Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The D3 dopamine receptor gene is an important candidate gene for schizophrenia, since (because of its almost exclusive expression in the limbic system) it combines the dopamine receptor hypothesis with the limbic system hypothesis of schizophrenia. A BalI restriction fragment length polymorphism of the D3 dopamine receptor gene has been typed in 107 schizophrenic patients and 98 normal controls from Sichuan (China). With regard to alleles or genotypes, no significant differences were obtained between controls from Europe and China, between patients and controls, and between patient subgroups and controls. These results indicate a lack of association between schizophrenia and the D3 dopamine receptor gene in our sample. Our findings are at variance with reports of a significant excess of homozygosity at the D3 dopamine receptor gene in schizophrenic patients from Wales (United Kingdom) and Alsace (France). In conclusion, further studies will be needed with larger samples of patients from Wales and Alsace as well as with samples of different racial groups to prove or disprove the initial positive association between schizophrenia and genotypes of the D3 dopamine receptor gene.
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PMID:No association between schizophrenia and homozygosity at the D3 dopamine receptor gene. 810 92

The D3 dopamine receptor gene is an important candidate gene for schizophrenia, since--because of its almost exclusive expression in the limbic system--it combines the dopamine receptor hypothesis with the limbic system hypothesis of schizophrenia. Pairwise linkage analyses were carried out between the D3 dopamine receptor gene locus (DRD3) and schizophrenia (including major depression among its pleiotropic manifestations). On the basis of these analyses, which assumed a penetrance of 0.71 and a dominant mode of inheritance, we were able to exclude the DRD3 locus with a lod score of -2.50 in four Icelandic pedigrees. The area of exclusion (lod score < -2.00) extended 1.2 centimorgans. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to a mutation in the DRD3 locus. However, these results cannot exclude the possibility that a defect in other genes regulating the expression of the D3 dopamine receptor gene could be involved in the pathogenesis of schizophrenia or that linkage analyses in other families or population-based association studies might show a positive result.
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PMID:No evidence of linkage between schizophrenia and D3 dopamine receptor gene locus in Icelandic pedigrees. 846 57

The neurotransmitter dopamine (DA) plays a central role in the control of motor function, emotional states, and endocrine physiology. The discovery that schizophrenic symptoms can be alleviated by neuroleptic drugs and the finding that these drugs interact at dopamine receptors has indicated involvement of the dopamine system in schizophrenia. The dopamine system has recently been shown to rely on the activation of five distinct subtypes of DA receptors (D1-D5) identified by molecular cloning, and pharmacological studies have specifically implicated the D2-like receptors (D2R, D3R and D4R) in antipsychotic action. In addition, the localization of D3R and D4R expression in the mesolimbic/mesocortical DA pathways is consistent with their proposed involvement in affective behaviour, and suggests that drugs developed specifically for these receptor subtypes might have potent antipsychotic activity with a lower propensity for extrapyramidal, endocrine, and cognitive side-effects.
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PMID:Molecular attributes of dopamine receptors: new potential for antipsychotic drug development. 881 Nov 64

Several studies have reported an association between schizophrenia and homozygosity for the MscI restriction site in exon 1 of the D3 dopamine receptor gene, but other studies have failed to find this association. Recent reports have suggested that the association is most salient in male patients with a family history of schizophrenia. We examined this restriction site in a group of schizophrenic patients (n = 84) and in normal controls (n = 77). Patients were subdivided according to demographic and clinical features, particular attention being paid to movement disorders. No significant difference in allelic or genotypic distribution was seen between the two groups. No association was seen between homozygosity and a positive family history, age at onset of illness, clinical subtype, negative symptom score, or movement disorder scores.
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PMID:Assessment of association of D3 dopamine receptor MscI polymorphism with schizophrenia: analysis of symptom ratings, family history, age at onset, and movement disorders. 888 61

The D3 dopamine receptor is a member of the family of D2-like dopamine receptors. Since the cloning and identification of the D3 receptor in 1990, considerable progress has been made towards understanding the function of this novel site. Although some avenues of investigation have yielded more definitive results than others, studies to date indicate the D3 receptor is localized preferentially in limbic brain areas and affects locomotion and perhaps reinforcement and reward. A subpopulation of the receptors appear to be autoreceptors which modulate dopamine synthesis, release, and neuronal activity. These observations have led to the hypothesis that the D3 receptor may be an appropriate target in the treatment of neuropsychiatric disorders such as schizophrenia and drug addiction. The role of D3 sites in disease, however, remains to be established. Genetic association of D3 receptor polymorphisms with neuropsychiatric disorders have been proposed. Alterations in expression of D3 sites may occur in some diseases. Although the study of this receptor is clearly in the early stages, these findings lay the foundation for future investigation. In this review, dopamine D3 receptor brain localization, cellular signaling mechanisms, and associated behavior will be discussed. The potential role of the D3 site in neuropsychiatric disorders and as a therapeutic target is also addressed.
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PMID:The D3 dopamine receptor in cellular and organismal function. 948 28

The D3 dopamine receptor, a D2-like receptor, is selectively expressed in the ventral striatum, particularly in the shell of nucleus accumbens and islands of Calleja, where it is found in medium sized substance P neurons. The latter co-express the D1 receptor whose interaction with the D3 receptor was studied by treating rats with selective agonists and antagonists. In agreement with the opposite cAMP response, they mediate in cultured neuroblastoma cells, the D1 and D3 receptors exerted opposite influences on c-fos expression in islands of Calleja. However, in agreement with the synergistic influence of cAMP on D3 receptor-mediated mitogenesis on the same cultured cells, D1 and D3 receptor stimulation in vivo synergistically enhanced preprotachykinin mRNA in the shell of accumbens. This indicates that the two receptor subtypes may affect neurons in either synergy or opposition according to the cell or signal generated. Levodopa-induced behavioral sensitization in hemiparkinsonian rats is another example of D1/D3 receptor interaction. Hence repeated levodopa administration induces the ectopic appearance of the D3 receptor in substance P/dynorphin, striatonigral neurons of the dorsal striatum. This induction is secondary to D1 receptor stimulation in neurons of the denervated side and fully accounts for the sensitization, i.e. the increased behavioral responsiveness to levodopa. During brain development, a similar process could operate to control the late appearance of the D3 receptor in D1-receptor bearing neurons of the ventral striatum at a time at which they start to be innervated by dopamine neurons. Finally, taking into account a variety of genetic, developmental, neuroimaging and pharmacological data, we postulate that imbalances between the levels of D1 and D3 receptors in the same neurons could be responsible for schizophrenic disorders.
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PMID:Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence. 965 37

The D3 dopamine receptor has been proposed as a potential target for the treatment of schizophrenia and drug abuse. This study compares the distribution of D3 sites in mouse, rat, guinea pig, and rabbit brain, and dog and human cerebellum using quantitative autoradiography with the putatively selective D3 receptor radioligand [3H]PD 128907. In the mouse, rat, guinea pig, and rabbit, specific [3H]PD 128907 binding was heterogeneously distributed with highest densities observed in the islands of Calleja, followed by the nucleus accumbens. Moderate densities of [3H]PD 128907 binding were observed in the anteroventral and dorsomedial caudate nucleus. Dense [3H]PD 128907-labelled sites were observed in the dorsal thalamus, posterior mamilliary nucleus, and dorsomedial interpeduncular nucleus of the rabbit that were not detected in the other species studied. Moderately dense []PD 128907 binding was also observed in the molecular layer of cerebellar lobule X of the rat but not in the mouse, guinea pig, rabbit, dog, or human. These observations indicate significant inter-species differences in the distribution of D3 receptors.
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PMID:Differential distribution of D3 dopamine receptors in the brains of several mammalian species. 968 76

We determined allele frequencies for polymorphisms at several loci of interest in neuropsychiatry-tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), ciliary neurotrophic factor (CNTF), and the mu opioid receptor (OPRM1)-in samples of individuals from populations in several different parts of the world. Associations with psychiatric illness have been proposed for specific polymorphisms at TPH (suicide-related behaviors and impulsivity), DRD3 (schizophrenia and bipolar affective disorder), SLC6A3 (susceptibility to cocaine-induced paranoia and attention-deficit disorder), CNTF (psychosis), and OPRM1 (substance dependence). APOE alleles are related to risk of Alzheimer disease. We found significant allele frequency variation among populations at all six loci. These results will provide a global framework of normal variation at these loci that might have functional significance or otherwise be related to susceptibility to various disorders or behavioral phenomena. Knowledge of this variation can be important for study design and data interpretation when individuals from various population groups are research subjects and may eventually help lead to a better understanding of behavioral adaptation.
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PMID:Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), mu opioid receptor (OPRM1), and ciliary neurotrophic factor (CNTF)). 979 Jul 47

The D3 receptor is recognized with high affinity by all antipsychotics and selectively expressed in limbic brain areas participating in the central of emotions, motivation and reward. In transfected cultured cells, stimulation of the D3 receptor inhibits cAMP formation and increases mitogenesis, which, in turn, is potentiated by activation of the cAMP cascade. This suggests that both opposite and synergistic interactions occur between the D3 receptor and the cydic AMP pathway, possibly underlying D1/D3 receptor interactions. In fact, D1 and D3 receptors colocalize in the islands of Calleja, in which they interact in opposition on c-fos mRNA expression, and in the shell of nucleus accumbens, in which they interact in synergy on substance P mRNA expression. The expression of the D3 receptor is highly dependent of the dopamine innervation: lesion of ascending dopamine neurons reduces D3 receptor mRNA and binding in the shell of nudeus accumbens, by deprivation of an unknown factor of dopamine neurons, distinct form dopamine and its cotransmitters. In agreement, expression of the D3 receptor in neurons during rat brain development starts after the settlement of dopamine innervation during the first postnatal week. However, in adult rats with a unilateral lesion of dopamine neurons, repeated treatment with levodopa rescues D3 receptor expression in the shell of nudeus accumbens and induces this expression in the dorsal striatum, a region controlling movements in which the D3 receptor is normally absent. This induction seems responsible for the behavioral sensitisation, i.e. increased responsiveness to levodopa. These observations suggest a role of the D3 receptor in the progressive increase in the therapeutic efficacy of levodopa in the initial treatment of Parkinson's disease, and/or its adversive motor and psychopathological effects during long-term treatment. Finally, various pharmacological and genetic data suggest a role of the D3 receptor in drug addiction and schizophrenia, the treatment of which could benefit from selective D3R agents.
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PMID:[Function and therapeutic potential of the dopamine D3 receptor]. 1010 7

Positron emission tomography (PET) has hitherto been used to examine D2 dopamine receptor binding in the striatum, a region with a high density of receptors. Research has been hampered by the lack of suitable radioligands for detection of the low-density D2 dopamine receptor populations in the limbic and cortical dopamine systems that are implicated in the pathophysiology of schizophrenia. [11C]FLB 457 is a new radioligand with the very high affinity of 20 pmol/L (K(i)) for the D2 and D3 dopamine receptor subtypes. This study in eight healthy subjects was designed to evaluate the suitability of [11C]FLB 457 for quantification of extrastriatal D2/D3 dopamine receptors. PET-data were acquired in the three-dimensional mode and the arterial input function was corrected for labeled metabolites. The standard three-compartment model and four derived approaches were applied to calculate and compare the binding potentials. Besides the striatum, conspicuous radioactivity was found in extrastriatal regions such as the thalamus, the anterior cinguli, and the temporal and frontal cortices. The time activity curves could be described by the three compartment model. The different approaches gave similar binding potential values and the rank order between regions was consistent with that found in vitro. The short time of a PET measurement using [11C]FLB 457 (63 minutes) seemed not to be sufficient for reliable determination of the high binding potential in the striatum. These results are of principal importance because they show the potential for PET quantification of minute receptor populations in the human brain.
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PMID:Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain. 1053 41


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