Declined memory is a hallmark of Alzheimer\'s disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HT2CR signaling regulates memory, which may inform the use of 5-HT2CR agonists in the treatment of dementia.

(1) Background: The effects of short-term social isolation during adulthood have not yet been fully established in rats behaviourally, and not at all transcriptomically in the medial prefrontal cortex (mPFC). (2) Methods: We measured the behavioural effects of housing adult male rats in pairs or alone for 10 days. We also used RNA sequencing to measure the accompanying gene expression alterations in the mPFC of male rats. (3) Results: The isolated animals exhibited reduced sociability and social novelty preference, but increased social interaction. There was no change in their aggression, anxiety, or depression-like activity. Transcriptomic analysis revealed a differential expression of 46 genes between the groups. The KEGG pathway analysis showed that differentially expressed genes are involved in neuroactive ligand-receptor interactions, particularly in the dopaminergic and peptidergic systems, and addiction. Subsequent validation confirmed the decreased level of three altered genes: regulator of G protein signalling 9 (Rgs9), serotonin receptor 2c (Htr2c), and Prodynorphin (Pdyn), which are involved in dopaminergic, serotonergic, and peptidergic function, respectively. Antagonizing Htr2c confirmed its role in social novelty discrimination. (4) Conclusions: Social homeostatic regulations include monoaminergic and peptidergic systems of the mPFC.

Dysfunction of central serotonergic neurons is known to cause depressive disorders in humans, who often show reproductive and/or glucose metabolism disorders. This study examined whether dorsal raphe (DR) serotonergic neurons sense high glucose availability to upregulate reproductive function via activating hypothalamic arcuate (ARC) kisspeptin neurons (= KNDy neurons), a dominant stimulator of gonadotropin-releasing hormone (GnRH)/gonadotropin pulses, using female rats and goats. RNA-seq and histological analysis revealed that stimulatory serotonin-2C receptor (5HT2CR) was mainly expressed in the KNDy neurons in female rats. The serotonergic reuptake inhibitor administration into the mediobasal hypothalamus (MBH), including the ARC, significantly blocked glucoprivic suppression of luteinizing hormone (LH) pulses and hyperglycemia induced by intravenous 2-deoxy-D-glucose (2DG) administration in female rats. A local infusion of glucose into the DR significantly increased in vivo serotonin release in the MBH and partly restored LH pulses and hyperglycemia in the 2DG-treated female rats. Furthermore, central administration of serotonin or a 5HT2CR agonist immediately evoked GnRH pulse generator activity, and central 5HT2CR antagonism blocked the serotonin-induced facilitation of GnRH pulse generator activity in ovariectomized goats. These results suggest that DR serotonergic neurons sense high glucose availability to reduce gluconeogenesis and upregulate reproductive function by activating GnRH/LH pulse generator activity in mammals.

OBJECTIVE: Several studies have investigated the association between anorexia nervosa and polymorphisms of genes regulating serotonin neurotransmission, with a focus on the rs6311 polymorphism of 5-HTR2A. However, inconsistent results of these studies and conflicting conclusions of existing meta-analyses complicate the understanding of a possible association. We have updated these results and evaluated the involvement of other serotonin receptor gene polymorphisms in anorexia nervosa.
METHODS: Adhering to PRISMA guidelines, we have searched studies on anorexia nervosa and serotonin-regulating genes published from 1997 to 2022, selected those concerning receptor genes and meta-analyzed the results from twenty candidate gene studies on the 5-HTR2A rs6311 polymorphism and the 5-HTR2C rs6318 polymorphism.
RESULTS: Present analyses reveal an association for the 5-HTR2A rs6311 polymorphism, with G and A alleles, across eighteen studies (2049 patients, 2877 controls; A vs. G allele, Odds Ratio = 1.24; 95% Confidence Interval = 1.06-1.47; p = 0.009). However, after geographic subgrouping, an association emerged only in a Southern European area, involving five studies (722 patients, 773 controls; A vs. G allele, Odds Ratio = 1.82; 95% Confidence Interval = 1.41-2.37; p < 0.00001). No association was observed for the 5-HTR2C rs6318 polymorphism across three studies.
CONCLUSIONS: To date, the involvement in the pathophysiology of anorexia nervosa of the 5-HTR2A rs6311 polymorphism appears limited to a specific genetic and/or environmental context, while that of the 5-HTR2C rs6318 polymorphism seems excluded. Genome-wide association studies and epigenetic studies will likely offer deeper insights of genetic and environmental factors possibly contributing to the disorder.
METHODS: III Evidence obtained from well-designed cohort or case-control analytic studies. Clinical trial registration PROSPERO registration number: CRD42021246122.

BACKGROUND: Cognitive flexibility, the ability to adapt behaviour in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder and major depressive disorder. Evidence suggests that flexibility, which can be operationalised using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behaviour and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown.
OBJECTIVE: We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on flexibility and underlying RL mechanisms.
METHODS: Thirty-six male Lister hooded rats were trained on a touchscreen visual discrimination and reversal task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to task choice data to extract RL parameters, including a novel model designed specifically for this task.
RESULTS: 5-HT2AR antagonism impaired reversal learning only after an initial perseverative phase, during a period of random choice and then new learning. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate (i.e. negative feedback) at high and low doses. The low dose also decreased reinforcement sensitivity (beta) and increased stimulus and side stickiness (i.e., the tendency to repeat a choice regardless of outcome). 5-HT2CR antagonism also decreased beta, but reduced side stickiness.
CONCLUSIONS: These data indicate that 5-HT2A and 5-HT2CRs both modulate different aspects of flexibility, with 5-HT2ARs modulating learning from negative feedback as measured using RL parameters and 5-HT2CRs for learning from positive feedback assessed through conventional measures.

BACKGROUND: Serotonin (5-HT) 5-HT2C receptor mRNA editing (at five sites, A-E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence-often accompanied by depressive symptoms.
METHODS: We used deep sequencing to investigate 5-HT2C receptor editing in mice during early ethanol deprivation following prolonged alcohol exposure and mice lacking tryptophan hydroxylase (TPH)2, a key enzyme in central 5-HT production. We also examined Tph2 expression in ethanol-deprived animals using quantitative real-time PCR (qPCR).
RESULTS: Cessation from chronic 10% ethanol exposure in a two-bottle choice paradigm enhanced immobility time and decreased latency in the forced swim test (FST), indicating a depression-like phenotype. In the hippocampus, ethanol-deprived \"high ethanol-drinking\" mice displayed reduced Tph2 expression, elevated 5-HT2C receptor editing efficiency, and decreased frequency of the D mRNA variant, encoding the less-edited INV protein isoform. Tph2-/- mice showed attenuated receptor editing in the hippocampus and elevated frequency of non-edited None and D variants. In the prefrontal cortex, Tph2 deficiency increased receptor mRNA editing at site D and reduced the frequency of AB transcript, predicting a reduction in the corresponding partially edited VNI isoform.
CONCLUSIONS: Our findings reveal differential effects of 5-HT depletion and ethanol cessation on 5-HT2C receptor editing. Central 5-HT depletion attenuated editing in the prefrontal cortex and the hippocampus, whereas ethanol deprivation, coinciding with reduced Tph2 expression in the hippocampus, enhanced receptor editing efficiency specifically in this brain region. This study highlights the interplay between 5-HT synthesis, ethanol cessation, and 5-HT2C receptor editing, providing potential mechanism underlying increased ethanol consumption and deprivation.

Orthogonal recreation of the signaling profile of a chemical synapse is a current challenge in neuroscience. This is due in part to the kinetics of synaptic signaling, where neurotransmitters are rapidly released and quickly cleared by active reuptake machinery. One strategy to produce a rapid rise in an orthogonally controlled signal is via photocaged compounds. In this work, photocaged compounds are employed to recreate both the rapid rise and equally rapid fall in activation at a chemical synapse. Specifically, a complementary pair of photocages based on BODIPY were conjugated to a 5-HT2C subtype-selective agonist, WAY-161503, and antagonist, N-desmethylclozapine, to generate \"caged\" versions of these drugs. These conjugates release the bioactive drug upon illumination with green light (agonist) or red light (antagonist). We report on the synthesis, characterization, and bioactivity testing of the conjugates against the 5-HT2C receptor. We then characterize the kinetics of photolysis quantitatively using HPLC and qualitatively in cell culture conditions stimulating live cells. The compounds are shown to be stable in the dark for 48 h at room temperature, yet photolyze rapidly when irradiated with visible light. In live cells expressing the 5-HT2C receptor, precise spatiotemporal control of the degree and length of calcium signaling is demonstrated. By loading both compounds in tandem and leveraging spectral multiplexing as a noninvasive method to control local small-molecule drug availability, we can reproducibly initiate and suppress intracellular calcium flux on a timescale not possible by traditional methods of drug dosing. These tools enable a greater spatiotemporal control of 5-HT2C modulation and will allow for more detailed studies of the receptors\' signaling, interactions with other proteins, and native physiology.

The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

Behaviors associated with distress can affect the anxiety-like states in observers and this social transfer of affect shapes social interactions among stressed individuals. We hypothesized that social reactions to stressed individuals engage the serotonergic dorsal raphe nucleus (DRN) which promotes anxiety-like behavior via postsynaptic action of serotonin at serotonin 2C (5-HT2C) receptors in the forebrain. First, we inhibited the DRN by administering an agonist (8-OH-DPAT, 1 μg in 0.5 μL) for the inhibitory 5-HT1A autoreceptors which silences 5-HT neuronal activity. 8-OH-DPAT prevented the approach and avoidance, respectively, of stressed juvenile (PN30) or stressed adult (PN60) conspecifics in the social affective preference (SAP) test in rats. Similarly, systemic administration of a 5-HT2C receptor antagonist (SB242084, 1 mg/kg, i.p.) prevented approach and avoidance of stressed juvenile or adult conspecifics, respectively. Seeking a locus of 5-HT2C action, we considered the posterior insular cortex which is critical for social affective behaviors and rich with 5-HT2C receptors. SB242084 administered directly into the insular cortex (5 μM in 0.5 μL bilaterally) interfered with the typical approach and avoidance behaviors observed in the SAP test. Finally, using fluorescent in situ hybridization, we found that 5-HT2C receptor mRNA (htr2c) is primarily colocalized with mRNA associated with excitatory glutamatergic neurons (vglut1) in the posterior insula. Importantly, the results of these treatments were the same in male and female rats. These data suggest that interactions with stressed others require the serotonergic DRN and that serotonin modulates social affective decision-making via action at insular 5-HT2C receptors.