A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes

Abstract

Dopamine is a major neurotransmitter in the central nervous system, and its receptors are associated with a number of neuropathological disorders such as Parkinson's disease and schizophrenia. Although the precise pathophysiology of schizophrenia remains unknown, the dopaminergic hypothesis of the illness assumes that the illness results from excessive activity at dopamine synapses in the brain. Because, at present, the diagnosis of schizophrenia relies on descriptive behavioral and symptomatic information, a peripheral measurable marker may enable a simpler, more rapid, and more accurate diagnosis and monitoring. In recent years, human peripheral blood lymphocytes have been found to express several dopamine receptors (D3, D4, and D5) by using molecular biology techniques and binding assays. It has been suggested that these dopamine receptors found on lymphocytes may reflect receptors found in the brain. Here we demonstrate a correlation between the D3 dopamine receptor on lymphocytes and schizophrenia and show a significant elevation of at least 2-fold in the mRNA level of the D3, but not of the D4, dopamine receptor in schizophrenic patients. This increase is not affected by different antipsychotic drug treatments (typical or atypical). Moreover, nonmedicated patients exhibit the same pattern, indicating that this change is not a result of medical treatment. We propose the D 3 receptor mRNA on blood lymphocytes as a marker for identification and followup of schizophrenia. S chizophrenia is a neuropsychiatric disorder afflicting about one percent of the population. Although its exact pathogenesis is still not known precisely, a common belief is that excessive activity at dopaminergic synapses in the brain plays a prominent role (1). To date, a definitive diagnosis of schizophrenia requires a 6-month duration of symptomatology and relies on heterogeneous symptoms. Because there is neither an effective biological marker for identifying schizophrenia (2, 3), nor an accurate and rapid diagnosis to ensure more optimal management at an early stage in the illness (4), there remains a vital need for a convenient assay for diagnosis and followup of schizophrenia.Most of the drugs used to treat schizophrenia act to control symptoms by neuroreceptor antagonism. Moreover, the dopaminergic basis of schizophrenia is strongly supported by the close correlation between clinical efficacy of antipsychotic medications and their potency to antagonize the binding of dopamine to its receptors (5).Dopamine receptors are divided into two subclasses, D1 and D2. The D1 subclass contains the D 1 and D 5 receptor subtypes, and the D2 subclass contains the D 2 , D 3 , and D 4 subtypes (6). The dopamine hypothesis of schizophrenia specifically relates to the D2 subclass. Notably, most drugs effective in treating schizophrenia exhibit D2 receptor antagonistic activity, and administration of a selective D1-like antagonist has been reported to result in the worsening of symptoms (7). The D 3 receptor, one among the three in the D2 subclass, is...

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