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An innovative nanovehicle based on lipid nanocapsules (LNC) was designed to facilitate the passage of a new 5-HT6 receptor antagonist, namely PUC-10, through the blood-brain barrier. PUC-10 is a new synthetic N-arylsulfonylindole that has demonstrated potent 5-HT6 receptor antagonist activity, but it exhibits poor solubility in water, which indicates limited absorption. The lipid nanocapsules designed had a nanometric size (53 nm), a monomodal distribution (PI

• Pharmacological activation of 5-HT 6 receptors increases the fIPSP of the dorsal hippocampus. • Activation of 5-HT 6 receptor decreases the amplitude of the pyramidal cells' population spike. • Blockade of 5-HT 6 receptors decreases the fIPSP amplitude and increases the pyramidal cells' population spike. • Paired-pulse inhibition is modulated by 5-HT 6 receptors acting via local interneurons. • Pharmacological blockade of GAT1 decreases associative memory performance induced by 5-HT6 receptor antagonism. The blockade of 5-HT 6 receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's disease and schizophrenia. However, the synaptic mechanism by which 5-HT 6 receptors control the GABAergic and glutamatergic synaptic transmission is barely understood. In this study, we demonstrate that pharmacological manipulation of 5-HT 6 receptors with the specific agonist EMD 386088 (7.4 nM) or the antagonist SB-399885 (300 nM) modulates the field inhibitory postsynaptic potentials of the dorsal hippocampus and controls the strength of the population spike of pyramidal cells. Likewise, pharmacological modulation of 5-HT 6 controls the magnitude of paired-pulse inhibition, a phenomenon mediated by GABAergic interneurons acting via GABA A receptors of pyramidal cells. The effects of pharmacological manipulation of the 5-HT 6 receptor were limited to GABAergic transmission and did not affect the strength of field excitatory postsynaptic potentials mediated by the Schaffer collaterals axons. Lastly, in a modified version of the Pavlovian autoshaping task that requires the activation of the hippocampal formation, we demonstrated that the anti-amnesic effect induced by the blockade of the 5-HT 6 receptor is prevented when the GAT1 transporter is blocked, suggesting that modulation of GABAergic transmission is required for the anti-amnesic properties of 5-HT 6 receptor antagonists. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is often associated with chronic pain. Serotonin type 6 (5-HT6) receptor ligands, particularly inverse agonists, have strong analgesic potential and may be new candidates for treating diabetic neuropathic pain and associated co-morbid cognitive deficits. The current study addressed the involvement of 5-HT6 receptor constitutive activity and mTOR signaling in an experimental model of diabetic neuropathic pain induced by streptozocin (STZ) injection in the rat. Here, we show that mechanical hyperalgesia and associated cognitive deficits are suppressed by the administration of 5-HT6 receptor inverse agonists or rapamycin. The 5-HT6 receptor ligands also reduced tactile allodynia in traumatic and toxic neuropathic pain induced by spinal nerve ligation and oxaliplatin injection. Furthermore, both painful and co-morbid cognitive symptoms in diabetic rats are reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor-mTOR physical interaction. These findings demonstrate the deleterious influence of the constitutive activity of spinal 5-HT6 receptors upon painful and cognitive symptoms in diabetic neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor-mTOR interaction might be valuable strategies for the alleviation of diabetic neuropathic pain and cognitive co-morbidities. [ABSTRACT FROM AUTHOR]

It is estimated that in patients taking antipsychotic drugs (APDs), metabolic syndrome occurs 2–3 times more often than in the general population. It manifests itself in abdominal obesity, elevated glucose concentration, and dyslipidemia. Despite the high prevalence of this disorder, only a small percentage of patients receive appropriate and effective treatment, and none of the available methods for preventing or treating APD-induced metabolic side effects is satisfactory. A promising supplement to antipsychotic therapy appears to be ligands of the serotonin 6 (5-HT6) receptor. The present study aimed to examine the chronic effects of the selected APDs (haloperidol, risperidone, olanzapine), administered alone and in combination with a selective 5-HT6 agonist (WAY-181187) or antagonist (SB-742457), on weight gain, food intake, serum lipid profile, glucose level, and a spectrum of hormones derived from adipose (leptin, adiponectin) and gastrointestinal (insulin, ghrelin) tissue in rats. SB-742457 inhibited increased weight gain and alleviated hyperglycemia induced by APDs more strongly than did WAY-181187, but also intensified dyslipidemia. WAY-181187 tended to improve the lipid profile, but increased the glucose level. The greatest benefits were obtained when WAY-181187 or SB-742457 were co-administered with haloperidol. It is difficult to assess whether the modification of the serum levels of insulin, leptin, ghrelin, and adiponectin depended on the treatment applied or other drug-independent factors; therefore, further research is needed. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, memory and activities of daily living. Selective blockade of serotonin-6 (5-HT6) receptors, which are exclusively localized to the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5-HT6 receptor antagonist with pro-cognitive properties in animal models of cognition. Methods: The efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio. The study consisted of a 26-week double-blind treatment period. The primary efficacy outcome was the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 11). Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). In exploratory post hoc analyses, patients were subdivided based on the use of memantine dosage forms and memantine plasma concentrations, to evaluate the impact of memantine on the efficacy of masupirdine. Results: In an exploratory post hoc analysis, less worsening in cognition (ADAS-Cog 11 scores) was observed with masupirdine treatment as compared with placebo in patients whose trough memantine plasma concentrations were ≤ 100 ng/mL. Conclusions: Although prespecified study endpoints of the phase 2 study were not met, these exploratory post hoc subgroup observations are hypothesis-generating and suggest that the efficacy of masupirdine was adversely affected by concurrent therapy with memantine. Further assessment of masupirdine to determine its potential role as a treatment option for cognitive deficits associated with AD is warranted. Trial Registration: The study was registered at ClinicalTrials.gov (NCT02580305). [ABSTRACT FROM AUTHOR]

The serotonin type 6 receptor (5-HT 6 R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT 6 R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT 6 R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT 6 R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT 6 R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT 6 R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT 6 R and provide insight into the glioprotective properties of 5-HT 6 R neutral antagonists at Gs signaling. [Display omitted] • A novel framework for 5-HT 6 R ligands derived from 2-phenylpyrrole. • Exposure of the basic center is cricial to target different active states of 5-HT 6 R. • Compound 30 behaves as neutral antagonist at 5-HT 6 R-operated Gs signaling. • 5-HT 6 R neutral antagonists show cytoprotective effect in C8-D1A and human astrocytes. • Agonists and inverse agonists of 5-HT 6 R produce no cytoprotective effect. [ABSTRACT FROM AUTHOR]

Objectives: The effects of masupirdine on the neuropsychiatric symptoms were explored.Methods: Masupirdine (SUVN-502) was evaluated for its effects on cognition in patients with moderate AD. The prespecified primary outcome showed no drug-placebo difference. Post hoc analyses of domains of the 12-item neuropsychiatric inventory scale were carried out.Results: In a subgroup of patients (placebo, n = 57; masupirdine 50 mg, n = 53; masupirdine 100 mg, n = 48) with baseline agitation/aggression symptoms ≥1, a statistically significant reduction in agitation/aggression scores was observed in masupirdine 50 mg (95% confidence interval (CI), -1.9 to -0.5, p < 0.001) and masupirdine 100 mg (95% CI, -1.7 to -0.3, p = 0.007) treated arms at Week 13 in comparison to placebo and the effect was sustained for trial duration of 26 weeks in the masupirdine 50 mg treatment arm (95% CI, -2.3 to -0.8, p < 0.001). Similar observations were noted in the subgroup of patients (placebo, n = 29; masupirdine 50 mg, n = 30; masupirdine 100 mg, n = 21) with baseline agitation/aggression symptoms ≥3. In the subgroup of patients (placebo, n = 28; masupirdine 50 mg, n = 28; masupirdine 100 mg, n = 28) who had baseline psychosis symptoms and/or symptom emergence, a significant reduction in psychosis scores was observed in the masupirdine 50 mg (Week 4: 95% CI, -2.8 to -1.4, p < 0.001; Week 13: 95% CI, -3.3 to -1.3, p < 0.001) and masupirdine 100 mg (Week 4: 95% CI, -1.4 to 0, p = 0.046; Week 13: 95% CI, -1.9 to 0.1, p = 0.073) treatment arms in comparison to placebo.Conclusion: Further research is warranted to explore the potential beneficial effects of masupirdine on NPS. [ABSTRACT FROM AUTHOR]

Introduction: This study explored the efficacy and safety of a serotonin-6 receptor antagonist, masupirdine, as adjunct treatment in patients with moderate Alzheimer's disease (AD) concomitantly treated with donepezil and memantine. Methods: The effects of masupirdine were evaluated in patients with moderate AD dementia on background treatment with donepezil and memantine. Five hundred thirty-seven patients were expected to be randomized in a 1:1:1 ratio, using permuted blocked randomization. After a 2- to 4-week screening period, the study consisted of a 26-week double-blind treatment period, and a 4-week washout period. The primary efficacy measure was the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 11). Secondary efficacy measures were Clinical Dementia Rating Scale-Sum of Boxes, Mini-Mental State Examination, 23-item Alzheimer's Disease Co-operative Study Activities of Daily Living, and 12-item Neuropsychiatric Inventory. Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). A total of 564 patients were randomized to receive either daily masupirdine 50 mg (190 patients), masupirdine 100 mg (185 patients), or placebo (189 patients). The study is registered at ClinicalTrials.gov (NCT02580305). Results: TheMMRMresults showed statistically non-significant treatment differences in change from baseline in ADAS-Cog 11 scores at week 26, comparing each masupirdine dose arm to the placebo arm. No significant treatment effects were observed in the secondary evaluations. Discussion: Masupirdine was generally safe andwell tolerated. Possible reasons for the observed trial results are discussed. [ABSTRACT FROM AUTHOR]

Introduction: of the study: Post-training administration of glucocorticoids enhance memory consolidation of inhibitory avoidance learning. Given the involvement of 5-HT6 receptors in memory processing and the interaction of glucocorticoids with the brain serotonergic system in modulating memory processing, we investigated whether the effect of glucocorticoids on the consolidation of emotionally arousing training depends on hippocampal 5-HT6 receptors. Methods: Rats were trained in an inhibitory avoidance task and immediately received the systemic injections of corticosterone (CORT) as well as the intra-hippocampal injections of 5-HT receptors agonist or antagonist. The memory retention test was done 48 hours after training and immediately after the behavioral test, the animals were sacrificed and the hippocampi (left and right) rapidly dissected out for molecular studies. Results: Post-training injections of different doses of CORT (1.25, 2.5, 5, and 10 mg/kg) enhanced memory retention in a dose-dependent manner. The CORT-induced enhancement of memory consolidation was blocked by bilateral intra-hippocampal injections of 5-HT6 receptor antagonist SB271046 (5 or 10 ng/per side), but not agonist EMD386088 (5 or 10 ng/per side). Furthermore, systemic CORT reduced 5-HT6 receptor mRNA and protein expression in the hippocampus. Both doses of 5-HT6 receptor agonist and antagonist significantly enhanced and reduced the expression of the 5-HT6 receptor, respectively, and both ligands at the higher dose (10 ng) enhanced memory consolidation. Moreover, CORT injection attenuated and enhanced, respectively, the effects of agonist and antagonist on 5-HT6 receptor expression. Conclusion: These behavioral and molecular findings indicated an interaction between glucocorticoids and hippocampal 5-HT6 receptors in the consolidation of emotionally arousing experiences.

Abstract Introduction This study explored the efficacy and safety of a serotonin‐6 receptor antagonist, masupirdine, as adjunct treatment in patients with moderate Alzheimer's disease (AD) concomitantly treated with donepezil and memantine. Methods The effects of masupirdine were evaluated in patients with moderate AD dementia on background treatment with donepezil and memantine. Five hundred thirty‐seven patients were expected to be randomized in a 1:1:1 ratio, using permuted blocked randomization. After a 2‐ to 4‐week screening period, the study consisted of a 26‐week double‐blind treatment period, and a 4‐week washout period. The primary efficacy measure was the 11‐item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS‐Cog 11). Secondary efficacy measures were Clinical Dementia Rating Scale–Sum of Boxes, Mini‐Mental State Examination, 23‐item Alzheimer's Disease Co‐operative Study Activities of Daily Living, and 12‐item Neuropsychiatric Inventory. Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). A total of 564 patients were randomized to receive either daily masupirdine 50 mg (190 patients), masupirdine 100 mg (185 patients), or placebo (189 patients). The study is registered at ClinicalTrials.gov (NCT02580305). Results The MMRM results showed statistically non‐significant treatment differences in change from baseline in ADAS‐Cog 11 scores at week 26, comparing each masupirdine dose arm to the placebo arm. No significant treatment effects were observed in the secondary evaluations. Discussion Masupirdine was generally safe and well tolerated. Possible reasons for the observed trial results are discussed. Highlights Masupirdine was evaluated in moderate Alzheimer's disease patients. First trial in class with background treatment of donepezil and memantine. Masupirdine was generally safe and well tolerated. Possible reasons for the observed trial results are discussed.

Diabetic neuropathy is often associated with chronic pain. Serotonin type 6 (5-HT6) receptor ligands, particularly inverse agonists, have strong analgesic potential and may be new candidates for treating diabetic neuropathic pain and associated co-morbid cognitive deficits. The current study addressed the involvement of 5-HT6 receptor constitutive activity and mTOR signaling in an experimental model of diabetic neuropathic pain induced by streptozocin (STZ) injection in the rat. Here, we show that mechanical hyperalgesia and associated cognitive deficits are suppressed by the administration of 5-HT6 receptor inverse agonists or rapamycin. The 5-HT6 receptor ligands also reduced tactile allodynia in traumatic and toxic neuropathic pain induced by spinal nerve ligation and oxaliplatin injection. Furthermore, both painful and co-morbid cognitive symptoms in diabetic rats are reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor-mTOR physical interaction. These findings demonstrate the deleterious influence of the constitutive activity of spinal 5-HT6 receptors upon painful and cognitive symptoms in diabetic neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor-mTOR interaction might be valuable strategies for the alleviation of diabetic neuropathic pain and cognitive co-morbidities.

It is estimated that in patients taking antipsychotic drugs (APDs), metabolic syndrome occurs 2–3 times more often than in the general population. It manifests itself in abdominal obesity, elevated glucose concentration, and dyslipidemia. Despite the high prevalence of this disorder, only a small percentage of patients receive appropriate and effective treatment, and none of the available methods for preventing or treating APD-induced metabolic side effects is satisfactory. A promising supplement to antipsychotic therapy appears to be ligands of the serotonin 6 (5-HT6) receptor. The present study aimed to examine the chronic effects of the selected APDs (haloperidol, risperidone, olanzapine), administered alone and in combination with a selective 5-HT6 agonist (WAY-181187) or antagonist (SB-742457), on weight gain, food intake, serum lipid profile, glucose level, and a spectrum of hormones derived from adipose (leptin, adiponectin) and gastrointestinal (insulin, ghrelin) tissue in rats. SB-742457 inhibited increased weight gain and alleviated hyperglycemia induced by APDs more strongly than did WAY-181187, but also intensified dyslipidemia. WAY-181187 tended to improve the lipid profile, but increased the glucose level. The greatest benefits were obtained when WAY-181187 or SB-742457 were co-administered with haloperidol. It is difficult to assess whether the modification of the serum levels of insulin, leptin, ghrelin, and adiponectin depended on the treatment applied or other drug-independent factors; therefore, further research is needed.

The interest in new 5-HT₆ agents stems from their ability to modulate cognition processing, food motivation and anxiety-like behaviors. While these findings come primarily from rodent studies, no studies on primates have been published. Furthermore, our understanding of where and how they act in the brain remains limited. Although the striatum is involved in all of these processes and expresses the highest levels of 5-HT₆ receptors, few studies have focused on it. We thus hypothesized that 5-HT 6 receptor blockade would influence food motivation and modulate behavioral expression in non-human primates through striatal 5-HT 6 receptors. This study thus aimed to determine the effects of acute administration of the SB-258585 selective 5-HT 6 receptor antagonist on the feeding motivation and behaviors of six male macaques. Additionally, we investigated potential 5-HT 6 targets using PET imaging to measure 5-HT 6 receptor occupancy throughout the brain and striatal subregions. We used a food-choice task paired with spontaneous behavioral observations, checking 5-HT 6 receptor occupancy with the specific PET imaging [18F]2FNQ1P radioligand. We demonstrated, for the first time in non-human primates, that modulation of 5-HT 6 transmission, most likely through the striatum (the putamen and caudate nucleus), significantly reduces food motivation while exhibiting variable, weaker effects on behavior. While these results are consistent with the literature showing a decrease in food intake in rodents and proposing that 5-HT 6 receptor antagonists can be used in obesity treatment, they question the antagonists' anxiolytic potential. • SB-258585 reduces food motivation and increases object-directed behaviors in macaques. • SB-258585 variably affects anxiety-like behaviors and overall activity. • SB-258585 reduced 5-HT 6 receptor occupancy only in the striatum. • The striatal 5-HT 6 receptors are central players in food-motivated behaviors. • The striatal 5-HT 6 receptor could be a valuable target for treating eating disorders. [ABSTRACT FROM AUTHOR]

Background: The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2-/-) are naturally highly aggressive, while heterozygous mice (Tph2+/-) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically 'susceptible' heterozygous mice (Tph2+/-).Methods: Tph2+/- male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied.Results: Stressed Tph2+/- mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/- mice.Limitations: Rescue experiments would help to verify causal relationships of reported changes.Conclusions: The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes. [ABSTRACT FROM AUTHOR]

Introduction: of the study: Post-training administration of glucocorticoids enhance memory consolidation of inhibitory avoidance learning. Given the involvement of 5-HT6 receptors in memory processing and the interaction of glucocorticoids with the brain serotonergic system in modulating memory processing, we investigated whether the effect of glucocorticoids on the consolidation of emotionally arousing training depends on hippocampal 5-HT6 receptors. Methods: Rats were trained in an inhibitory avoidance task and immediately received the systemic injections of corticosterone (CORT) as well as the intra-hippocampal injections of 5-HT receptors agonist or antagonist. The memory retention test was done 48 hours after training and immediately after the behavioral test, the animals were sacrificed and the hippocampi (left and right) rapidly dissected out for molecular studies. Results: Post-training injections of different doses of CORT (1.25, 2.5, 5, and 10 mg/kg) enhanced memory retention in a dose-dependent manner. The CORT-induced enhancement of memory consolidation was blocked by bilateral intra-hippocampal injections of 5-HT6 receptor antagonist SB271046 (5 or 10 ng/per side), but not agonist EMD386088 (5 or 10 ng/per side). Furthermore, systemic CORT reduced 5-HT6 receptor mRNA and protein expression in the hippocampus. Both doses of 5-HT6 receptor agonist and antagonist significantly enhanced and reduced the expression of the 5-HT6 receptor, respectively, and both ligands at the higher dose (10 ng) enhanced memory consolidation. Moreover, CORT injection attenuated and enhanced, respectively, the effects of agonist and antagonist on 5-HT6 receptor expression. Conclusion: These behavioral and molecular findings indicated an interaction between glucocorticoids and hippocampal 5-HT6 receptors in the consolidation of emotionally arousing experiences. [ABSTRACT FROM AUTHOR]

Background: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer's disease (AD) and associated disorders.Objective: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages.Methods: Patients were classified according to the "ABC" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD ("High"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), "Low" (n = 18), "Int" (n = 20), and "High" (n = 15).Results: In vitro binding assays did not show significant differences for the KD and Bmax parameters between "High" and HC groups. In vitro quantitative autoradiography showed a significant difference between the "High" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined ("Low", "Intermediate", and "High") (p = 0.011).Conclusion: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors. [ABSTRACT FROM AUTHOR]

The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of 18 F]2FNQ1P, a new PET radiotracer of 5-HT 6 receptors, in rat, pig, non-human primate and human tissues. The 5-HT 6 receptor is one of the more recently identified serotonin receptors in central nervous system and, because of its role in memory and cognitive processes, is considered as a promising therapeutic target. In-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat. In all species, autoradiography data revealed high binding levels of 18 F]2FNQ1P in cerebral regions with high 5-HT 6 receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided K D and B max values of respectively 1.34 nM and 0.03 pmol·mg−1 in rat, 0.60 nM and 0.04 pmol·mg−1 in pig, 1.38 nM and 0.07 pmol·mg−1 in non-human primate, and 1.39 nM and 0.15 pmol·mg−1 in human caudate nucleus. In rat brain, the proportion of unmetabolized 18 F]2FNQ1P was >99% 5 min after iv injection and 89% at 40 min. The biodistribution studies found maximal radioactivity in lungs and kidneys (3.5 ± 1.2% ID/g and 2.0 ± 0.7% ID/g, respectively, 15 min post-injection). These radiopharmacological data confirm that 18 F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT 6 receptors and suggest that it could be used as a radiopharmaceutical in humans. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+/− mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+/− mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.

A new series of twenty-two C-5 substituted N-arylsulfonylindoles was prepared with the aim of exploring the influence of C-5 substitution on 5-HT6 receptor affinity. Eleven compounds showed moderate to high affinity at the receptor (Ki = 58–403 nM), with compound 4d being identified as the most potent ligand. However, regarding C-5 substitution, both methoxy and fluorine were detrimental for receptor affinity compared to our previously published unsubstituted compounds. In order to shed light on these observations, we performed docking and molecular dynamics simulations with the most potent compounds of each series (4d and 4l) and PUC-10, a highly active ligand previously reported by our group. The comparison brings about deeper insight about the influence of the C-5 substitution on the binding mode of the ligands, suggesting that these replacements are detrimental to the affinity due to precluding a ligand from reaching deeper inside the binding site. Additionally, CoMFA/CoMSIA studies were performed to systematize the information of the main structural and physicochemical characteristics of the ligands, which are responsible for their biological activity. The CoMFA and CoMSIA models presented high values of q2 (0.653; 0.692) and r2 (0.879; 0.970), respectively. Although the biological activity of the ligands can be explained in terms of the steric and electronic properties, it depends mainly on the electronic nature.

Cognitive impairment is a common comorbidity in patients with temporal lobe epilepsy (TLE) that severely affects patients' quality of life. Also, serotonin 5-hydroxytryptamine 6 (5-HT6) receptor plays an important role in cognition. This study aimed to investigate effects of 5-HT6 receptor on learning-memory capacities in epileptic rats. Total of 36 adult Sprague-Dawley (SD) rats were divided into vehicle (n = 6) and epileptic group (n = 30). Status epilepticus (SE) was induced via systemic injection of pilocarpine. Epileptic group was sub-divided into vehicle, 10, 20, and 30 μg SB-271046 groups, six mice per group. Learning-memory performance of rats was evaluated by using Y maze and Morris water maze test. 5-HT6 receptor expression was examined using immunostaining and Western blot. The other six rats were used to make epileptic model and Jab-1/p-c-Jun were detected. Results showed that frequency of spontaneous recurrent seizures (SRSs) was significantly decreased in pilocarpine-induced epileptic rats that treated with SB-271046. Alternation rate and new arm percentage were decreased in epileptic rats compared to control. The 5-day mean latency was prolonged in epileptic rats compared to control rats. During retention stage, mean latency, number of target crossings, and percentage of time spent in target zone were decreased in epileptic rats, but not in those treated with SB-271046. The number of apoptotic neurons was significantly increased in epileptic rats, which was decreased by SB-271046. 5-HT6 expression was significantly increased in hippocampus and cortex following recurrent seizures. Jab-1 level was decreased after SB-271046 administration. p-c-Jun level was elevated in epileptic rats and decreased in a dose-dependent manner after the SB-271046 administration. In conclusion, the over-expression of 5-HT6 receptor and activated Jab-1/p-c-Jun plays an important role in pilocarpine-induced seizures and learning-memory impairment. [ABSTRACT FROM AUTHOR]

Highlights • Serotonergic 5-HT 6 receptor tone on memory and/or amnesia. • Dose-response curves of 5-HT 6 receptor experimental molecules. • Different intrinsic activity. • Hippocampal serotonergic tone under amnesic states. Abstract To our knowledge the intrahippocampal serotonergic 5-HT 6 receptor tone on memory and amnesia models remains unexplored. Hence, in the present work we tested intrahippocampal administration of serotonin or 5-hydroxytryptamine (5-HT) 6 receptor experimental molecules with differential intrinsic activity. Methods: In the present study, Automatized Autoshaping memory task was used, useful measuring memory, neural markers, and pharmacological effects. We are hypothesizing that experimental molecules with differential intrinsic activity might reveal serotonergic tone. Particularly, intrahippocampal administration of 5-HT 6 receptor compounds with differential intrinsic activity (i.e., agonistic and antagonistic) might evidencing a serotonergic tone via this receptor. Bilateral intrahippocampal dose-response curves show that administration of EMD386088 (10 and 100 μg) had no effect or (50 μg) decreased conditioned responses (CR) in short- and long-term memory (STM and LTM, respectively); while SB-399885 (10 or 100 μg) significantly decreased CR in STM and LTM (24 and 48-h) or (50 μg) had no effect; thus suggesting that there is a 5-HT 6 receptor tone regulating both STM and LTM. Moreover, intrahippocampal inactive doses of EMD386088 (5 μg) plus SB-399885 (0.5 μg) did not affect STM and LTM; however, partially or completely prevented the scopolamine or dizocilpine-induced amnesia. Thus confirming that both drugs exerted their effects through 5-HT 6 receptor and that there is a hippocampal serotonergic tone under amnesic states, similar to that striatal. [ABSTRACT FROM AUTHOR]

[Display omitted] In this study, we present the discovery and pharmacological characterization of a new series of 6-piperazinyl-7-azaindoles. These compounds demonstrate potent antagonism and selectivity against the 5-HT 6 receptor. Our research primarily focuses on optimizing the lead structure and investigating the structure–activity relationship (SAR) of these compounds. Our main objective is to improve their activity and selectivity against off-target receptors. Overall, our findings contribute to the advancement of novel compounds targeting the 5-HT 6 receptor. Compound 29 exhibits significant promise in terms of pharmacological, physicochemical, and ADME (Absorption, Distribution, Metabolism, and Excretion) properties. Consequently, it merits thorough exploration as a potential drug candidate due to its favorable activity profile and successful outcomes in a range of in vivo experiments. [ABSTRACT FROM AUTHOR]

The involvement of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing in the central nervous system (CNS) has been reported using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the roles of 5-HT receptor family in acute pruriceptive processing have not been fully elucidated in the CNS. In the present study, scratching behavior induced by chloroquine (CQ) was ameliorated by milnacipran or mirtazapine, and these effects were reversed by SB207266, a 5-HT 4 antagonist, or SB258585, a 5-HT 6 antagonist, but not by SB258585, a 5-HT 5 antagonist. Moreover, CQ-induced scratches were mitigated by intrathecal injection of 5-HT 4 agonists, such as BIMU8 and ML10302, and the 5-HT 6 agonist, WAY208466. Conversely, histamine-induced scratches were not affected by the 5-HT 4 agonists or a 5-HT 6 agonist. Similarly, the amelioration of histamine-induced scratches by these antidepressants was not reversed by the 5-HT 4 , 5-HT 5 , or 5-HT 6 receptor antagonist. Therefore, 5-HT is involved in the amelioration of CQ-induced scratches by milnacipran and mirtazapine, and 5-HT 4 , 5-HT 5 , and 5-HT 6 receptors play differential roles in acute pruriceptive processing after administration of CQ or histamine.

Serotonin 6 (5-HT6) receptors are primarily expressed in the central nervous system and to an even further extent brain regions responsible for learning and memory. Recent studies have demonstrated 5-HT6 receptor involvement in pathophysiological processes highlighting their therapeutic possibilities. Most research concerning the effects of 5-HT6 receptor modulation has focused on blockade despite paradoxical findings that 5-HT6 agonists and antagonists can both have pro-cognitive effects. The current experiments examine the effects of the 5-HT6 receptor agonist EMD386088 on behavioral flexibility and working memory. C57BL/6J mice received systemic injections of either 0, 2, or 4 mg/kg EMD386088 before being tested on probabilistic reversal learning, spontaneous alternation, and locomotor activity. In the probabilistic reversal learning task, the high dose of 4 mg/kg significantly impaired performance requiring more trials to reach criterion. The same dose significantly increased perseverative type errors, suggesting that the probabilistic reversal learning impairment was due to an inability to inhibit the previously learned choice pattern, rather than maintaining the new optimal choice pattern. Acute EMD386088 administration at 2 mg/kg significantly impaired spontaneous alternation performance, while the high dose of 4 mg/kg did not reach significance. These learning impairments were not due to an overall locomotor impairment as evidenced by comparable locomotor activity scores. Acute systemic 5-HT6 receptor activation with EMD386088 led to impaired behavior flexibility and working memory performance. Current findings support previous research suggesting that novel therapeutics directed at down regulation of 5-HT6 receptors may be effective in attenuating working memory and behavioral flexibility impairments commonly found in neuropsychiatric disorders such as Alzheimer’s and schizophrenia. [ABSTRACT FROM AUTHOR]

Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT6 receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister hooded rats (weaned on post-natal days 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a 2-week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: 5-HT6 receptors are mainly expressed in brain areas associated with learning and memory. Several studies have reported procognitive effects of both 5-HT6 agonist and antagonists. However, the exact mechanism 5-HT6 receptor modulation has not been properly studied especially in the context of cholinergic functions, cerebral blood flow (CBF), brain-derived neural factor (BDNF), oxidative stress, and behavioral changes.Methods: In the present study, memory impairment was induced in albino Wistar rats by two doses of intracerebroventricular (ICV) injection of streptozotocin (STZ, 3 mg/kg) on first and third day. These rats were evaluated in a battery of behavioral tasks after 14 days from the first day of ICV-STZ.Results: Significant memory impairment was seen when ICV-STZ induced rats are assessed by Morris water maze, novel object recognition, social recognition, and passive avoidance tests. There was a significant reduction in CBF, increased oxidative stress (MDA, GSH, and ROS), acetylcholinesterase (AChE) activity, and a decrease in BDNF. Treatment with selective 5-HT6 agonist EMD-386088 (5 mg/kg) and antagonist SB-399885 (10 mg/kg) prevented ICV-STZ-induced memory impairment when assessed by behavioral tests. Treatment with 5-HT6 ligands significantly prevented the change in CBF and BDNF. Further, protected from MDA and ROS and decreasing GSH in the brain compared to ICV-STZ rats. The rice in brain AChE activity was normalized by both ligands. The changes in locomotor activity by EMD-386088 and SB-399885 treatment were negligible.Conclusion: The findings in this study support the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction. [ABSTRACT FROM AUTHOR]

The dorsomedial prefrontal cortex (dmPFC) plays a very important role in decision-related and anxiety-related information processing. It has enriched 5-HT6 receptors; however, the precise role of dmPFC 5-HT6 receptors in anxiety remains to be fully investigated. In this study, we injected dmPFC with the 5-HT6 receptor agonist EMD 386088 and antagonist SB 271046 using stereotactic technology. 5-HT6 receptor activation in mice increased time spent in the center area on the open-field test, increased exploration of the open arms on the elevated plus maze test, and increased ratio on the social interaction test. 5-HT6 receptor inactivation induced the opposite effects. In brain slices, EMD 386088 decreased both spontaneous inhibitory postsynaptic currents (sIPSC) and spontaneous excitatory postsynaptic currents (sEPSC), while SB 271046 only increased sEPSC. These effects of EMD 386088 and SB 271046 could be reversed by the GABAA receptor antagonist bicuculline (BMI) and positive allosteric modulator clonazepam (CLZ), respectively. Our results suggest that neurotransmission in the dmPFC by 5-HT6 receptor activation and inhibition may play an important role in anxiety-like behavior, and may provide new insight into the pathological mechanism and potential target of anxiety disorders. [ABSTRACT FROM AUTHOR]

A comparative study performed in mice investigating the action of DF302, a novel fluoride-containing gamma-carboline derivative, in comparison to the structurally similar neuroprotective drug dimebon. Drug effects on learning and memory, emotionality, hippocampal neurogenesis and mitochondrial functions, as well as AMPA-mediated currents and the 5-HT6 receptor are reported. In the step-down avoidance and fear-conditioning paradigms, bolus administration of drugs at doses of 10 or 40 mg/kg showed that only the higher dose of DF302 improved long-term memory while dimebon was ineffective at either dosage. Short-term memory and fear extinction remained unaltered across treatment groups. During the 5-day predation stress paradigm, oral drug treatment over a period of 2 weeks at the higher dosage regimen decreased anxiety-like behaviour. Both compounds supressed inter-male aggression in CD1 mice, the most eminent being the effects of DF302 in its highest dose. DF302 at the higher dose decreased floating behaviour in a 2-day swim test and after 21-day ultrasound stress. The density of Ki67-positive cells, a marker of adult neurogenesis, was reduced in the dentate gyrus of stressed dimebon-treated and non-treated mice, but not in DF302-treated mice. Non-stressed mice that received DF302 had a higher density of Ki67-positive cells than controls unlike dimebon-treated mice. Similar to dimebon, DF302 effectively potentiated AMPA receptor-mediated currents, bound to the 5-HT6 receptor, inhibited mitochondrial permeability transition and displayed cytoprotective properties in cellular models of neurodegeneration. Thus, DF302 exerts multi-target effects on the key mechanisms of neurodegenerative pathologies and can be considered as an optimized novel analogue of the neuroprotective agent dimebon. [ABSTRACT FROM AUTHOR]

Brain serotonin-6 receptor (5-HT6R) is the one of the most recently identified serotonin receptors. Accumulating evidence suggests that it is a potent therapeutic target for psychiatric and neurological diseases. Since [18F]2FNQ1P was recently proposed as the first fluorinated positron emission tomography (PET) radioligand for this receptor, the objective of the present study was to demonstrate its suitability for 5-HT6R neuroimaging in primates. [18F]2FNQ1P was characterized by in vitro autoradiography and in vivo PET imaging in cynomolgus monkeys. Following in vivo PET imaging, tracer binding indices were computed using the simplified reference tissue model and Logan graphical model, with cerebellum as reference region. The tracer binding reproducibility was assessed by test–retest in five animals. Finally, specificity was assessed by pre-injection of a 5-HT6R antagonist, SB258585. In vitro, results showed wide cerebral distribution of the tracer with specificity toward 5-HT6Rs as binding was effectively displaced by SB258585. In vivo brain penetration was good with reproducible distribution at cortical and subcortical levels. The automated method gave the best spatial normalization. The Logan graphical model showed the best tracer binding indices, giving the highest magnitude, lowest standard deviation and best reproducibility and robustness. Finally, 5-HT6R antagonist pre-injection significantly decreased [18F]2FNQ1P binding mainly in the striatum and sensorimotor cortex. Taken together, these preclinical results show that [18F]2FNQ1P is a good candidate to address 5-HT6 receptors in clinical studies.

Brain serotonin-6 receptor (5-HT6R) is the one of the most recently identified serotonin receptors. Accumulating evidence suggests that it is a potent therapeutic target for psychiatric and neurological diseases. Since [18F]2FNQ1P was recently proposed as the first fluorinated positron emission tomography (PET) radioligand for this receptor, the objective of the present study was to demonstrate its suitability for 5-HT6R neuroimaging in primates. [18F]2FNQ1P was characterized by in vitro autoradiography and in vivo PET imaging in cynomolgus monkeys. Following in vivo PET imaging, tracer binding indices were computed using the simplified reference tissue model and Logan graphical model, with cerebellum as reference region. The tracer binding reproducibility was assessed by test-retest in five animals. Finally, specificity was assessed by pre-injection of a 5-HT6R antagonist, SB258585. In vitro, results showed wide cerebral distribution of the tracer with specificity toward 5-HT6Rs as binding was effectively displaced by SB258585. In vivo brain penetration was good with reproducible distribution at cortical and subcortical levels. The automated method gave the best spatial normalization. The Logan graphical model showed the best tracer binding indices, giving the highest magnitude, lowest standard deviation and best reproducibility and robustness. Finally, 5-HT6R antagonist pre-injection significantly decreased [18F]2FNQ1P binding mainly in the striatum and sensorimotor cortex. Taken together, these preclinical results show that [18F]2FNQ1P is a good candidate to address 5-HT6 receptors in clinical studies. [ABSTRACT FROM AUTHOR]

Beta-amyloid peptide (Aβ) induced neurotoxicity is considered as a hallmark of the pathogenesis of Alzheimer's disease (AD). The present study demonstrated the neuroprotective role of 5-HT6 receptors against Aβ-induced neurotoxicity in PC-12 cells. The 5-HT6 receptor agonist EMD-386088 and antagonist SB-399885 were used as pharmacological tools. The NMDA receptor antagonist, memantine, was used as reference standard. The Aβ (50 µM) induced apoptosis, increased reactive oxygen species (ROS) generation and impaired neurite outgrowth in PC-12 cells. Pre-treatment with 10 µM EMD-386088 and SB-399885 had significantly protected neuronal cell death by maintaining higher cell viability through attenuation of intracellular ROS. Further, both compounds significantly prevented Aβ-induced impairment in neurite outgrowth in PC-12 cells. Similarly, memantine prevented Aβ-induced neurotoxicity in PC-12 cells. These findings suggest that 5-HT6 receptor ligands have protected neurons from Aβ induced toxicity by reducing ROS and through prevention of impairment in neurite outgrowth. Therefore, 5-HT6 receptor could be an important disease-modifying therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Discovery of 5-HT6 receptor subtype and its exclusive localization within the central nervous system led to extensive investigations of its role in Alzheimer's disease, schizophrenia, and obesity. In the present study, we present preclinical evaluation of a novel highly-potent and highly-selective 5-HT6R antagonist, AVN-492. The affinity of AVN-492 to bind to 5-HT6R (Ki = 91 pM) was more than three orders of magnitude higher than that to bind to the only other target, 5-HT2BR, (Ki = 170 nM). Thus, the compound displayed great 5-HT6R selectivity against all other serotonin receptor subtypes, and is extremely specific against any other receptors such as adrenergic, GABAergic, dopaminergic, histaminergic, etc. AVN-492 demonstrates good in vitro and in vivo ADME profile with high oral bioavailability and good brain permeability in rodents. In behavioral tests, AVN-492 shows anxiolytic effect in elevated plus-maze model, prevents an apomorphine-induced disruption of startle pre-pulse inhibition (the PPI model) and reverses a scopolamine- and MK-801-induced memory deficit in passive avoidance model. No anti-obesity effect of AVN-492 was found in a murine model. The data presented here strongly indicate that due to its high oral bioavailability, extremely high selectivity, and potency to block the 5-HT6 receptor, AVN-492 is a very promising tool for evaluating the role the 5-HT6 receptor might play in cognitive and neurodegenerative impairments. AVN-492 is an excellent drug candidate to be tested for treatment of such diseases, and is currently being tested in Phase I trials. [ABSTRACT FROM AUTHOR]

Abstract Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5‐HT6 receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5‐HT6 receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5‐HT6 receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5‐HT6 agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post‐weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5‐HT6 antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5‐HT6 receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.

While monoaminergic deficits are evident in all depressed patients, nonresponders are characterized by impaired GABA-ergic signaling and the simultaneous presence of the inflammatory component. Pharmacological agents able to curb pathological immune responses and modulate ineffective GABA-ergic neurotransmission are thought to improve therapeutic outcomes in the treatment-resistant subgroup of depressed patients. Here, we report on a set of dually acting molecules designed to simultaneously modulate GABA-A and 5-HT 6 receptor activity. The serotonin 5-HT 6 receptor was chosen as a complementary molecular target, due to its promising antidepressant-like activities reported in animal studies. Within the study we identified that lead molecule 16 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, 16 was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, 16 exerted antidepressant-like activity deriving from a synergic interplay between 5-HT 6 and GABA-A receptors. Altogether, the presented findings point to hybrid 16 as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.

Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT6) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1+/- mice compared with WT mice. Moreover, systemic administration of a 5-HT6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1+/- mice. Collectively, these findings suggest that disrupting 5-HT6 receptor-neurofibromin interaction prevents agonist-independent 5-HT6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients. [ABSTRACT FROM AUTHOR]

Our previous results suggest that the Rosa rugosa Thunb. (family Rosaceae) alleviates endurance exerciseinduced stress by decreasing oxidative stress levels. This study aimed to screen and identify the physiological antistress effects of an extract of R. rugosa (RO) on sleep deprivation-induced anxiety-like behavior and cognitive tests (in vivo) and tested for hippocampal CORT and monoamine levels (ex vivo), corticosterone (CORT)-induced injury, N-methyl-d-aspartate (NMDA) receptor, and serotonin 6 (5-hydroxytryptamine 6, 5-HT6) receptor activities (in vitro) in search of active principles and underlying mechanisms of action. We confirmed the antistress effects of RO in a sleep-deprived stress model in rat and explored the underlying mechanisms of its action. In conclusion, an R. rugosa extract showed efficacy and potential for use as an antistress therapy to treat sleep deprivation through its antagonism of the 5-HT6 receptor and resulting inhibition of cAMP activity. [ABSTRACT FROM AUTHOR]