity all patients heterogeneity were unavailable D3 genotype was the only factor that significantly contributed to the TD phenotype. environmental influences ? • As the data in the study correlates to the CHO cell study findings perhaps the functional differences may contribute to the TD phenotype, although it is difficult to speculate further on the precise mechanism involved. • It could be suggested that the higher affinity of the glycine allele may be involved in the pathogenesis of TD. Alternatively, this Ser9Gly polymorphism may be in linkage disequilibrium with another site conferring susceptibility to TD. Closing Remarks • The results presented in this study suggest the involvement of the Ser9Gly DRD3 polymorphism as a predisposing risk factor for TD. This genetic information may, in future, assist clinicians in determining patient susceptibility to TD and ultimately may aid in the elucidation of the pathophysiological mechanisms.