Polymorphism of Serotonin 5-HT Receptors as the Basis of the Multifunctionality of Serotonin

This review addresses a question at the junction of neurophysiology and neurogenetics – the multiplicity of types and subtypes of serotonin (5-HT) receptors and their roles in the physiological effects of the brain neurotransmitter serotonin. Particular attention is paid to comparison of the behavioral effects of related subtypes of 5-HT receptors – 5-HT₁ (5-HT_1A and 5-HT_1B) and 5-HT₂ (5-HT_2A and 5-HT_2C) receptors – which are involved in the mechanisms regulating behavior and psychopathology. Published data are presented, along with results obtained at the Laboratory for Behavioral Neurogenics, providing evidence that different types of 5-HT receptors can act in different directions as well as similarly, supplementing each other, in the control of physiological functions and behavior. The roles of 5-HT_1A and 5-HT_1B receptors in regulating aggressive behavior, sexual arousal, drinking behavior, and food consumption are discussed. Experimental results demonstrating reciprocal relationships between 5-HT_2A and 5-HT_2C receptors and interactions between 5-HT_1A and 5-HT₃ receptors are presented. These data provide evidence of a complex system for these interactions not only at the receptor level, but also with the involvement of genes controlling the main elements of the serotonin system. Interaction of receptors evidently underlies neuroplasticity and plays a significant role in compensatory processes and in adaptive mechanisms.     

Effect of chronic activation of 5-HT3 receptors on 5-HT3, 5-HT(1A) and 5-HT(2A) receptors functional activity and expression of key genes of the brain serotonin system

The dopamine D3 receptor gene (DRD3) is considered being one of the candidate genes contributing to the development of tardive dyskinesia (TD). In a recent meta-analysis with mixed ethnicities, only a barely positive association was found between the functional DRD3 Ser9Gly polymorphism and TD in patients with schizophrenia (OR = 1.17; 95% CI: 1.01-1.37; p = 0.041). To further evaluate the controversial association between the polymorphism and TD using only Japanese subjects, we tested the association in a case-control design. We also conducted a meta-analysis including 8 studies with 3 East Asian populations (Japanese, Chinese, and Korean). In our Japanese case-control sample (43 with TD/157 without TD), we found no association between the DRD3 Ser9Gly polymorphism in schizophrenia and TD (genotype: p = 0.92; allele: p = 1.00). Furthermore, no significant difference in the mean AIMS score among the three genotypic groups was observed in our sample. The meta-analysis comprising 1291 East Asian subjects also showed no association between the polymorphism and TD; the Mantel-Haenszel pooled OR for TD among carriers of the DRD3 Ser9Gly of the eight Asian studies was 0.94 (95% CI: 0.78-1.12). Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to TD in East Asian populations. Given that the Ser9Gly variant may play a putative role in the DRD3 function, further studies on the DRD3 are warranted.     

Results endodissection of perforating leg ulcers in the treatment of trophic ulcers of venous etiology

This article analyzes the results of endoscopic dissection of perforating veins in the calf against trophic disorders in 106 patients. All the patients were performed endodissection perforating veins in combination with phlebectomy (remove any large or small subcutaneous Vienna throughout). Catamnesis in these patients was about 8 years.     

Gestational hypothyroxinemia and cognitive function in offspring

The effects of gestational hypothyroxinemia on the neurointellectual prognosis of children in the first year of life living in an industrial city (megalopolis) with mild iodine deficiency were studied in 13 children of mothers with thyroid hormone-corrected gestational hypothyroxinemia in the first trimester and 10 children of mothers with normal levels of free thyroxine by assessing cognitive functions at ages six, nine, and 12 months using the Gnome mental development scale. The results showed that maternal free thyroxine levels at the early stages (5–9 weeks) of pregnancy correlated significantly with the coefficients of mental development among the children at ages 6, 9, and 12 months, i.e., represented one of the factors defining the neuropsychological development of offspring. Early (not later than nine weeks) correction of gestational hypothyroxinemia with levothyroxine at a mean daily dose of at lest 1.2 μg/kg improved the neurointellectual prognosis of the offspring, increasing the coefficient of mental development of children to 92–97 points during the first year of life, i.e., to the level of development of mental functions of children born to mothers with normal thyroxine levels. __________ Translated from Problemy éndokrinologii, Vol. 51, No. 5, pp. 27–31, September–October, 2005.     

A pharmacological evidence of positive association between mouse intermale aggression and brain serotonin metabolism

The neurotransmitter serotonin (5-HT) is involved in the regulation of mouse intermale aggression. Previously, it was shown that intensity of mouse intermale aggression was positively associated with activity of the key enzyme of 5-HT synthesis - tryptophan hydroxylase 2 (TPH2) in mouse brain. The aim of the present study was to investigate the effect of pharmacological activation or inhibition of 5-HT synthesis in the brain on intermale aggression in two mouse strains differing in the TPH2 activity: C57BL/6J (B6, high TPH2 activity, high aggressiveness) and CC57BR/Mv (BR, low TPH2 activity, low aggressiveness). Administration of 5-HT precursor L-tryptophan (300 mg/kg, i.p.) to BR mice significantly increased the 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in the midbrain as well as the number of attacks and their duration in the resident-intruder test. And vice versa, administration of TPH2 inhibitor p-chlorophenylalanine (pCPA) (300 mg/kg, i.p., for 3 consecutive days) to B6 mice dramatically reduced the 5-HT and 5-HIAA contents in brain structures and attenuated the frequency and the duration of aggressive attacks. At the same time, L-tryptophan or pCPA did not influence the percentage of aggressive mice and the attack latency reflecting the threshold of aggressive reaction. This result indicated that the intensity of intermale aggression, but not the threshold of aggressive reaction is positively dependent on 5-HT metabolism in mouse brain.     

Utilization of a two-standard system in real-time PCR for quantification of gene expression in the brain

In this study, we applied for real-time PCR the two-standard system that we had worked out previously for PCR with gel-detection of products. Genomic DNA of a known concentration was used as external standard and mRNA of the DNA-dependent RNA-polymerase II was used as internal standard. It was shown that PCR with gel-detection of products and real-time PCR provide similar results and demonstrate almost identical accuracy and repeatability when the two-standard system is used. With the help of the both methods and using the two-standard system we have confirmed the link between the genetically determined freezing reaction in mice and reduced 5-HT_1A receptor mRNA level in the midbrain. We have also found that the genetically determined freezing reaction in mice is not connected with changes in Tph2 gene expression.