Genetic association between the dopamine D3 gene polymorphism (Ser9Gly) and schizophrenia in Japanese populations: evidence from a case-control study and meta-analysis

Dysregulation in the dopaminergic system has been implicated in the pathophysiology of schizophrenia (SCZ). Dopamine D3 receptors (DRD3) concentrated in limbic regions of the brain (important for cognitive, emotional and endocrine function) may be particularly relevant to SCZ. A recent meta-analysis with mixed ethnicities reported a marginal significant association between the Ser9Gly homozygosity in the first exon of the DRD3 gene and SCZ. To further evaluate the controversial association between this polymorphism and SCZ, a case–control study and meta-analysis was conducted using the homogeneous Japanese population. In our Japanese case–control sample (246 cases/198 controls), we found an association between the DRD3 Ser9Gly polymorphism and SCZ (genotype: χ² = 9.76, d.f. = 2, p = 0.008; Ser allele versus Gly allele: χ² = 7.96, d.f. = 1, p = 0.0048; OR = 0.65; 95% CI = 0.48–0.88). However in a meta-analysis of nine Japanese case–control studies comprising 2056 subjects the association between DRD3 Ser9Gly polymorphism and SCZ did not persisted. The Mantel–Haenszel pooled OR for SCZ among carriers of the DRD3 Ser9Gly homozygosity (Ser/Ser homozygotes and Gly/Gly homozygotes) of the nine Japanese studies was 1.16 (95% CI 0.97–1.39), pointing to a non-significant effect of the DRD3 Ser9Gly homozygosity as a risk factor for SCZ. Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to SCZ in the Japanese population. Given that the Ser9Gly variant may play a putative role in DRD3 function, further studies on the DRD3 with linked variants are warranted.     

Effect of chronic activation of 5-HT3 receptors on 5-HT3, 5-HT1A and 5-HT2A receptors functional activity and expression of key genes of the brain serotonin system

Among serotonin (5-HT) receptors, the 5-HT₃ receptor is the only ligand-gated ion-channel. Little is known about the interaction between the 5-HT₃ receptor and other 5-HT receptors and influence of 5-HT₃ chronic activation on other 5-HT receptors and the expression of key genes of 5-HT system. Chronic activation of 5-HT₃ receptor with intracerebroventricularly administrated selective agonist 1-(3-chlorophenyl)biguanide hydrochloride (m-CPBG) (14 days, 40 nmol, i.c.v.) produced significant desensitization of 5-HT₃ and 5-HT_1A receptors. The hypothermic responses produced by acute administration of selective agonist of 5-HT₃ receptor (m-CPBG, 40 nmol, i.c.v.) or selective agonist of 5-HT_1A receptor (8-hydroxy-2-(di-n-propylamino)tetralin) (8-OH-DPAT, 1 mg/kg, i.p.) was significantly lower in m-CPBG treated mice compared with the mice of control groups. Chronic m-CPBG administration failed to induce any significant change in the 5-HT_2A receptor functional activity and in the expression of the gene encoding 5-HT_2A receptor. Chronic activation of 5-HT₃ receptor produced no considerable effect on the expression on 5-HT₃, 5-HT_1A, and 5-HT transporter (5-HTT) and tryptophan hydroxylase-2 (TPH-2) genes – the key genes of brain 5-HT system, in the midbrain, frontal cortex and hippocampus. In conclusion, chronic activation of ionotropic 5-HT₃ receptor produced significant desensitization of 5-HT₃ and postsynaptic 5-HT_1A receptors but caused no considerable changes in the expression of key genes of the brain 5-HT system.     

Association of polymorphisms in the BDNF,DRD1 and DRD3 genes with tobacco smoking in schizophrenia

Emerging evidence indicates that the DRD1‐BDNF‐DRD3 cluster plays an important role in nicotine addiction. We have performed an association analysis of 42 SNPs within these genes with cigarette consumption in a group of 341 schizophrenia patients. The ACCG haplotype consisting of four BDNF markers (Val66Met (rs6265), rs11030104, rs2049045 and rs7103411) showed an association with the risk of smoking (p = 0.0002). Both DRD1 markers tested (rs4532 and rs686) and the DRD3 marker (rs1025398) showed association with quantity of tobacco smoked (p = 0.01, 0.005 and 0.002, respectively). Our findings are preliminary; however, they support the involvement of the DRD1, BDNF and DRD3 genes in smoking behaviour.     

慢性应激抑郁模型大鼠脑内5-HT1A和5-HT2A受体的变化

为了在5-羟色胺受体水平研究抑郁症的机制和三环类抗抑郁药物(TCAs)阿米替林的药理学机理,将24只SD雄性大鼠随机均分为三组,即对照组、抑郁组、阿米替林治疗组.应用[3H]8-OH-DPAT、[3H]Ketanserin作为标记配基,采用放射性配体受体结合法,分别测定大鼠海马5-HT1A受体、大脑皮层5-HT2A受体结合.结果显示抑郁大鼠海马 [3H]8-OH-DPAT 特异性结合(18.78±5.62 fmol/mg prot),较正常对照组(26.12±5.52fmol/mg prot )明显下降(P＜0.05).抑郁大鼠大脑皮层[3H]Ketanserin特异性结合(112.58±4.21fmol/mg prot),较正常对照组(86.28±4.24fmol/mg prot)明显增加( P＜0.05).阿米替林治疗3周后,可使抑郁大鼠海马5-HT1A受体与大脑皮层5-HT2A受体结合恢复正常.提示 海马5-HT1A受体结合下降、大脑皮层5-HT2A受体结合增加可能与抑郁症病因有关;海马5-HT1A受体、大脑皮层5-HT2A受体是阿米替林发挥抗抑郁作用的环节.     

Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum

Although serotonin (5-hydroxytryptamine, 5-HT) is known to exert a modulatory action on cerebellar function, our current knowledge of the nature of receptor subtypes mediating serotonergic activity in this part of the brain remains fragmentary. In this study, we report the presence and distribution of 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum using immunofluorescence histochemistry. 5-HT3 immunoreactivity was found in fibers sparsely distributed throughout the cerebellum. Most of them were seen in the cerebellar cortex as fine varicose 5-HT3-positive axonal processes. 5-HT5A immunoreactivity, on the other hand, was observed in neuronal somata of the cerebellar cortex and deep cerebellar nuclei. Based upon cell morphology and the use of cell-specific markers, Purkinje cells, molecular layer interneurons and Golgi cells were found to be 5-HT5A immunopositive. In addition, the use of cell-specific markers allowed us to identify previously reported large 5-HT2A-positive cells in the granular layer as being Golgi cells. Finally, 5-HT7 immunoreactivity was observed only in Purkinje cells. Corroborating previous radioligand-binding, in situ hybridization and immunohistochemical studies, our data relate serotonin receptor subtypes to specific cerebellar cell types and may consequently contribute to the elucidation of serotonergic actions in the cerebellum.     

Muramyl dipeptide (MDP) and 5-HT receptors. Neuroimmunomodulatory effects of MDP are probably not mediated through 5-HT4 or 5-HT1A receptors

A possible interaction of immunomodulator muramyl dipeptide (MDP) with 5-HT₄ and 5-HT_1A receptors was investigated. The activation of 5-HT₄ receptors releases acetylcholine from nerve terminals, thereby contracting the guinea-pig distal ileum. The whole ileum segments were therefore cut and placed into the bath. The preparations were contracted by 5-HT (10 nM-3.2 µM); these contractions were totally abolished in the presence of atropine (1 µM) and significantly attenuated in the presence of SDZ-205,557 (320 nM). The 5-HT evoked contractions remained unchanged in the presence of MDP (5, 50 or 500 nM). MDP (10 nM-3.2 µM) could not directly contract the preparations. In further experiments, the possible interaction of MDP with 5-HT_1A receptors was investigated. The activation of 5-HT_1A receptors inhibits the release of acetylcholine from nerve terminals, thereby decreasing the height of electrically evoked neurogenic twitches of guinea-pig ileum. The whole ileum segments were cut, placed into the bath and stimulated electrically. Selective 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) decreased the height of twitches and this effect was significantly attenuated in the presence of 5-HT antagonist metergoline (1 µM). The effect of 8-OH-DPAT remained unchanged in the presence of MDP (5, 50 or 500 nM). MDP (10 nM-3.2 µM) did not exert any direct effect on the preparations. These results suggest that MDP interacts with neither 5-HT₄ nor 5-HT_1A receptors.     

Elucidating the role of 5-HT(1A) and 5-HT(7) receptors on 8-OH-DPAT-induced behavioral recovery after experimental traumatic brain injury

8-OH-DPAT is a 5-HT(1A/7) receptor agonist that enhances behavioral recovery after traumatic brain injury (TBI). This study is a first attempt to decipher whether the benefits induced by 8-OH-DPAT after TBI are mediated by 5-HT(1A) or 5-HT(7) receptors. A single i.p. injection of 8-OH-DPAT (0.5 mg/kg) alone or co-administered with either the 5-HT(1A) or 5-HT(7) receptor antagonists WAY 100635 (0.5 mg/kg) or SB 269970 HCl (2.0 mg/kg), respectively, or vehicle control (1.0 mL/kg) was given 15 min after cortical impact or sham injury. Function was assessed by established motor and cognitive tests. No difference in motor performance was observed among the TBI groups. Spatial acquisition was enhanced, relative to vehicle controls, by 8-OH-DPAT alone and when co-administered with WAY 100635, but not when combined with SB 269970 HCl. These data imply that 5-HT(1A) receptor antagonism does not abate the 8-OH-DPAT-induced cognitive benefits, but 5-HT(7) receptor antagonism does, which suggests that the 8-OH-DPAT-induced benefits in this single administration paradigm may be mediated more by 5-HT(7) versus 5-HT(1A) receptors. Evaluation of a specific 5-HT(7) receptor agonist will further elucidate the contribution of 5-HT(1A) and 5-HT(7) receptors on behavioral recovery conferred by acute 8-OH-DPAT treatment after TBI.     

5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: Interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms

We recently reported an association between the long repeat allele of the dopamine D4 exon III receptor polymorphism and a human personality dimension, novelty seeking, as measured by the tridimensional personality questionnaire (TPQ), a personality instrument designed by Cloninger to reflect heritable facets of human temperament. The D4 receptor polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT_2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT_2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT_2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT_2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT_2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT_2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort. Am. J. Med. Genet. 74:65–72, 1997. © 1997 Wiley-Liss, Inc.     

Role of 5-HT(1A) and 5-HT(1B) receptors in the antidepressant-like effect of piperine in the forced swim test

Our previous studies have showed that treating mice with piperine significantly decreased the immobility time of the animals in the forced swim test and tail suspension test, which was related to up-regulation of serotonin (5-HT) level in the brain. The purpose of this study is to explore the contribution of 5-HT receptors in the antidepressant-like effect of piperine. The results showed that pre-treating mice with methiothepin (a non-selective 5-HT receptor antagonist, 0.1 mg/kg, intraperitoneally), 4-(2′-methoxy-phenyl)-1-[2′-(n-2″-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (a selective 5-HT_1A receptor antagonist, 1 mg/kg, subcutaneously) or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (a 5-HT_1B receptor antagonist, 2.5 mg/kg, intraperitoneally) was found to abolish the anti-immobility effect of piperine (10 mg/kg, intraperitoneally) in the forced swim test. On the other hand, a sub-effective dose of piperine (1 mg/kg, intraperitoneally) produced a synergistic antidepressant-like effect with (+)-8-hydroxy-2-(di-n-propylamino)tetralin (a 5-HT_1A receptor agonist, 1 mg/kg, intraperitoneally) or anpirtoline (a 5-HT_1B receptor agonist, 0.25 mg/kg, intraperitoneally). Taken together, these results suggest that the antidepressant-like effect of piperine in the mouse forced swim test may be mediated, at least in part, by the activation of 5-HT_1A and 5-HT_1B receptors.     

Effect of antagonists and agonists of 5-HT1 and 5-HT2 serotonin receptors on the predator aggressiveness of wild norway rats

The effect of agonists of serotonin receptors on predator aggressiveness (the “mouse killing” test) is studied on Norway rats. Ipsapirone and eltoprazine are found to have no effect on predator aggressiveness. 1-[3-(Trifluoromethyl)phenyl]piperazine×HCl (TFMPP) considerably reduces aggressiveness. The serotonin precursor 5-hydroxyptryptophan also lowers it, while the antagonist of 5-HT_2A receptors ketanserin abolishes the inhibitory effect of 5-hydroxytryptophan. Presumably, the inhibitory effects of serotonin on predator aggressiveness are realized via the 5-HT_2A and 5-HT_2C brain serotonin receptors. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, No. 5, pp. 687–689, June, 1996     

Receptor-genes cross-talk: effect of chronic 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin treatment on the expression of key genes in brain serotonin system and on behavior

Dysfunction in brain serotonin (5-HT) system has been implicated in the psychopathology of anxiety, depression, drug addiction, and schizophrenia. The 5-HT_1A receptors play a central role in the control of 5-HTergic neurotransmission. There are some scarce data showing cross-regulation between 5-HT receptors. Here, we investigated whether interaction exists between 5-HT_1A receptor and genes encoding key members in brain 5-HT system. Chronic treatment with selective agonist of 5-HT_1A receptor 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) produced considerable decrease in hypothermic response to acute administration of 8-OH-DPAT in CBA/Lac mice indicating desensitization of 5-HT_1A receptors. The decrease in 5-HT_1A gene expression as well as decrease in the expression of gene encoding key enzyme in 5-HT synthesis, tryptophan hydroxylase-2 (TPH-2) in the midbrain, and the expression of the gene encoding 5-HT_2A receptor in the frontal cortex was shown. There were no significant changes in 5-HT transporter mRNA level in the midbrain. Despite considerable decrease in the expression of the genes encoding tryptophan hydroxylase-2, 5-HT_1A and 5-HT_2A receptors, chronic 8-OH-DPAT treatment failed to produce significant changes in 5-HT_1A-linked behavior (intermale aggression, open-field behavior, light-dark box, and pinch-induced catalepsy), suggesting compensatory and adaptive effect of genes suppression. The obtained data on the effect of 8-OH-DPAT-induced desensitization of 5-HT_1A receptors on 5-HT_1A, 5-HT_2A and TPH-2 gene expression demonstrated the role of 5-HT_1A receptor as indirect regulator of gene expression. The results provide the first evidence of receptor-key genes interaction in brain 5-HT system and may have profound implications in understanding the functioning of the brain neurotransmitter systems.     

Effect of chronic treatment with clozapine and haloperidol on 5-HT(2A and 2C) receptor mRNA expression in the rat brain

This study examined regional changes of 5-HT(2A and 2C) receptor mRNA expression in the rat brain after chronic administration of clozapine (1.5 mg/kg/day) and haloperidol (2.0 mg/kg/day) for 36 days. 5-HT(2A and 2C) receptor mRNA expression and distributions were detected by in situ hybridization after rats were sacrificed either 2 or 48 h after the last drug administration to examine both immediate and delayed effects following drug withdrawal. Following 2 h of drug withdrawal, it showed that clozapine administration significantly decreased 5-HT(2A) receptor mRNA, predominantly in the nucleus accumbens (65%), hippocampus (80%), lasteral septal nucleus (61%) and striatum (68%) compared to controls, whilst rebound increases were observed in most of these regions 48 h later. In contrast, no change in 5-HT(2A) receptor mRNA expression was found in the haloperidol treated groups either 2 h or 48 h after drug withdrawal. Clozapine also decreased 5-HT(2C) receptor mRNA expression in the posteromedial cortical amygdala (32%) and substantia nigra (35%) 2 h after the last drug administration, while rebound effects were also observed 48 h later. 5-HT(2C) receptor mRNA was only decreased in the substantia nigra at both 2 h (42%) and 48 h (54%) after the last haloperidol administration. Alterations in serotonin receptor expression in limbic system region such as the nucleus accumbens, hippocampus and lateral septal nucleus as well as the striatum may represent the specific regional targets that mediate the clinical effects of antipsychotics via the serotonin system.     

Allelic association analysis of the dopamine D2, D3, 5-HT2A, and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects

Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA(A)gamma2, and the serotonin transporter (5-HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter - 141DeltaC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter - 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5-HTT gene, and one polymorphism (G3145A) in GABA(A)gamma2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism - 141DeltaC (genotype-wise and allele-wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the - 141DeltaC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype-wise, P = 0.006, allele-wise, P = 0.016) but not for injectors of heroin (genotype-wise, P = 0.81, allele-wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5-HTT, DRD3 and GABA(A)gamma2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter - 141DeltaC polymorphism.     

Effect of enterosorbent noolith on behavior and serotonin (1A) receptors in mouse brain

Protective properties of a new enterosorbent noolith (lithium ions immobilized on mineral matrix) were studied in C57Bl/6J mice predisposed to depression caused by intermale confrontations. The drug was administered daily for 15 days after the 5th confrontation and then the animals were tested in the forced swimming test. The number of specific ³H-8-OH-DPAT binding sites in 3 brain regions was determined. It is shown that noolith produced an antidepressive effect manifested in decreased immobility time in the Porsolt test. Moreover, noolith reduced the number of 1A-serotonin receptors in the frontal cortex and hypothalamus. It is concluded that noolith possesses protective properties.     

The effects of antipsychotic drugs administration on 5-HT1A receptor expression in the limbic system of the rat brain

Increasing evidence suggests that 5-HT1A receptors are involved in the pathophysiology and treatment of schizophrenia. This paper investigated 5-HT1A receptor mRNA expression and binding density in female rats treated with aripiprazole (2.25 mg/kg/day), olanzapine (1.5 mg/kg/day), haloperidol (0.3 mg/kg/day) or vehicle (control) orally three times/day for 1 or 12 weeks. Animals were sacrificed 48 h after the last administration. Aripiprazole significantly increased 5-HT1A receptor binding density by 33% in the CA1 region of the hippocampus and by 21% in the medial posterodorsal nuclei of posterior amygdala (MeP) compared to the control group after 1 week of treatment. Olanzapine significantly decreased 5-HT1A receptor binding density by 17–22% in Layers I–IV of the cingulate cortex after 1 week of treatment. Neither of these antipsychotic drugs affected 5-HT1A receptor binding density after 12 weeks drug treatment. As expected, haloperidol treatment did not have any significant effect on 5-HT1A binding density after 1 or 12 weeks of treatment. 5-HT1A receptor mRNA expression was not altered by antipsychotic treatment in any brain region. The results indicate that aripiprazole and olanzapine have differential effects on 5-HT1A receptor expression, which may contribute to their distinct profiles in improving negative symptoms and cognitive deficits in schizophrenia. Aripiprazole and olanzapine may produce adaptation and desensitization of 5-HT1A receptor expression after long term treatment.     

Association between the GABAA receptor α5 subunit gene locus (GABRA5) and bipolar affective disorder

Genetic factors seem to play an important role in the pathogenesis of affective disorder. The candidate gene strategies are being used, among others, to identify the genes conferring vulnerability to the disease. The genes coding for the receptors of gamma-aminobutyric acid (GABA) have been proposed as candidates for affective disorder, since the GABA neurotransmitter system has been implicated in the pathogenesis of the illness. We examined the possible genetic association between the GABA_A receptor α5 subunit gene locus (GABRA5) on chromosome 15 and affective disorder, in 48 bipolar patients (BP), 40 unipolar patients (UP), and 50 healthy individuals, age- and sex-matched to the patients. All patients and controls were unrelated Greeks. Diagnoses were made after direct interviews according to the DSM-IV and ICD-10 criteria. For the genotyping, a dinucleotide (CA) repeat marker was used. The polymerase chain reaction (PCR) products found were nine alleles with lengths between 272 and 290 base pairs (bp). The distribution of allelic frequencies of the GABRA5 locus differed significantly between BP patients and controls with the 282-bp allele found to be associated with BP affective disorder, while no such difference was observed between the groups of UP patients and controls nor between the two patient groups. The presence or absence of the 282-bp allele in the genotype of BP patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:73–80, 1998. © 1998 Wiley-Liss, Inc.     

Effects of intronic and exonic polymorphisms of paraoxonase 1 (PON1) gene on serum PON1 activity in a Korean population

Paraoxonase 1 (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces lipid peroxide accumulation, and PON1 genetic polymorphisms in the coding region modulate serum PON1 activity. In this study, we investigated the association between 3 polymorphisms of PON1 located in intron 5 (17899insdelTT and 17974CT) and exon 6 (192QR) and serum PON1 activity. The genetic polymorphisms and serum activity of PON1 were analyzed in 153 healthy Koreans by using a direct sequencing assay and spectrophotometric method, respectively. A significant linkage disequilibrium (LD) was observed between all tested single nucleotide polymorphisms, with the strongest LD observed between 17899insdelTT and 192QR (D' = 0.984). The 17899insdelTT, 17974CT and 192QR genetic polymorphisms were associated with significant differences in serum paraoxonase activity. In multiple regression analyses, smoking, triglyceride level, high-density lipoprotein (HDL) level, and the 17899insdelTT and 192QR genetic polymorphisms were significant determinants of serum paraoxonase activity, while age, smoking, triglyceride level, HDL level, and the 192QR genetic polymorphism were significant determinants of serum arylesterase activity. These results suggest that although the 192QR genetic polymorphism in the coding region of PON1 is primarily associated with serum PON1 activity, the intronic polymorphisms are also involved in serum PON1 activity, and this association may be mediated by LD.     

Cloning of serotonin 5-HT(1) receptor subtypes from the chimpanzee, gorilla and Rhesus monkey and their agonist-induced guanosine 5'gamma(35)S triphosphate binding

5-HT₁ receptor subtypes (_1B, _1D and _1F) have been implicated in migraine pathophysiology and their ligands have been examined for pharmacological actions in various experimental animal models. Considerable divergences exist, however, in their primary sequences between experimental animals and human, and additional models closer to human, such as non-human primates seem to be useful for migraine research. Earlier, we cloned the 5-HT_1D, and here 5-HT_1B and 5-HT_1F receptors from the chimpanzee, gorilla and Rhesus monkey, via polymerase chain reactions with their genomic DNAs and primers designed from the corresponding human receptors. Direct sequencing of PCR products showed that the 5-HT_1B receptors from the chimpanzee, gorilla and monkey differ from the human receptor by 0, 1 and 7 residues, respectively while 5-HT_1F receptors differ by 0, 3 and 10 residues, respectively. These divergent residues are mostly conservatively substituted and also largely confined to the N-terminal region and the 3rd intracellular loop, away from transmembrane segments and intracellular loops near membrane which are critical for ligand binding and G protein coupling. The chimpanzee 5-HT_1D, 5-HT_1B and monkey 5-HT_1F receptors, as heterologously expressed in human embryonic kidney 293 cells, showed robust agonist-induced guanosine 5′gamma ³⁵S triphosphate (GTPγ³⁵S) binding through activation of G proteins containing Gγ_i subunits. Moreover, pronounced inhibition of basal GTPγ³⁵S binding by methiothepin (an antagonist), representing constitutively active receptors, was observed with only 5-HT_1D. Overall, ligand binding and GTPγ³⁵S binding profiles for these primate receptors are comparable to those for the human receptors and validate non-human primates as useful models for human migraine research.     

Effect of imipramine on the behavior and cerebral 5-HT1A serotonin receptors in mice genetically predisposed to catalepsy

Acute injection of imipramine to NPK mice hereditary predisposed to pinching catalepsy reduced immobility in the forced swimming test, but had no effect on catalepsy. Chronic treatment with imipramine reduced the severity of catalepsy and functional activity of 5-HT_1A serotonin receptors, but did not modify their expression in the hippocampus. NPK mice can be a convenient model for studies of the effects of antidepressant. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 1, pp. 53–55, January, 2006