Psychedelic-inspired drug discovery using an engineered biosensor.

Ligands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated with distinct functional and behavioral consequences. For example, the 5-hydroxytryptamine 2A receptor (5-HT2AR) is the target of classic hallucinogens, atypical antipsychotics, and psychoplastogens. However, currently available methods are inadequate for directly assessing 5-HT2AR conformation both in vitro and in vivo. Here, we developed psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-HT2AR ligands. We further used psychLight to identify a non-hallucinogenic psychedelic analog, which produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.

Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo.

Head-twitch behavior (HTR) is the behavioral signature of psychedelic drugs upon stimulation of the serotonin 5-HT2A receptor (5-HT2AR) in rodents. Following the previous report of a semi-automated detection of HTR based on the dynamics of mouse's head movement, here we present a system for the identification of individual HTR events in a fully automated fashion. The validity of this fully automated HTR detection system was tested with the psychedelic drug DOI in 5-HT2AR-KO mice, and via evaluation of potential sources of false-positive and false-negative HTR events. The increased throughput in data processing achieved via automation afforded the possibility of conducting otherwise time consuming HTR time-course studies. To further assess the versatility of our system, we also explored the pharmacological interactions between 5-HT2AR and the metabotropic glutamate receptor 2 (mGluR2). Our data demonstrate the potentiation effect of the mGluR2/3 antagonist LY341495 on DOI-induced HTR, as well as the HTR-blocking effect of the mGluR2/3 agonist and antipsychotic drug in development LY404039. This fully automated system can contribute to speed up our understanding of 5-HT2AR's pharmacology and its characteristic behavioral outputs in rodents.

Regulatory effects of Ningdong granule on dopaminergic and serotonergic neurotransmission in a rat model of Tourette syndrome assessed by PET.

Dysfunctions in dopamine (DA) and serotonin (5­HT) metabolism have been widely implicated in Tourette syndrome (TS); however, the exact nature of these dysfunctions remains unclear. The objective of the present study was to investigate the variation in DA and 5­HT metabolism in a rat model of TS, and to evaluate the therapeutic effect of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation used specifically for the treatment of TS. Rats were treated with 3,3'­iminodipropionitrile for 7 days to induce the model of TS, and were then intragastrically administered NDG each day. After 8 weeks of treatment, micro­positron emission tomography was used to measure the binding of DA D2 receptors (D2Rs), DA transporters (DATs), 5­HT2A receptors (5­HT2ARs) and 5­HT transporters (SERTs) in brain regions of interest. The results indicated that NDG could significantly reduce the typical characteristics of TS in the rat model. Decreased D2R binding and increased DAT binding were detected in the striatum compared with the binding activities in untreated rats. The density of 5­HT2AR was also significantly increased in the striatum following NDG treatment; however, SERT levels were decreased in certain brain regions, including the striatum, cortex, nucleus accumbens and amygdala. Taken together, the current results demonstrated that NDG may be effective in treating patients with TS.

Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice.

A recent report suggested that brain-derived serotonin (5-HT) is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1) receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph) inhibitor p-chlorophenylalanine (PCPA) for 3 days and mice without PCPA treatment. Treatment with PCPA did not affect hypothalamic 5-HT2A receptor expression. Despite the anorexic effect of liraglutide disappearing after the first day of treatment, the body weight loss induced by liraglutide persisted for 4 days in mice treated with or without PCPA. Intraperitoneal administration of liraglutide significantly decreased the gene expression of hypothalamic 5-HT2A receptors 1 h after injection. Moreover, the acute anorexic effects of liraglutide were blunted in mice treated with the high-affinity 5-HT2A agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide 14 h or 24 h before liraglutide injection. These findings suggest that liraglutide reduces appetite and body weight independently of 5-HT synthesis in mice, whereas GLP-1 receptor activation downregulates the gene expression of hypothalamic 5-HT2A receptors.

The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors.

5-MeO-DMT is a natural hallucinogen acting as serotonin 5-HT1A/5-HT2A receptor agonist. Its ability to evoke hallucinations could be used to study the neurobiology of psychotic symptoms and to identify new treatment targets. Moreover, recent studies revealed the therapeutic potential of serotonin hallucinogens in treating mood and anxiety disorders. Our previous results in anesthetized animals show that 5-MeO-DMT alters cortical activity via 5-HT1A and 5-HT2A receptors. Here, we examined 5-MeO-DMT effects on oscillatory activity in prefrontal (PFC) and visual (V1) cortices, and in mediodorsal thalamus (MD) of freely-moving wild-type (WT) and 5-HT2A-R knockout (KO2A) mice. We performed local field potential multi-recordings evaluating the power at different frequency bands and coherence between areas. We also examined the prevention of 5-MeO-DMT effects by the 5-HT1A-R antagonist WAY-100635. 5-MeO-DMT affected oscillatory activity more in cortical than in thalamic areas. More marked effects were observed in delta power in V1 of KO2A mice. 5-MeO-DMT increased beta band coherence between all examined areas. In KO2A mice, WAY100635 prevented most of 5-MeO-DMT effects on oscillatory activity. The present results indicate that hallucinatory activity of 5-MeO-DMT is likely mediated by simultaneous alteration of prefrontal and visual activities. The prevention of these effects by WAY-100635 in KO2A mice supports the potential usefulness of 5-HT1A receptor antagonists to treat visual hallucinations. 5-MeO-DMT effects on PFC theta activity and cortico-thalamic coherence may be related to its antidepressant activity. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

5-HT2A/5-HT2C Receptor Pharmacology and Intrinsic Clearance of N-Benzylphenethylamines Modified at the Primary Site of Metabolism.

The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT2A/5-HT2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT2 receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism.

Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning.

Higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT)2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions.

Contribution of serotonin to cardiac remodeling associated with hypertensive diastolic ventricular dysfunction in rats.

OBJECTIVE: Left-ventricular hypertrophy and interstitial fibrosis are the main pathophysiological factors of heart failure with preserved ejection fraction. Blockade of the serotonin 5-HT2B receptor (5-HT2BR) has been shown to reduce cardiac hypertrophy, oxidative stress, and extracellular cell matrix activation. In this study, we evaluated the effects of the 5-HT2BR blockade, on hemodynamic and cardiac remodeling, in spontaneously hypertensive rats (SHRs) that display a diastolic dysfunction with preserved ejection fraction. METHOD: Thirty-seven-week-old SHRs were randomized in four groups receiving either saline, the selective 5-HT2BR antagonist RS-127445 (1 mg/kg per day), a calcium channel blocker nicardipine (6 mg/kg per day), or RS-127445 + nicardipine. During the 14 weeks of treatment period, cardiac function and blood pressure were monitored by echocardiography and tail-cuff. Finally, electrocardiograms and invasive hemodynamics were obtained before blood collection. Heart was analyzed for morphology and mRNA expression. A complementary study evaluated the cardiac and vascular effects of serotonin on wild-type and mice knockout for the 5-HT2BR (Htr2B) and/or the 5-HT2AR (Htr2A). RESULTS: Despite the left ventricular 5-HT2BR overexpression, 5-HT2BR blockade by RS-127445 did not affect left ventricular hypertrophy and fibrosis in SHRs. This antagonist did not improve diastolic dysfunction, neither alone nor in combination with nicardipine, although it induced plasma brain natriuretic peptide decrease. Moreover, RS-127445 amplified subendocardial fibrosis and favored left ventricular dilatation. Finally, a subendocardial left ventricular fibrosis was induced by chronic serotonin in wild-type mice, which was increased in Htr2B animals, but prevented in Htr2A and Htr2A/2B mice, and could be explained by a contribution of the endothelial 5-HT2BRs to coronary vasodilatation. CONCLUSION: This work is the first to identify a cardioprotective function of the 5-HT2BR in an integrated model of diastolic dysfunction with preserved ejection fraction.

Association study of gene polymorphisms and depression with abnormal humor in traditional Uighur medicine.

BACKGROUND: According to the humor theory of Traditional Uighur Medicine (TUM), a same disease is classified into different abnormal humor types and corresponding methods are applied to treat the diseases according to the type of abnormal humor characteristics. To date the biological foundation of classification of diseases by humor theory has been little studied and the mechanism of action is still unclear. In the present study, we aimed to investigate the association between some related gene polymorphisms and depression with abnormal humor in TUM. METHODS: 201 cases of depression patients in a Uighur population were divided into two groups as: 107 cases of depression patients with abnormal black bile (ABB), 94 cases of depression patients with none abnormal black bile (nABB), and 50 healthy people were served as control group. Venous blood was used to isolate DNA samples, and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used for genotyping of single nucleotide polymorphisms (SNPs). Polymorphisms in the serotonin 2A (5-HT2A) receptor gene, brain derived neurotrophic factor (BDNF), serotonin 1A (5-HT1A) receptor gene were investigated in each groups, respectively. RESULTS: The 5-HT2A A-1438G, 5-HT2A T102C, BDNF Val66Met, and 5-HT1A C-1019G gene polymorphisms showed significant association with ABB. However, no difference between nABB and controls was found for those genotype distribution and allele frequency. Moreover, the T102C and A1438G SNPs in the 5-HT2A receptor gene polymorphisms were in linkage disequilibrium. In addition, the OR associated with the combination of Val66Met-Val/Val genotype plus the presence of -1019C allele was 8.393 for ABB compared with controls (OR 8.393; 95% CI 1.807 ~ 38.991; P = 0.003). Moreover, the OR associated with the presence of -Met plus -1019C alleles was 12.194 for ABB compared with controls (OR 12.194; 95% CI 1.433 ~ 103.776; P = 0.005). The OR associated with the presence of -1438C/C plus Val/Val genotypes was 7.738 for ABB compared with controls (OR 7.738; 95% CI 1.566 ~ 38.241; P = 0.005). CONCLUSION: It was concluded that there were significant relationship between the gene polymorphisms and classification of depression with abnormal humor in TUM. The 5-HT2A A-1438G, 5-HT2A T102C, BDNF Val66Met, and 5-HT1A C-1019G gene polymorphisms might predict the incidence of depression with ABB.

Systems pharmacology identifies drug targets for Stargardt disease-associated retinal degeneration.

A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.

Metabotropic glutamate receptor 2 and corticotrophin-releasing factor receptor-1 gene expression is differently regulated by BDNF in rat primary cortical neurons.

Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and plasticity. Incorporation of matured receptor proteins is an integral part of synapse formation. However, whether BDNF increases synthesis and integration of receptors in functional synapses directly is unclear. We are particularly interested in the regulation of the 5-hydroxytryptamine receptor 2A (5-HT(2A)R). This receptor form a functional complex with the metabotropic glutamate receptor 2 (mGluR2) and is recruited to the cell membrane by the corticotrophin-releasing factor receptor 1 (CRF-R1). The effect of BDNF on gene expression for all these receptors, as well as a number of immediate-early genes, was pharmacologically characterized in primary neurons from rat frontal cortex. BDNF increased CRF-R1 mRNA levels up to fivefold, whereas mGluR2 mRNA levels were proportionally downregulated. No effect on 5-HT(2A)R mRNA was seen. The effects were dose-dependent with half-maximal effective concentrations (EC(50)) around 1 ng/ml. After 24 h of incubation with BDNF, CRF-R1 mRNA levels had returned to baseline levels, whereas mGluR2 mRNA levels remained low. A significant reduction of all three receptor transcripts was observed after neuronal depolarization produced by high potassium. This study emphasizes the role of BDNF as an important regulator of receptor compositions in the synapse and provides further evidence that BDNF directly regulates important drug targets involved in cognition and mood.

Repressive epigenetic changes at the mGlu2 promoter in frontal cortex of 5-HT2A knockout mice.

Serotonin 5-HT(2A) and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders, such as schizophrenia, depression, and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT(2A)-KO mice. Disruption of 5-HT(2A) receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter, epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor in which promoter activity was positively regulated by the 5-HT(2A) receptor agonist 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide, binds less to the mGlu2 promoter in frontal cortex of 5-HT(2A)-KO, compared with wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of FLAG-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT(2A) receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex.

Sexually dimorphic serotonergic dysfunction in a mouse model of Huntington's disease and depression.

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A) receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A) receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.

[Effects of electroacupuncture at "Futu" (LI 18), etc. on expression of spinal 5-HT 1 AR mRNA, 5-HT 2 AR mRNA and protein in rats with neck incision pain].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at bilateral "Futu" (LI 18), etc. on the expression of 5-HT 1 A receptor (R) mRNA, 5-HT2 AR mRNA and protein in the spinal cord of rats with neck incision pain, so as to explore its underlying mechanism in relieving incision pain. METHODS: A total of 48 Wistar rats were randomly divided into control, model (incision pain), Futu (LI 18), Hegu (LI 4)-Neiguan (PC 6, LI 4-PC 6), Zusanli (ST 36)-Yanglingquan (GB 34) cervical cord (ST 36-GB 34 C) and lumbar cord (ST 36-GB 34 L) groups. A 1.5 cm longitudinal incision was made in the middle of the neck under Isoflurane inhalation anesthesia. Pain threshold (PT) was measured using radiant heat. EA (1-2 mA, 2 Hz/15 Hz) was applied to bilateral LI 18, LI 4-PC 6, ST 36-GB 34 for 30 min. The expression of 5-HT 1 AR mRNA, 5-HT 2 AR mRNA and protein in the cervical spinal cord (C1-C4) tissue, and 5-HT 1 AR mRNA and 5-HT 2 AR mRNA in the lumbar cord (L1- L3) were detected with Real-time PCR and Western blot analysis, respectively. RESULTS: After the operation, the thermal PT was shortened obviously In comparison with pre-operation (P < 0.05). Compared with post-operation, the PT values were increased markedly in the LI 18 group and LI 4-PC 6 group (P < 0.05), rather than in the ST 36-GB 34 group (P > 0.05). The expression levels of 5-HT 1 AR mRNA, 5-HT 2 AR mRNA and 5-HT 2 AR protein in the cervical cord of the model group were increased significantly compared with those of the control group (P < 0.05). In comparison with the model group, the expression level of 5-HT 1 AR mRNA was down-regulated considerably in the LI 18 and LI 4-PC 6 groups (P < 0.05), and those of spinal 5-HT 2 AR mRNA and protein were up-regulated significantly in the LI 18 and LI 4-PC 6 groups (P < 0.05). No significant changes were found in the expression of 5-HT 1 AR mRNA and 5-HT 2 AR mRNA in the ST 36-GB 34 C group in comparison with the model group (P > 0.05). The expression levels of 5-HT 1 AR mRNA and 5-HT 2 AR mRNA in the ST 36-GB 34 L group were significantly lower than those of the ST 36-GB 34 C group (P < 0.05). CONCLUSION: EA of LI 18 and LI 4-PC 6 can significantly suppress pain reaction of neck incision in the rat, which is closely associated with its effects in down-regulating the expression of 5-HT 1 AR mRNA and in up-regulating 5-HT 2 AR mRNA and 5-HT 2 AR protein in the cervical spinal cord.

Alterations in hippocampal serotonergic and INSR function in streptozotocin induced diabetic rats exposed to stress: neuroprotective role of pyridoxine and Aegle marmelose.

Diabetes and stress stimulate hippocampal 5-HT synthesis, metabolism and release. The present study was carried out to find the effects of insulin, Aegle marmelose alone and in combination with pyridoxine on the hippocampal 5-HT, 5-HT(2A) receptor subtype, gene expression studies on 5-HT(2A), 5-HTT, INSR, immunohistochemical studies and elevated plus maze in streptozotocin induced diabetic rats. 5-HT content showed a significant decrease (p < 0.001) and a significant increase (p < 0.001) in 5-HIAA in hippocampus of diabetic rats compared to control. 5-HT receptor binding parameters B(max) and Kd showed a significant decrease (p < 0.001) whereas 5-HT(2A) receptor binding parameters Bmax showed a significant decrease (p < 0.001) with a significant increase (p < 0.05) in Kd in hippocampus of diabetic rats compared to control. Gene expression studies of 5-HT(2A), 5-HTT and INSR in hippocampus showed a significant down regulation (p < 0.001) in diabetic rats compared to control. Pyridoxine treated in combination with insulin and A. marmelose to diabetic rats reversed the 5-HT content, B(max), Kd of 5-HT, 5-HT(2A) and gene expression of 5-HT(2A), 5-HTT and INSR in hippocampus to near control. The gene expression of 5-HT(2A) and 5-HTT were confirmed by immunohistochemical studies. Behavioural studies using elevated plus maze showed that serotonin through its transporter significantly increased (p < 0.001) anxiety-related traits in diabetic rats which were corrected by combination therapy. Our results suggest that pyridoxine treated in combination with insulin and A. marmelose has a role in the regulation of insulin synthesis and release, normalising diabetic related stress and anxiety through hippocampal serotonergic function. This has clinical significance in the management of diabetes.

Sensorimotor gating depends on polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase, but not on neuregulin-1 Arg38Gln genotype: a replication study.

BACKGROUND: Prepulse inhibition (PPI) of the acoustic startle response (ASR) is an operational measure of sensorimotor gating and a promising endophenotype of schizophrenia. We have recently shown that the linked serotonin-2A receptor (5-HT(2A)R) A-1438 G and T102C polymorphisms modulate PPI in schizophrenia patients. Moreover, it was shown that genetic variation in the catechol-O-methyltransferase (COMT) and the neuregulin-1 (NRG-1) proteins influences PPI in schizophrenia patients and healthy volunteers. Therefore, we aimed to replicate these results and investigated the impact of the related polymorphisms on PPI in healthy human volunteers. METHODS: We analyzed the 5-HT(2A)R A-1438 G/T102C (rs6311/rs6313), the COMT Val158Met (rs4680), and the NRG-1 Arg38Gln (rs3924999) polymorphisms, assessing startle reactivity, habituation, and PPI of ASR in 107 healthy Caucasian volunteers. RESULTS: Subjects homozygous for the 5-HT(2A)R T102C-T/A-1438 G-A allele showed increased PPI levels. In particular, male subjects with the COMT Met158Met-genotype also showed elevated PPI. The NRG-1 Arg38Gln genotype did not have a significant impact on PPI. Startle reactivity was not affected by any of the investigated polymorphisms. CONCLUSIONS: We confirmed in an independent sample of healthy volunteers that PPI is influenced by genetic variation in the 5-HT(2A)R gene. The influence of the COMT Val158Met genotype on PPI appears to be sex-specific. These results underscore the significance of the serotonin and dopamine systems in the modulation of sensorimotor gating.

From genes to psychoses and back: the role of the 5HT2alpha-receptor and prepulse inhibition in schizophrenia.

Decomposition of schizophrenia into neurobiological vulnerability traits is necessary to understand the complex genetic underpinnings of this phenomenologically defined disorder. This issue is discussed with a focus on prepulse inhibition (PPI) as a neurobiological phenotype and the 5HT2a-receptor as a candidate gene. A series of recent studies illuminates that PPI and 5HT2a-receptors present as vulnerability markers for schizophrenia; a functional sequence variant in the 5HT2a-gene is contributing to this relationship and might consequently contribute to the genetic predisposition to schizophrenia with a very small risk increase.

LG839: anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome.

INTRODUCTION: This study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical, LG839 (LifeGen, Inc., La Jolla, CA, USA). METHODS: A total of 1058 subjects who participated in the overall D.I.E.T. study were genotyped and administered an LG839 variant based on polymorphic outcomes. A subset of 27 self-identified obese subjects of Dutch descent, having the same DNA pattern of four out of the five candidate genes tested (chi-square analysis) as the entire data set, was subsequently evaluated. Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed. RESULTS: Significant results were observed for weight loss, sugar craving reduction, appetite suppression, snack reduction, reduction of late night eating (all P<0.01), increased perception of overeating, enhanced quality of sleep, increased happiness (all P<0.05), and increased energy (P<0.001). Polymorphic correlates were obtained for a number of genes (LEP, PPAR-gamma2, MTHFR, 5-HT2A, and DRD2 genes) with positive clinical parameters tested in this study. Of all the outcomes and gene polymorphisms, only the DRD2 gene polymorphism (A1 allele) had a significant Pearson correlation with days on treatment (r=0.42, P=0.045). CONCLUSION: If these results are confirmed in additional rigorous, controlled studies, we carefully suggest that DNA-directed targeting of certain regulator genes, along with customized nutraceutical intervention, provides a unique framework and strategic modality to combat obesity.

Sensorimotor gating of schizophrenia patients is influenced by 5-HT2A receptor polymorphisms.

BACKGROUND: Schizophrenia patients exhibit impairment in prepulse inhibition (PPI) of the acoustic startle response (ASR), suggesting a sensorimotor gating deficit. The serotonin-2A receptor (5-HT(2A)R) has been implicated in both the pathogenesis of schizophrenia and the PPI deficits of schizophrenia patients. Moreover, both schizophrenia and PPI are thought to be inheritable. We investigated the impact of three 5-HT(2A)R polymorphisms (A-1438G, T102C, H452Y) on PPI in schizophrenia patients. METHODS: We analyzed the 5-HT(2A)R A-1438G, T102C, and H452Y polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Patients were also examined with the Positive and Negative Syndrome Scale. RESULTS: The 5-HT(2A)R A-1438G and T102C polymorphisms were in complete linkage disequilibrium. Patients carrying the T102C TT and the A-1438G AA allele show significantly higher PPI levels and a faster early habituation compared with all other variants. 5-HT(2A)R A-1438G and T102C genotype explained approximately 11% of the PPI and early habituation variance. In contrast, the 5-HT(2A)R H452Y polymorphism did not affect startle parameters. CONCLUSIONS: Our findings suggest that PPI and habituation are modulated by 5-HT(2A)R A-1438G and T102C genotype in schizophrenia. Consequently, alterations within brain 5-HT(2A)Rs may contribute to the PPI deficits in schizophrenia.

Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese Ay mice.

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A(y) mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration of sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A(y) mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A(y) mice, but did not increase plasma adiponectin levels.