5-HT2A Receptor Gene Promoter Research Articles

Psychological, Neuroimaging, and Biochemical Studies on Functional Association between Impulsive Behavior and the 5‐HT2A Receptor Gene Polymorphism in Humans

It has been suggested that impulsive behavior is caused by dysfunctional serotonergic 5-HT neurotransmission in the central nervous system (CNS). Brain neuroimaging studies have shown that behavioral inhibition is linked to the activation of cortex sites such as the ventral frontal cortex. Positron emission tomography (PET) imaging with [(18)F]altanserin to characterize 5-HT(2A) receptor binding revealed a reduction in 5-HT(2A) binding in the ventral frontal cortex in women who had recovered from impulsive diseases. These clinical, neuroimaging, and pharmacological studies appear to support the hypothesis that functional alteration of neurotransmission due to genetic polymorphisms of the 5-HT receptors may be involved in impulsive behavior modulation. Following evaluation by a self-reporting measure, it was proposed that a polymorphism in the promoter of the 5-HT(2A) receptor gene is the underlying cause of impulsive behavior; however, this hypothesis is not convincing. We examined whether the polymorphism in the 5-HT(2A) receptor gene promoter is involved in impulsive aggression by evaluating a behavioral task (Go/No-go task) in normal volunteers. The polymorphism of the 5-HT(2A) receptor gene promoter in lymphocytes from 71 volunteers was analyzed by using PCR. Impulsivity was defined as the number of commission errors (responding when one should not) recorded during a Go/No-go task; a larger number of commission errors indicate greater difficulty in inhibiting impulsive behavior. The subjects of the A-1438A allele group for the 5-HT(2A) receptor gene made more commission errors under the punishment-reward (PR)condition in a Go/No-go task than those in the G-1438G group. In the present review, we discuss and suggest the possible involvement of the A-1438A polymorphism of the 5HT2A receptor gene promoter in impulsive behavior. This hypothesis was evaluated by using a behavioral task measure that could directly reveal impulsive behavioral traits in humans.

Involvement of a polymorphism in the 5-HT2A receptor gene in impulsive behavior

Impulsive behavior has been suggested to occur due to a dysfunction of serotonergic 5-HT neurotransmission. After evaluation by a self-reporting measure, a polymorphism in the promoter of the 5-HT2A receptor gene has been proposed to underlie the impulsive behavior; however, this hypothesis is not convincing. In this study, we examined whether this 5-HT2A receptor gene polymorphism is involved in impulsive aggression by evaluating a behavioral task (go/no-go task) in normal volunteers. The polymorphism of the 5-HT2A receptor gene promoter was analyzed by polymerase chain reaction using lymphocytes from 71 volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a go/no-go task (a larger number of commission errors indicates greater difficulty in inhibiting the behavior). The subjects in the group with the A-1438A allele of the 5-HT2A receptor gene (A-1438A group) made more commission errors under the punishment-reward condition in a go/no-go task than those in the G-1438G group. These results suggest the possible involvement of the A-1438A polymorphism of the 5-HT2A receptor gene in impulsive behavior; this was evaluated using a behavioral task measure that can directly reveal the traits of human impulsive behavior.

Association of the promoter polymorphism −1438G/A of the 5-HT2A receptor gene with behavioral impulsiveness and serotonin function in women with bulimia nervosa

Separate lines of research suggest that the functional alterations in the serotonin (5-HT) 2A receptor are associated with 5-HT tone, behavioral impulsiveness, and bulimia nervosa (BN). We explored the effect of allelic variations within the 5-HT2A receptor gene promoter polymorphism -1438G/A on trait impulsiveness and serotonin function in women with BN. Participants included women with BN having the A allele (i.e., AA homozygotes and AG heterozygotes, BNA+, N = 21); women with BN but without the A allele (i.e., GG homozygotes, BNGG, N = 12), and normal eater control women having the A allele (NEA+, N = 19) or without the A allele (NEGG; N = 9). The women were assessed for psychopathological tendencies and eating disorder symptoms, and provided blood samples for measurement of serial prolactin responses following oral administration of the post-synaptic partial 5-HT agonist meta-chlorophenylpiperazine (m-CPP). The BNGG group had higher scores than the other groups on self-report measures of non-planning and overall impulsiveness and had blunted prolactin response following m-CPP. The bulimic groups did not differ from each other on current eating symptoms or on frequencies of other Axis I mental disorders. Findings indicate that women with BN who are GG homozygotes on the -1438G/A promoter polymorphism are characterized by increased impulsiveness and lower sensitivity to post-synaptic serotonin activation. These findings implicate the GG genotype in the co-aggregation of impulsive behaviors and alterations of post-synaptic 5-HT functioning in women with BN.

5-HT2A receptor gene promoter polymorphism in relation to abdominal obesity and cortisol.

There is considerable evidence that cortisol secretion is associated with obesity. The regulation of the 5-hydroxytryptamine receptor 2A (5-HT2A) gene might play an essential role because it is involved in the control of cortisol secretion. Therefore, we examined the potential impact of the 5-HT2A -1438G/A promoter polymorphism on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol, in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using polymerase chain reaction amplification of the promoter region of the gene for 5-HT2A followed by digestion of the reaction product with the restriction enzyme MspI. The frequencies were 0.39 for allele -1438A and 0.61 for allele -1438G. Homozygotes for the -1438G allele had, in comparison with -1438A/A subjects, higher body mass index, waist-to-hip ratio, and abdominal sagittal diameter. Moreover, cortisol escape from 0.25-mg dexamethasone suppression was found in subjects with the -1438A/G genotype. Serum leptin, fasting insulin, and glucose, as well as serum lipids, were not different across the -1438G/A genotype groups. From these results, we suggest the possibility that an abnormal production rate of the 5-HT2A gene product might lead to the development of abdominal obesity. The pathophysiology could involve stress factors that destabilize the serotonin-hypothalamic-pituitary-adrenal system in those with genetic vulnerability in the serotonin receptor gene.

5-HT2A receptor gene promoter polymorphism –1438A/G and bipolar disorder

Genetic factors, such as the genes involved in the serotonin pathway, probably play an important role in the pathogenesis of bipolar disorder, and serotonin type 2A (5-HT2A) receptor gene promoter polymorphism -1438A/G has been reported. This study investigated the association between -1438A/G polymorphism of 5-HT2A receptor gene promoter and bipolar disorder in a Korean population. Using the polymerase chain reaction, -1438A/G polymorphism typed in 142 patients with bipolar disorder and in 148 normal control subjects. Differences in genotype distributions and allele frequencies of -1438A/G between patients with bipolar disorder and normal control subjects were tested for significance using the chi-squared test. There were significant differences in genotype distributions [chi2 = 9.697, degrees of freedom (df) = 2, P = 0.008] and allele frequencies (chi2 = 7.284, df = 1, P = 0.007) of -1438A/G between patients with bipolar disorder and normal control subjects. Although further studies are necessary, these results in a Korean population suggest that -1438A/G polymorphism of 5-HT2A receptor gene promoter may be causally related to the development of bipolar disorder.

Association between 5HT2A receptor gene promoter region polymorphism and eating disorders in Japanese patients

Background: Evidence from family and twin studies suggests a genetic contribution to the etiology of eating disorders (EDs). Recently, researchers have reported genetic associations between the MspI polymorphism (-1438A/G) of the promoter region of the 5HT2A receptor gene and EDs; however, reports of evidence against these findings make the association controversial. Methods: The authors examined the prevalence of the -1438A/G polymorphism of the 5HT2A receptor gene among 182 Japanese patients with EDs and 374 normal control subjects. Interactions of the association of this polymorphism with subtypes of anorexia nervosa (AN), bulimia nervosa (BN), and various clinical characteristics were also assessed. Results: In contrast to previous studies reporting elevated A allele frequencies in patients with AN, the G allele had a significantly higher frequency in patients with BN but not in patients with AN, than in control subjects. Examination of the interactions revealed that the presence of the binge eating and/or purging behavior and comorbid borderline personality disorder (BPD) tended to be associated with increased frequency of the G allele. Conclusions: Though preliminary, these results can be interpreted as suggesting that the G allele of the 5HT2A receptor gene -1438A/G polymorphism may be associated with pathological features that EDs and BPD have in common, especially disinhibition in eating behavior and personality trait.

No Correlation between A(–1438)G Polymorphism in 5-HT2A Receptor Gene Promoter and the Density of Frontal Cortical 5-HT2A Receptors in Schizophrenia

The A(–1438)G promoter polymorphism of the 5-hydroxytryptamine 2a receptor (5-HT2AR) gene and its influence on the cortical density of 5-HT2AR was studied using brain tissue donated at autopsy from 58 schizophrenic and 64 non-schizophrenic subjects. A linkage between genotypes for the A(–1438)G and a T102C polymorphic site identified in a previous study was observed. Our data suggest no association of the A(–1438)G polymorphism with schizophrenia and no effect of the promoter genotype upon 5-HT2AR densities in either the schizophrenic or non-schizophrenic groups.

Association of a polymorphism of the 5HT2A receptor gene promoter region with alcohol dependence.

Approximately 10% of Japanese alcoholics develop their disease despite having an inactive form of aldehyde dehydrogenase-2 (ALDH2), known as a genetic deterrent of heavy drinking due to adverse reactions after drinking. Such alcoholics are considered to be advantageous in genetic research because they should show reduced heterogeneity and possess genetic factors conferring susceptibility to alcohol dependence. Examination of the -1438 A/G polymorphism of the serotonin 2A (5HT2A) receptor gene in 225 Japanese alcoholics with inactive ALDH2 revealed the presence of significantly more of the G allele than was found in 361 control subjects. The frequency of the G allele in 282 alcoholics with active ALDH2 fell between the G allele frequencies of controls and subjects with inactive ALDH2. These data suggest that although the effect is relatively small, genetic variability in the 5HT2A receptor is involved in the development of alcohol dependence.

Characterization of the human 5-HT2A receptor gene promoter

The regulation of 5-HT2A receptor (5-HT2AR) expression has been implicated in a variety of pathological processes and has been shown to be extremely complicated and controversial. In order to understand the mechanisms of regulation of this receptor, it is important to characterize its promoter. In this report, the 5' end of the human 5-HT2AR gene was cloned and characterized. Anchored PCR mapped multiple transcription initiation sites at nucleotides -1157, -1137, -1127, and -496. Transfection of chimeric growth hormone plasmids containing various DNA fragments into 5-HT2AR-positive human cell lines (SHSY-5Y, neuroblastoma; HeLa, cervix carcinoma) showed that the 0.74 kb HaeIII/PvuII fragment, which encompasses the initiation sites between -1157 and -1127 and 5' of the downstream initiation site (at -496), exhibited significant promoter activity. This promoter activity was not affected by the sequence upstream of the 0.74 kb fragment. The sequence downstream (the 0.45 kb PvuII/SmaI fragment) strongly repressed this promoter activity, suggesting the presence of a silencer. Sequence analysis combined with gel retardation and Dnase 1 footprinting assay identified multiple cis and trans elements for this fragment, including Sp1, PEA3, cyclic AMP response element (CRE)-like sequence, and E-boxes. Two novel transcription factors have been detected by gel retardation and DNase 1 footprinting assay; one of them may be specific for human. The transcription factors and promoter activities were low in the negative cell line NCI-H460 (human lung large cell carcinoma). Interestingly, the 0.39 kb fragment, isolated from the 3' end of the 0.74 kb fragment, exhibited the highest promoter activity. The possibility that this 0.39 kb fragment may be an alternative promoter is discussed. These new data are essential for further study of the regulation of 5-HT2AR gene expression.