Abstract
The regulator of G-protein signaling (RGS) modulates the functioning of heterotrimeric G protein. RGS9-2 is highly expressed in the striatum and plays a role in modulating dopaminergic receptor-mediated signaling cascades. Previous studies suggested that the RGS9 gene might contribute to the susceptibility to psychotic diseases. Therefore, we investigated the association between the RGS9 gene and two related dopamine psychoses, schizophrenia and methamphetamine use disorders. The subjects comprised 487 patients of schizophrenia and 464 age- and sex-matched healthy controls and 220 patients of methamphetamine use disorder and 289 controls. We genotyped two nonsynonymous polymorphisms, rs12452285 (Leu225Ser) and rs34797451 (His498Arg), of the RGS9 gene. Rs34797451 showed monomorphism in the present Japanese population, but rs12452285 showed polymorphism. There were no significant differences in genotypic or allelic distributions of rs12452285 between patients with schizophrenia and the corresponding control or between patients with methamphetamine use disorder and the corresponding control. We also analyzed the clinical features of methamphetamine use disorder. We found a significant association in allelic distribution with the phenotypes of age at first consumption (p=0.047). The present study suggested that the RGS9 gene is unlikely to play a major role in schizophrenia and methamphetamine dependence liability and/or the development of methamphetamine induced psychosis, at least in a Japanese population.
Highlights
Human and animal studies suggest that the D2-like dopamine receptors play a central role in the development of substance dependence and substance-induced psychotic disorders due to consumption of a diverse class of drugs, e.g., alcohol, nicotine, opioids, cannabinoids, cocaine, and amphetamines, and of endogenous psychosis of schizophrenia [1,2,3]
Based on the above rationale, we investigated the association between the RGS9 gene and methamphetamine use disorder or schizophrenia in a Japanese population
To investigate further the roles of the RGS9 gene in the pathophysiology of psychosis and drug-taking behaviors, we examined the association of the RGS9 gene with several clinical phenotypes of methamphetamine dependence and psychosis, i.e., the age at first consumption of methamphetamine, latency to onset of psychosis after abuse, prognosis of psychosis after therapy, spontaneous relapse even without reconsumption of methamphetamine, and multiple substance abuse status, which show individual variation and may in part be regulated genetically
Summary
Human and animal studies suggest that the D2-like dopamine receptors play a central role in the development of substance dependence and substance-induced psychotic disorders due to consumption of a diverse class of drugs, e.g., alcohol, nicotine, opioids, cannabinoids, cocaine, and amphetamines, and of endogenous psychosis of schizophrenia [1,2,3]. Two animal models of schizophrenia, an amphetamine-sensitized rat and the phencyclidine-treated rat, showed marked dopamine supersensitivity and an increase in the proportion of striatal D2 receptors in the high-affinity state [4,5,6,7]. These findings indicate that the dopamine system is involved in the neural mechanisms of psychiatric disorders, substance use disorders, and schizophrenia. RGS9 knockout mice showed supersensitivity to dopamine and marked elevation in the proportion of D2 high-affinity receptors [13] These findings suggest that the RGS9 gene variation contributes to the sensitivity of D2 receptors in the brain and to development of psychotic disorders
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