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Cocaine blocks dopamine reuptake, thereby producing rewarding effects that are widely studied. However, cocaine also blocks serotonin uptake, which we show drives, in rats, individually variable aversive effects that depend on serotonin 2C receptors (5-HT2CRs) in the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons. 5-HT2CRs produce depolarizing effects in RMTg neurons that are particularly strong in some rats, leading to aversive effects that reduce acquisition of and relapse to cocaine seeking. In contrast, 5-HT2CR signaling is largely lost after cocaine exposure in other rats, leading to reduced aversive effects and increased cocaine seeking. These results suggest a serotonergic biological marker of cocaine-seeking vulnerability that can be targeted to modulate drug seeking., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which, respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization., Competing Interests: Declaration of Competing Interest MG reports receiving consulting fees from Psygen Labs Inc. and EntheoTech Bioscience. RLCH reports receiving consulting fees from COMPASS Pathways, Entheon Biomedical, Mydecine, Synthesis Institute, Tryp Therapeutics, and Usona Institute. BB, JS, RNS, and LR report no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period., Methods: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed., Results: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research., Conclusions: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions., (Published by Oxford University Press on behalf of CINP 2020.)

An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy.

p-Chloroamphetamine (PCA), an amphetamine derivative, has been shown to induce serotonergic toxicity. However, the precise mechanism of serotonergic toxicity induced by PCA remains unclear. In this study, PCA treatment (20 mg/kg, i.p.) did not significantly change 5-HT 1A receptor gene expression, but significantly increased 5-HT 2A receptor gene expression. Furthermore, 5-HT 2A receptor antagonist MDL11939, but not 5-HT 1A receptor antagonist WAY100635, significantly attenuated PCA-induced serotonergic impairments. We investigated whether PCA activated a specific isoform of protein kinase C (PKC), since previous evidence indicated the involvement of PKC in neurotoxicity induced by amphetamines. We observed that PCA treatment significantly increased the expression levels of PKCδ among all PKC isoforms. MDL11939 treatment significantly attenuated PCA-induced phosphorylation of PKCδ. However, PCA-induced increase in 5-HT 2A receptor gene expression was not altered by rottlerin (a pharmacological inhibitor of PKCδ) in mice, suggesting that 5-HT 2A receptor is an upstream molecule for the activation of PKCδ. Rottlerin or PKCδ knockout significantly attenuated serotonergic behaviors. However, MDL11939 did not show any additional effects against the attenuation caused by PKCδ knockout in mice, suggesting that PKCδ gene is a molecular target for 5-HT 2A receptor-mediated serotonergic effects. Our results suggest that 5-HT 2A receptor mediates PCA-induced serotonergic impairments via activation of PKC.δ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The assessment of clinical efficacy and toxicity is very important in pharmacology and toxicology. The effects of psychostimulants (e.g. amphetamine), psychotomimetics (e.g. Cannabis sativus) and snake antivenoms are sometimes unpredictable even at lower doses, leading to serious intoxication and fatal consequences. Hence, there is need to re-assess some formulas for calculation of therapeutic index, lethal time and safety margin with a view to identifying therapeutic agents with remarkable toxicity potentials., Results: The therapeutic index formula [Formula: see text] was derived from T 1  = LD 50 /ED 50 and ED 50  = [Formula: see text]. Findings have shown that, therapeutic index is a function of death reversal (s), safety factor (10 -4 ) and weight of animal (Wa). However, the new safety margin formula [Formula: see text] derived from LT 50  = [Formula: see text] and MS = [Formula: see text] shows that safety margin is a function of cube root of ratio between LT 50 and LD 50 and ED 100th . Concentration (k) of toxicant at the receptor [Formula: see text] derived from D 1 × T n  = K and LD 1  = [Formula: see text] shows that therapeutic index, lethal time and safety margin is a function of drug or toxicant concentration at the receptor, the drug-receptor interaction and dose of toxicant or drug administered at a particular time.

Chikungunya virus (CHIKV) is an important reemerging human pathogen transmitted by mosquitoes. The virus causes an acute febrile illness, chikungunya fever, which is characterized by headache, rash, and debilitating (poly)arthralgia that can reside for months to years after infection. Currently, effective antiviral therapies and vaccines are lacking. Due to the high morbidity and economic burden in the countries affected by CHIKV, there is a strong need for new strategies to inhibit CHIKV replication. The serotonergic drug 5-nonyloxytryptamine (5-NT) was previously identified as a potential host-directed inhibitor for CHIKV infection. In this study, we determined the mechanism of action by which the serotonin receptor agonist 5-NT controls CHIKV infection. Using time-of-addition and entry bypass assays, we found that 5-NT predominantly inhibits CHIKV in the early phases of the replication cycle, at a step prior to RNA translation and genome replication. Intriguingly, however, no effect was seen during virus-cell binding, internalization, membrane fusion and genomic RNA (gRNA) release into the cell cytosol. In addition, we show that the serotonin receptor antagonist methiothepin mesylate (MM) also has antiviral properties toward CHIKV and specifically interferes with the cell entry process and/or membrane fusion. Taken together, pharmacological targeting of 5-HT receptors may represent a potent way to limit viral spread and disease severity. IMPORTANCE The rapid spread of mosquito-borne viral diseases in humans puts a huge economic burden on developing countries. For many of these infections, including those caused by chikungunya virus (CHIKV), there are no specific treatment possibilities to alleviate disease symptoms. Understanding the virus-host interactions that are involved in the viral replication cycle is imperative for the rational design of therapeutic strategies. In this study, we discovered an antiviral compound, elucidated its mechanism of action, and propose serotonergic drugs as potential host-directed antivirals for CHIKV., (Copyright © 2020 American Society for Microbiology.)

Background: This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5-3 mg/d) for major depressive disorder where antidepressant treatment had failed., Methods: The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression-Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose)., Results: We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89-0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93-0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = -0.20, 95% CI = -0.29, -0.11), Sheehan Disability Scale score (standardized mean difference = -0.12, 95% CI = -0.21, -0.04), and Clinical Global Impression-Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50)., Conclusions: Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than >2 mg/d., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

The metacercariae of the Clonorchis sinensis liver fluke excyst in the duodenum of mammalian hosts, and the newly excysted juveniles (CsNEJs) migrate along the bile duct via bile chemotaxis. Cholic acid is a major component of bile that induces this migration. We investigated the neuronal control of chemotactic behavior of CsNEJs toward cholic acid. The migration of CsNEJs was strongly inhibited at sub-micromolar concentration by dopamine D1 (LE-300 and SKF-83566), D2 (spiramide, nemonapride, and sulpiride), and D3 (GR-103691 and NGB-2904) receptor antagonists, as well as a dopamine reuptake inhibitor (BTCP). Neuropeptides, FMRFamide, peptide YY, and neuropeptide Y were also potent inhibitors of chemotaxis. Meanwhile, serotonergic, glutamatergic, and cholinergic inhibitors did not affect chemotaxis, with the exception of fluoxetine and CNQX. Confocal immunofluorescence analysis indicated that dopaminergic and cholinergic neurons were colocalized in the somatic muscle tissues of adult C. sinensis. Our findings suggest that dopaminergic neurons and neuropeptides play a major role in the chemotactic migration of CsNEJs to bile, and their inhibitors or modulators could be utilized to prevent their migration from the bile duct., Competing Interests: The authors have declared that no competing interests exist.

Key Points: 5-HT increases the excitability of brainstem and spinal motoneurons, including the jaw-closing motoneurons, by depolarizing the membrane potential and decreasing the medium-duration afterhyperpolarization. In this study, we focused on how 5-HT enhances postsynaptic glutamatergic responses in the dendrites of the jaw-closing motoneurons. We demonstrate that 5-HT augments glutamatergic signalling by enhancing the function of the GluN2A-containing NMDA receptor (NMDAR) through the activation of 5-HT 2A receptors (5-HT 2A Rs) and Src kinase. To enhance glutamatergic responses, activation of the 5-HT 2A Rs must occur within ∼60 μm of the location of the glutamate responses. 5-HT inputs to the jaw-closing motoneurons can significantly vary their input-output relationship, which may contribute to wide-range regulation of contractile forces of the jaw-closing muscles., Abstract: Various motor behaviours are modulated by 5-HT. Although the masseter (jaw-closing) motoneurons receive both glutamatergic and serotonergic inputs, it remains unclear how 5-HT affects the glutamatergic inputs to the motoneuronal dendrites. We examined the effects of 5-HT on postsynaptic responses evoked by single- or two-photon uncaging of caged glutamate (glutamate responses) to the dendrites of masseter motoneurons in postnatal day 2-5 rats of either sex. Application of 5-HT induced membrane depolarization and enhanced the glutamate-response amplitude. This enhancement was mimicked by the 5-HT 2A receptor (5-HT 2A R) agonist and was blocked by the 5-HT 2A/2C R antagonist. However, neither the 5-HT 2B R nor the 5-HT 2C R agonists altered glutamate responses. Blockade of the NMDA receptors (NMDARs), but not AMPA receptors, abolished the 5-HT-induced enhancement. Furthermore, the selective antagonist for the GluN2A subunit abolished the 5-HT-induced enhancement. 5-HT increased GluN2A phosphorylation, while the Src kinase inhibitor reduced the 5-HT-induced enhancement and GluN2A phosphorylation. When exposure to the 5-HT 2A R agonist was targeted to the dendrites, the enhancement of glutamate responses was restricted to the loci of the dendrites near the puff loci. Electron microscopic immunohistochemistry revealed that both the NMDARs and the 5-HT 2A Rs were close to each other in the same dendrite. These results suggest that activation of dendritic 5-HT 2A Rs enhances the function of local GluN2A-containing NMDARs through Src kinase. Such enhancement of the glutamate responses by 5-HT may contribute to wide-range regulation of contractile forces of the jaw-closing muscles., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Social decision-making is fundamental for successful functioning and can be affected in psychiatric illness and by serotoninergic modulation. The Prisoner's Dilemma is the archetypal paradigm to model cooperation and trust. However, the effect of serotonergic enhancement is poorly characterized, and its influence on the effect of variations in opponent behavior unknown. To address this, we conducted a study investigating how the serotonergic enhancer 3,4-methylenedioxy-methamphetamine (MDMA) modulates behavior and its neural correlates during an iterated Prisoner's Dilemma with both trustworthy and untrustworthy opponents. We administered 100 mg MDMA or placebo to 20 male participants in a double-blind, placebo-controlled, crossover study. While being scanned, participants played repeated rounds with opponents who differed in levels of cooperation. On each round, participants chose to compete or cooperate and were asked to rate their trust in the other player. Cooperation with trustworthy, but not untrustworthy, opponents was enhanced following MDMA but not placebo (respectively: odds ratio = 2.01; 95% CI, 1.42-2.84, p < 0.001; odds ratio = 1.37; 95% CI, 0.78-2.30, not significant). Specifically, MDMA enhanced recovery from, but not the impact of, breaches in cooperation. During trial outcome, MDMA increased activation of four clusters incorporating precentral and supramarginal gyri, superior temporal cortex, central operculum/posterior insula, and supplementary motor area. There was a treatment × opponent interaction in right anterior insula and dorsal caudate. Trust ratings did not change across treatment sessions. MDMA increased cooperative behavior when playing trustworthy opponents. Underlying this was a change in brain activity of regions linked to social cognition. Our findings highlight the context-specific nature of MDMA's effect on social decision-making. SIGNIFICANCE STATEMENT We provide a detailed analysis of the effect of 3,4-methylenedioxy-methamphetamine (MDMA) on cooperative behavior during interpersonal interactions, as well as the neural correlates underlying these effects. We find that, following administration of MDMA, participants behave more cooperatively, but only when interacting with trustworthy partners. While breaches of trustworthy behavior have a similar impact following administration of MDMA compared with placebo, MDMA facilitates a greater recovery from these breaches of trust. Underlying this altered behavior are changes in brain activity during the viewing of opponents' behavior in regions whose involvement in social processing is well established. This work provides new insights into the impact of MDMA on social interactions, emphasizing the important role of the behavior of others toward us., (Copyright © 2019 the authors 0270-6474/19/390308-14$15.00/0.)

Understanding how afferent information is integrated by cortical structures requires identifying the factors shaping excitation and inhibition within their input layers. The input layer of the cerebellar cortex integrates diverse sensorimotor information to enable learned associations that refine the dynamics of movement. Specifically, mossy fiber afferents relay sensorimotor input into the cerebellum to excite granule cells, whose activity is regulated by inhibitory Golgi cells. To test how this integration can be modulated, we have used an acute brain slice preparation from young adult rats and found that encoding of mossy fiber input in the cerebellar granule cell layer can be regulated by serotonin (5-hydroxytryptamine, 5-HT) via a specific action on Golgi cells. We find that 5-HT depolarizes Golgi cells, likely by activating 5-HT2A receptors, but does not directly act on either granule cells or mossy fibers. As a result of Golgi cell depolarization, 5-HT significantly increases tonic inhibition onto both granule cells and Golgi cells. 5-HT-mediated Golgi cell depolarization is not sufficient, however, to alter the probability or timing of mossy fiber-evoked feed-forward inhibition onto granule cells. Together, increased granule cell tonic inhibition paired with normal feed-forward inhibition acts to reduce granule cell spike probability without altering spike timing. Hence, these data provide a circuit mechanism by which 5-HT can reduce granule cell activity without altering temporal representations of mossy fiber input. Such changes in network integration could enable flexible, state-specific suppression of cerebellar sensorimotor input that should not be learned or enable reversal learning for unwanted associations. NEW & NOTEWORTHY Serotonin (5-hydroxytryptamine, 5-HT) regulates synaptic integration at the input stage of cerebellar processing by increasing tonic inhibition of granule cells. This circuit mechanism reduces the probability of granule cell spiking without altering spike timing, thus suppressing cerebellar input without altering its temporal representation in the granule cell layer.

The association of chronic pain with depression is becoming increasingly recognized. Treating both the conditions together is essential for an effective treatment outcome. In this regard, it is important to identify a shared mechanism involved in the association of chronic pain with depression. Central serotonin (5-hydroxytryptamine; 5-HT) neurotransmission has long been known to participate in the processing of signals related to pain. It also plays a key role in the pathogenesis and treatment of depression. Although functional responses to serotonin are mediated via the activation of multiple receptor types and subtypes, the 5-HT1A subtype is involved in the processing of nociception as well as the pathogenesis and treatment of depression. This receptor is located presynaptically, as an autoreceptor, on the perikaryon and dendritic spines of serotonin-containing neurons. It is also expressed as a heteroreceptor on neurons receiving input from serotonergic neurons. This article targets the 5-HT1A receptors to show that indiscriminate activation of pre and postsynaptic 5-HT1A receptors is likely to produce no therapeutic benefits; biased activation of the 5-HT heteroreceptors may be a useful strategy for treating chronic pain and depression individually as well as in a comorbid condition., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Serotonergic (5-HT) modulation of the lateral habenula (LHb) activity is central in normal and pathologic conditions such as mood disorders. Among the multiple 5-HT receptors (5-HTRs) involved, the 5-HT 2C R seems to play a pivotal role. Yet, the role of 5-HT 2A Rs in the control of the LHb neuronal activity is completely unknown., Methods: Single-cell extracellular recording of the LHb neurons was used in rats to study the effect of the general activation and blockade of the 5-HT 2C R and 5-HT 2A R with Ro 60-0175 and SB242084, TCB-2 and MDL11939, respectively. The expression of both receptors in the LHb was confirmed using immunohistochemistry., Results: Cumulative doses (5-640 μg/kg, iv) of Ro 60-0175 and TCB-2 affected the activity of 34% and 63% of the LHb recorded neurons, respectively. LHb neurons were either inhibited at low doses or excited at higher doses of the 5-HT 2A/C R agonists. SB242084 or MDL11939 (both at 200 μg/kg, iv) did not modify neuronal firing when injected alone, but reverted the bidirectional effects of Ro 60-0175 or TCB-2, respectively. 5-HT 2C Rs and 5-HT 2A Rs are expressed in less than the 20% of the LHb neurons, and they neither colocalize nor make heterodimers. Strikingly, only 5-HT 2A Rs are expressed by the majority of LHb astrocyte cells., Conclusions: Peripheral administration of 5-HT 2A R agonist promotes a heterogeneous pattern of neuronal responses in the LHb, and these effects are more prominent than those induced by the 5-HT 2C R activation., (© 2018 John Wiley & Sons Ltd.)

A developing brain shows intense reorganization and heightened neuronal plasticity allowing for environmental modulation of its development. During early life, maternal care is a key factor of this environment and defects in this care can derail adaptive brain development and may result in susceptibility to neuropsychiatric disorders. Nevertheless, the mechanisms by which those maternal interactions immediately impact the offspring's brain activity to initiate the pathway to pathology are not well understood. We do know that multiple neurotransmitter systems are involved, including the serotonergic system, a key neuromodulator involved in brain development and emotional regulation. We tested the importance of the serotonergic system and pups' immediate neural response to maternal presence using wireless electrophysiological recordings, a novel approach allowing us to record neural activity during pups' interactions with their mother. We found that maternal contact modulates the P10-P12 rat pups' anterior cingulate cortex (ACC) activity by notably increasing local-field potential (LFP) power in low-frequency bands. We demonstrated, by blocking serotonergic receptors, that this increase is mediated through 5-HT2 receptors (5-HT2Rs). Finally, we showed in isolated pups that enhancing serotonergic transmission, using a selective-serotonin-reuptake-inhibitor, is sufficient to enhance LFP power in low-frequency bands in a pattern similar to that observed when the mother is in the nest. Our results highlight a significant contribution of the serotonergic system in mediating changes of cortical activity in pups related to maternal presence.

In patients with obstructive sleep apnea (OSA), the pharyngeal muscles become relaxed during sleep, which leads to a partial or complete closure of upper airway. Experimental studies suggest that withdrawal of noradrenergic and serotonergic drives importantly contributes to depression of hypoglossal motoneurons and, therefore, may contribute to OSA pathophysiology; however, specific cellular and synaptic mechanisms remain unknown. In this new study, we developed a biophysical network model to test the hypothesis that, to explain experimental observations, the neuronal network for monoaminergic control of excitability of hypoglossal motoneurons needs to include excitatory and inhibitory perihypoglossal interneurons that mediate noradrenergic and serotonergic drives to hypoglossal motoneurons. In the model, the state-dependent activation of the hypoglossal motoneurons was in qualitative agreement with in vivo data during simulated rapid eye movement (REM) and non-REM sleep. The model was applied to test the mechanisms of action of noradrenergic and serotonergic drugs during REM sleep as observed in vivo. We conclude that the proposed minimal neuronal circuit is sufficient to explain in vivo data and supports the hypothesis that perihypoglossal interneurons may mediate state-dependent monoaminergic drive to hypoglossal motoneurons. The population of the hypothesized perihypoglossal interneurons may serve as novel targets for pharmacological treatment of OSA. NEW & NOTEWORTHY In vivo studies suggest that during rapid eye movement sleep, withdrawal of noradrenergic and serotonergic drives critically contributes to depression of hypoglossal motoneurons (HMs), which innervate the tongue muscles. By means of a biophysical model, which is consistent with a broad range of empirical data, we demonstrate that the neuronal network controlling the excitability of HMs needs to include excitatory and inhibitory interneurons that mediate noradrenergic and serotonergic drives to HMs.

The ability of parasites to manipulate the behaviour of their hosts has evolved multiple times, and has a clear fitness benefit to the parasite in terms of facilitating growth, reproduction and transfer to suitable hosts. The mechanisms by which these behavioural changes are induced are poorly understood, but in many cases parasite manipulation of serotonergic signalling in the host brain is implicated. Here we report that Phasmarhabditis hermaphrodita, a parasite of terrestrial gastropod molluscs, can alter the behaviour of slugs. Uninfected slugs (Deroceras panormitanum, Arion subfuscus and Arion hortensis) avoid areas where P. hermaphrodita is present, but slugs infected with P. hermaphrodita are more likely to be found where the nematodes are present. This ability is specific to P. hermaphrodita and other nematodes (Steinernema carpocapsae and Heterorhabditis bacteriophora) do not induce this behavioural change. To investigate how P. hermaphrodita changes slug behaviour we exposed slugs to fluoxetine (a selective serotonin reuptake inhibitor) and cyproheptadine (a serotonin receptor antagonist). Uninfected slugs fed fluoxetine no longer avoided areas where P. hermaphrodita was present; and conversely, infected slugs fed cyproheptadine showed no increased attraction to areas with nematodes. These findings suggest that a possible mechanism by which P. hermaphrodita is able to manipulate parasite avoidance behaviour in host slugs is by manipulating serotonergic signalling in the brain, and that increased serotonin levels are potentially associated with a reduction in parasite avoidance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

PCC0104005 is a novel drug candidate for treating schizophrenia that displays high affinity for serotonin, dopamine, and noradrenaline receptors, including partial agonism at dopamine D 2 , D 3 , D 4 , serotonin 5-HT 1A , and 5-HT 2A receptors and antagonism at 5-HT 2B , 5-HT 6 , and 5-HT 7 receptors. PCC0104005 blocks MK-801-induced hyperactivity in rats, consistent with the reduction in dopamine D 2 receptor stimulation and increased dopamine release in the medial prefrontal cortex. PCC0104005 inhibits 5-HTP-induced head twitches in rats, due to its moderate affinity for human 5-HT 2A receptors (Ki = 5.1 nM). PCC0104005 significantly reduced the escape latency of rats and improved the MK-801-induced memory impairment. In the object recognition experiment, PCC0104005 significantly improved the recognition disorder induced by MK-801. PCC0104005 did not significantly increase the plasma prolactin level, which is thought to be related to the preferential affinity of PCC0104005 for dopamine D 2 receptors compared with 5-HT 1A receptors, as well as the relative antagonistic activity toward the D 2 receptor. Due to its 5-HT 1A agonism, PCC0104005 does not produce catalepsy in mice, a behaviour predictive of the occurrence of extra-pyramidal syndrome (EPS) in humans. PCC0104005 has unique affinities for dopamine receptors and serotonin receptors, which may lead to clinical advantages, as well as fewer adverse reactions.

Prefrontal cortex is a hub for attention processing and receives abundant innervation from cholinergic and serotonergic afferents. A growing body of evidence suggests that acetylcholine (ACh) and serotonin (5-HT) have opposing influences on tasks requiring attention, but the underlying neurophysiology of their opposition is unclear. One candidate target population is medial prefrontal layer 6 pyramidal neurons, which provide feedback modulation of the thalamus, as well as feed-forward excitation of cortical interneurons. Here, we assess the response of these neurons to ACh and 5-HT using whole cell recordings in acute brain slices from mouse cortex. With application of exogenous agonists, we show that individual layer 6 pyramidal neurons are bidirectionally-modulated, with ACh and 5-HT exerting opposite effects on excitability across a number of concentrations. Next, we tested the responses of layer 6 pyramidal neurons to optogenetic release of endogenous ACh or 5-HT. These experiments were performed in brain slices from transgenic mice expressing channelrhodopsin in either ChAT-expressing cholinergic neurons or Pet1-expressing serotonergic neurons. Light-evoked endogenous neuromodulation recapitulated the effects of exogenous neurotransmitters, showing opposing modulation of layer 6 pyramidal neurons by ACh and 5-HT. Lastly, the addition of 5-HT to either endogenous or exogenous ACh significantly suppressed the excitation of pyramidal neurons in prefrontal layer 6. Taken together, this work suggests that the major corticothalamic layer of prefrontal cortex is a substrate for opposing modulatory influences on neuronal activity that could have implications for regulation of attention.

Background: Epilepsy is a syndrome of brain dysfunction caused by spontaneous, abnormal discharge. Many anti-epileptic drugs have developed in past decades. 5-HT is an important neurotransmitter in the central and peripheral nervous system of the human body which is involved in a number of physiological activities, such as sensation, movement, and behavior. 5-HT subtype have been divided into seven sub-groups from 5-HT1 to 5HT7. However, the role of 5-HT3 receptor on epilepsy is unclear. Therefore, in this article, the possible role of 5-HT3 receptor on epilepsy was systemically reviewed., Methods: Data were collected from Web of Science, Medline, Pubmed, Scopus, through searching of these keywords: "5-HT3" and "epilepsy"., Results: An increasing number of studies have shown that the activation of the 5-HT3 receptor can inhibit epileptic seizures, while inhibition of the 5-HT3 receptor can promote spike waves., Conclusion: In this review, we discuss the relationship between the 5HT3 receptor and epilepsy; this review may provide a new insight for clinical application of epilepsy treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Using transgenic (TG) mice that overexpress the human serotonin (5-HT) 4a receptor specifically in cardiomyocytes, we wanted to know whether 5-HT can be formed and degraded in the mammalian heart and whether this can likewise lead to inotropic and chronotropic effects in this TG model. We noted that the 5-HT precursor 5-hydroxy-tryptophan (5-HTP) can exert inotropic and chronotropic effects in cardiac preparations from TG mice but not from wild-type (WT) mice; similar results were found in human atrial preparations as well as in intact TG animals using echocardiography. Moreover, by immunohistochemistry we could detect 5-HT metabolizing enzymes and 5-HT transporters in mouse hearts as well as in human atria. Hence, in the presence of an inhibitor of aromatic l-amino acid decarboxylase, the positive inotropic effects of 5-HTP were absent in TG and isolated human atrial preparations, and, moreover, inhibitors of enzymes involved in 5-HT degradation enhanced the efficacy of 5-HT in TG atria. A releaser of neurotransmitters increased inotropy in the isolated TG atrium, and this effect could be blocked by a 5-HT 4a receptor antagonist. Fluoxetine, an inhibitor of 5-HT uptake, elevated the potency of 5-HT to increase contractility in the TG atrium. In addition, inhibitors of organic cation and monoamine transporters apparently reduced the positive inotropic potency of 5-HT in the TG atrium. Hence, we tentatively conclude that a local production and degradation of 5-HT in the mammalian heart and more specifically in mammalian myocytes probably occurs. Conceivably, this formation of 5-HT and possibly impaired degradation may be clinically relevant in cases of unexplained tachycardia and other arrhythmias. NEW & NOTEWORTHY The present work suggests that inotropically active serotonin (5-HT) can be formed in the mouse and human heart and probably by cardiomyocytes themselves. Moreover, active degradation of 5-HT seems to occur in the mammalian heart. These findings may again increase the interest of researchers for cardiac effects of 5-HT., (Copyright © 2017 the American Physiological Society.)

Converging lines of behavioral, electrophysiological, and biochemical evidence suggest that 5-HT 2C receptor signaling may bidirectionally influence reward-related behavior through an interaction with the mesolimbic dopamine (DA) system. Here we directly test this hypothesis by examining how modulating 5-HT 2C receptor activity affects DA-dependent behaviors and relate these effects to changes in nucleus accumbens (NAc) DA release. In C57BL/6 mice, locomotor activity and responding for a conditioned reinforcer (CRf), a measure of incentive motivation, were examined following treatment with three 5-HT 2C receptor ligands: the agonist CP809101 (0.25-3 mg/kg), the antagonist SB242084 (0.25-1 mg/kg), or the antagonist/inverse agonist SB206553 (1-5 mg/kg). We further tested whether doses of these compounds that changed locomotor activity and responding for a CRf (1 mg/kg CP809101, 0.5 mg/kg SB242084, or 2.5 mg/kg SB206553) also altered NAc DA release using in vivo microdialysis in anesthetized mice. CP809101 reduced locomotor activity, responding for a CRf, and NAc DA release. In contrast, both SB242084 and SB206553 enhanced locomotor activity, responding for a CRf, and NAc DA release, although higher doses of SB206553 produced opposite behavioral effects. Pretreatment with the non-selective DA receptor antagonist α-flupenthixol prevented SB242084 from enhancing responding for a CRf. Thus blocking tonic 5-HT 2C receptor signaling can release serotonergic inhibition of mesolimbic DA activity and enhance reward-related behavior. The observed bidirectional effects of 5-HT 2C receptor ligands may have important implications when considering the 5-HT 2C receptor as a therapeutic target for psychiatric disorders, particularly those presenting with motivational dysfunctions.

3,4-Methylenedioxymethamphetamine (MDMA) increases sociality in humans and animals. Release of serotonin (5-HT) is thought to have an important role in the increase in social behaviors, but the mechanisms underlying these effects are poorly understood. Despite the advantages of nonhuman primate models, no studies have examined the mechanisms of the social effects of MDMA in nonhuman primates. The behavior and vocalizations of four group-housed squirrel monkeys were examined following administration of MDMA, its enantiomers, and methamphetamine. 5-HT receptor antagonists and agonists were given as drug pretreatments. Data were analyzed using linear mixed-effects models. MDMA and its enantiomers increased affiliative social behaviors and vocalizations, whereas methamphetamine had only modest effects on affiliative behaviors. Pretreatment with a 5-HT 2A receptor antagonist and a 5-HT 2C receptor agonist attenuated the MDMA-induced increase in social behaviors, while a 5-HT 1A receptor antagonist did not alter affiliative vocalizations and increased MDMA-induced social contact. Nonhuman primates show MDMA-specific increases in affiliative social behaviors following MDMA administration, in concordance with human and rodent studies. MDMA-induced increases in social behaviors are 5-HT 2A , but not 5-HT 1A , receptor dependent. Understanding the neurochemical mechanisms mediating the prosocial effects of MDMA could help in the development of novel therapeutics with the unique social effects of MDMA but fewer of its limitations.

Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain., Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region., Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex., Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Aim: Asenapine is a new atypical antipsychotic prescribed for the treatment of psychosis/bipolar disorders that presents higher affinity for serotonergic than dopaminergic receptors. The objective of this study was to investigate its antidepressant-like and antimanic-like properties on relevant animal models of depression and mania and to assess the acute and chronic effect of Asenapine on dorsal raphe nucleus (DRN) 5-HT cell firing activity., Methods: We assessed the effects of Asenapine using in vivo electrophysiological and behavioral assays in rats., Results: Behavioral experiments showed that Asenapine had no significant effect on immobility time in the forced swim test (FST) in control rats. In the ACTH-treated rats, a model of antidepressant-resistance, Asenapine failed to alter immobility time in the FST. In contrast in the sleep deprivation (SD) model of mania, acute administration of Asenapine significantly decreased the hyperlocomotion of SD rats. In the DRN, acute administration of Asenapine reduced the suppressant effect of the selective 5-HT 7 receptor agonist LP-44 and of the prototypical 5-HT 1A receptor agonist 8-OH-DPAT on 5-HT neuronal firing activity. In addition, chronic treatment with Asenapine enhanced DRN 5-HT neuronal firing and this effect was associated with an alteration of the 5-HT 7 receptor responsiveness., Conclusion: These results confirm that Asenapine displays robust antimanic property and effective in vivo antagonistic activity at 5-HT 1A/7 receptors., (© 2017 John Wiley & Sons Ltd.)

Background: Isolation-reared mice show social encounter-induced hyperactivity with activation of prefrontal serotonergic and dopaminergic systems, but it is not known whether this stress response is observed in other pathological conditions. Here we examined whether the social encounter stimulation induces abnormal behavior during withdrawal in chronic methamphetamine-treated mice., Methods: To induce methamphetamine-induced behavioral sensitization, male mice were injected with methamphetamine (1 mg/kg) once daily for 7 days., Results: The encounter with an intruder elicited hyperactivity 24 h after the last injection of methamphetamine in methamphetamine-sensitized mice. This response was observed even as long as 2 weeks after withdrawal of methamphetamine. The encounter increased c-Fos expression in the prefrontal cortex, dorsal raphe nucleus and ventral tegmental area in methamphetamine-sensitized mice, while it did not in control mice. Furthermore, the encounter increased extracellular serotonin (5-HT) and dopamine, but not noradrenaline, levels in the prefrontal cortex in methamphetamine-sensitized mice. Local injection of 5,7-dihydroxytryptamine and 6-hydroxydopamine into the prefrontal cortex attenuated encounter-induced hyperactivity in methamphetamine-sensitized mice and it markedly decreased prefrontal 5-HT and dopamine levels, respectively. Pharmacological analysis showed that the encounter-induced hyperactivity is mediated by dopamine D1 receptors and 5-HT2A receptors and attenuated by anxiolytics and antidepressants such as diazepam, osemozotan and selective 5-HT reuptake inhibitors. The effect of paroxetine was blocked by the 5-HT3 receptor antagonist azasetron., Conclusions: The present study shows that psychological stress elicits hyperactivity with activation of prefrontal 5-HT and dopamine systems in methamphetamine-dependent mice and suggests that the abnormal behavior is associated with anxiety and depression., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2 fl ° x conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion. Strikingly, these defects are rescued following reestablishment of brain 5-HT signaling via administration of the serotonin precursor 5-hydroxytryptophan (5-HTP). Finally, 3D reconstruction of serotonergic fibers reveals that changes in serotonin homeostasis affect axonal branching complexity. These data demonstrate that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring.

We previously demonstrated that chotosan (CTS), a traditional herbal formula called Kampo medicine, improves diabetes-induced cognitive deficits. In the present study, we investigated the antidepressant-like effects of CTS in mice. The administration of CTS (1.0 g/kg, for 3 days) decreased the immobility time in the forced-swim test, and this decrease was prevented by the prior administration of sulpiride (an antagonist of D 2/3 receptors) and WAY100635 (an antagonist of 5-HT 1A receptors). None of the treatments tested altered the locomotor activity of mice. These results suggest that CTS exerts antidepressant-like effects through changes in the serotonergic and dopaminergic systems., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT 2A receptor agonist PET radioligand, [ 11 C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [ 11 C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [ 11 C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2-11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [ 11 C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT 2A receptor occupancy indicates that [ 11 C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high.

Background Although pain is one of the most distressing non-motor symptoms among patients with Parkinson's disease, the underlying mechanisms of pain in Parkinson's disease remain elusive. The aim of the present study was to investigate the role of serotonin (5-hydroxytryptamine) in the rostral ventromedial medulla (RVM) and spinal cord in pain sensory abnormalities in a 6-hydroxydopamine-treated rat model of Parkinson's disease. Methods The rotarod test was used to evaluate motor function. The radiant heat test and von Frey test were conducted to evaluate thermal and mechanical pain thresholds, respectively. Immunofluorescence was used to examine 5-hydroxytryptamine neurons and fibers in the rostral ventromedial medulla and spinal cord. High-performance liquid chromatography was used to determine 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels. Results The duration of running time on the rotarod test was significantly reduced in 6-hydroxydopamine-treated rats. Nociceptive thresholds of both mechanical and heat pain were reduced compared to sham-treated rats. In addition to the degeneration of cell bodies and fibers in the substantia nigra pars compacta, the number of rostral ventromedial medulla 5-hydroxytryptamine neurons and 5-hydroxytryptamine fibers in the spinal dorsal horn was dramatically decreased. 5-Hydroxytryptamine concentrations in both the rostral ventromedial medulla and spinal cord were reduced. Furthermore, the administration of citalopram significantly attenuated pain hypersensitivity. Interestingly, Intra-rostral ventromedial medulla (intra-RVM) microinjection of 5,7-dihydroxytryptamine partially reversed pain hypersensitivity of 6-hydroxydopamine-treated rats. Conclusions These results suggest that the decreased 5-hydroxytryptamine contents in the rostral ventromedial medulla and spinal dorsal horn may be involved in hyperalgesia in the 6-hydroxydopamine-induced rat model of Parkinson's disease.

As the use of serotonergic agents to treat depression has increased, so too has the incidence of serotonin syndrome. We identify the common agents implicated in serotonin syndrome and the clinical tools to diagnose, manage, and prevent serotonergic toxicity., (Copyright © 2016 Cleveland Clinic.)

Purpose: To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model., Methods: Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections., Results: A five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice., Conclusions: Intraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation.

Objective: The underlying mechanisms for the analgesic action of paracetamol (PCT) are still under considerable debate. It has been recently proposed that PCT may act by modulating the Serotonin system. This study was conducted to verify the influence of Serotonin modulating drugs (buspirone, ondansetron, and fluoxetine) on the analgesic effect of PCT., Materials and Methods: Thirty adult albino mice were assigned to five groups: Normal saline, PCT, fluoxetine selective serotonin reuptake inhibitor (SSRI) + PCT, buspirone (5-HT1A Agonist) + PCT, and ondansetron (5HT3 antagonist) + PCT. Hot-plate and formalin test were used to determine pain threshold, tests being conducted 60 min after the last treatment. Statistical analysis was done using analysis of variance followed by Dunnet's test., Results: Coadministration of buspirone with PCT attenuated the antinociceptive activity of PCT (P < 0.001), whereas fluoxetine + PCT increased pain threshold in the hot-plate and formalin test (P = 0.0046). Analgesic effect of PCT was not affected by ondansetron in formalin models. It attenuated analgesic action of PCT in hot-plate test (P = 0.0137)., Conclusion: The results suggest that 5-HT1 receptors could also be responsible for the analgesic effect of PCT. Also, higher analgesia is produced by co-administration of SSRI (fluoxetine) + PCT.

Gamma-frequency oscillatory activity plays an important role in information integration across brain areas. Disruption in gamma oscillations is implicated in cognitive impairments in psychiatric disorders, and 5-HT3 receptors (5-HT3Rs) are suggested as therapeutic targets for cognitive dysfunction in psychiatric disorders. Using a 5-HT3aR-EGFP transgenic mouse line and inducing gamma oscillations by carbachol in hippocampal slices, we show that activation of 5-HT3aRs, which are exclusively expressed in cholecystokinin (CCK)-containing interneurons, selectively suppressed and desynchronized firings in these interneurons by enhancing spike-frequency accommodation in a small conductance potassium (SK)-channel-dependent manner. Parvalbumin-positive interneurons therefore received diminished inhibitory input leading to increased but desynchronized firings of PV cells. As a consequence, the firing of pyramidal neurons was desynchronized and gamma oscillations were impaired. These effects were independent of 5-HT3aR-mediated CCK release. Our results therefore revealed an important role of 5-HT3aRs in gamma oscillations and identified a novel crosstalk among different types of interneurons for regulation of network oscillations. The functional link between 5-HT3aR and gamma oscillations may have implications for understanding the cognitive impairments in psychiatric disorders., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Unilateral cervical spinal cord hemisection (i.e., C2Hx) usually interrupts the bulbospinal respiratory pathways and results in respiratory impairment. It has been demonstrated that activation of the serotonin system can promote locomotor recovery after spinal cord injury. The present study was designed to investigate whether serotonergic activation can improve respiratory function during the chronic injury state. Bilateral diaphragm electromyogram and tidal volume were measured in anesthetized and spontaneously breathing adult rats at 8 wk post-C2Hx or C2 laminectomy. A bolus intravenous injection of a serotonin precursor [5-hydroxytryptophan (5-HTP), 10 mg/kg], a serotonin reuptake inhibitor (fluoxetine, 10 mg/kg), or a potent agonist for serotonin 2A receptors (TCB-2, 0.05 mg/kg) was used to activate the serotonergic system. Present results demonstrated that 5-HTP and TCB-2, but not fluoxetine, significantly increased the inspiratory activity of the diaphragm electromyogram ipsilateral to the lesion for at least 30 min in C2Hx animals, but not in animals that received sham surgery. However, the tidal volume was not increased after administration of 5-HTP or TCB-2, indicating that the enhancement of ipsilateral diaphragm activity is not associated with improvement of the tidal volume. These results suggest that exogenous activation of the serotonergic system can specifically enhance the ipsilateral diaphragmatic motor outputs, but this approach may not be sufficient to improve respiratory functional recovery following chronic cervical spinal injury., (Copyright © 2015 the American Physiological Society.)

The serotonergic system is a subcortical neuromodulatory center that controls cortical information processing in a state-dependent manner. In the hippocampus, serotonin (5-HT) is released by ascending serotonergic fibers from the midbrain raphe nuclei, thereby mediating numerous modulatory functions on various neuronal subtypes. Here, we focus on the neuromodulatory effects of 5-HT on GABAergic inhibitory oriens lacunosum-moleculare (O-LM) cells in the hippocampal area CA1 of the rat. These interneurons are thought to receive primarily local excitatory input and are, via their axonal projections to stratum lacunosum-moleculare, ideally suited to control entorhinal cortex input. We show that 5-HT reduces excitatory glutamatergic transmission onto O-LM interneurons. By means of paired recordings from synaptically connected CA1 pyramidal cells and O-LM interneurons we reveal that this synapse is modulated by 5-HT. Furthermore, we demonstrate that the reduction of glutamatergic transmission by serotonin is likely to be mediated via a decrease of calcium influx into presynaptic terminals of CA1 pyramidal cells. This modulation of excitatory synaptic transmission onto O-LM interneurons by 5-HT might be a mechanism to vary the activation of O-LM interneurons during ongoing network activity and serve as a brain state-dependent switch gating the efficiency of entorhinal cortex input to CA1 pyramidal neurons., (© The Author 2015. Published by Oxford University Press.)

Exercise has a variety of beneficial effects on brain structure and function, such as hippocampal neurogenesis, mood and memory. Previous studies have shown that exercise enhances hippocampal neurogenesis, induces antidepressant effects and improves learning behavior. Brain serotonin (5-hydroxytryptamine, 5-HT) levels increase following exercise, and the 5-HT system has been suggested to have an important role in these exercise-induced neuronal effects. However, the precise mechanism remains unclear. In this study, analysis of the 5-HT type 3A receptor subunit-deficient (htr3a(-/-)) mice revealed that lack of the 5-HT type 3 (5-HT3) receptor resulted in loss of exercise-induced hippocampal neurogenesis and antidepressant effects, but not of learning enhancement. Furthermore, stimulation of the 5-HT3 receptor promoted neurogenesis. These findings demonstrate that the 5-HT3 receptor is the critical target of 5-HT action in the brain following exercise, and is indispensable for hippocampal neurogenesis and antidepressant effects induced by exercise. This is the first report of a pivotal 5-HT receptor subtype that has a fundamental role in exercise-induced morphological changes and psychological effects.

Impulsivity is an important feature of multiple neuropsychiatric disorders, and individual variation in the degree of inherent impulsivity could play a role in the generation or exacerbation of problematic behaviors. Serotonin (5-HT) actions at the 5-HT2AR receptor (5-HT2AR) promote and 5-HT2AR antagonists suppress impulsive action (the inability to withhold premature responses; motor impulsivity) upon systemic administration or microinfusion directly into the medial prefrontal cortex (mPFC), a node in the corticostriatal circuit that is thought to play a role in the regulation of impulsive action. We hypothesized that the functional capacity of the 5-HT2AR, which is governed by its expression, localization, and protein/protein interactions (eg, postsynaptic density 95 (PSD95)), may drive the predisposition to inherent impulsive action. Stable high-impulsive (HI) and low-impulsive (LI) phenotypes were identified from an outbred rodent population with the 1-choice serial reaction time (1-CSRT) task. HI rats exhibited a greater head-twitch response following administration of the preferential 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and were more sensitive to the effects of the selective 5-HT2AR antagonist M100907 to suppress impulsive action relative to LI rats. A positive correlation was observed between levels of premature responses and 5-HT2AR binding density in frontal cortex ([(3)H]-ketanserin radioligand binding). Elevated mPFC 5-HT2AR protein expression concomitant with augmented association of the 5-HT2AR with PSD95 differentiated HI from LI rats. The observed differential sensitivity of HI and LI rats to 5-HT2AR ligands and associated distinct 5-HT2AR protein profiles provide evidence that spontaneously occurring individual differences in impulsive action reflect variation in the cortical 5-HT2AR system.

The physiological and molecular mechanisms of age-related memory loss are complicated by the complexity of vertebrate nervous systems. This study takes advantage of a simple neural model to investigate nervous system aging, focusing on changes in learning and memory in the form of behavioral sensitization in vivo and synaptic facilitation in vitro. The effect of aging on the tail withdrawal reflex (TWR) was studied in Aplysia californica at maturity and late in the annual lifecycle. We found that short-term sensitization in TWR was absent in aged Aplysia. This implied that the neuronal machinery governing nonassociative learning was compromised during aging. Synaptic plasticity in the form of short-term facilitation between tail sensory and motor neurons decreased during aging whether the sensitizing stimulus was tail shock or the heterosynaptic modulator serotonin (5-HT). Together, these results suggest that the cellular mechanisms governing behavioral sensitization are compromised during aging, thereby nearly eliminating sensitization in aged Aplysia.

The striatonigral projection is a striatal output pathway critical to motor control, cognition, and emotion regulation. Its axon terminals in the substantia nigra pars reticulata (SNr) express a high level of serotonin (5-HT) type 1B receptors (5-HT(1B)Rs), whereas the SNr also receives an intense 5-HT innervation that expresses 5-HT transporters, providing an anatomic substrate for 5-HT and selective 5-HT reuptake inhibitor (SSRI)-based antidepressant treatment to regulate the striatonigral output. In this article we show that 5-HT, by activating presynaptic 5-HT(1B)Rs on the striatonigral axon terminals, potently inhibited the striatonigral GABA output, as reflected in the reduction of the striatonigral inhibitory postsynaptic currents in SNr GABA neurons. Functionally, 5-HT(1B)R agonism reduced the striatonigral GABA output-induced pause of the spontaneous high-frequency firing in SNr GABA neurons. Equally important, chronic SSRI treatment with fluoxetine enhanced this presynaptic 5-HT(1B)R-mediated pause reduction in SNr GABA neurons. Taken together, these results indicate that activation of the 5-HT(1B)Rs on the striatonigral axon terminals can limit the motor-promoting GABA output. Furthermore, in contrast to the desensitization of 5-HT1 autoreceptors, chronic SSRI-based antidepressant treatment sensitizes this presynaptic 5-HT(1B)R-mediated effect in the SNr, a novel cellular mechanism that alters the striatonigral information transfer, potentially contributing to the behavioral effects of chronic SSRI treatment., (Copyright © 2015 the American Physiological Society.)

The nonmedical use of synthetic cathinones is increasing on a global scale. 4-Methyl-N-methylcathinone (mephedrone) is a popular synthetic cathinone that is now illegal in the United States and other countries. Since the legislative ban on mephedrone, a number of 'second-generation' analogs have appeared in the street drug marketplace, including 4-methyl-N-ethylcathinone (4-MEC) and 4'-methyl-α-pyrrolidinopropiophenone (4-MePPP). Here we characterized the interactions of 4-MEC and 4-MePPP with transporters for 5-HT (SERT) and dopamine (DAT) using molecular, cellular, and whole-animal methods. In vitro transporter assays revealed that 4-MEC displays unusual 'hybrid' activity as a SERT substrate (ie, 5-HT releaser) and DAT blocker, whereas 4-MePPP is a blocker at both transporters but more potent at DAT. In vivo microdialysis experiments in rat brain demonstrated that 4-MEC (1-3 mg/kg, i.v.) produced large increases in extracellular 5-HT, small increases in dopamine, and minimal motor stimulation. In contrast, 4-MePPP (1-3 mg/kg, i.v.) produced selective increases in dopamine and robust motor stimulation. Consistent with its activity as a SERT substrate, 4-MEC evoked inward current in SERT-expressing Xenopus oocytes, whereas 4-MePPP was inactive in this regard. To examine drug-transporter interactions at the molecular level, we modeled the fit of 4-MEC and 4-MePPP into the binding pockets for DAT and SERT. Subtle distinctions in ligand-transporter binding were found that account for the differential effects of 4-MEC and 4-MePPP at SERT. Collectively, our results provide key information about the pharmacology of newly emerging mephedrone analogs, and give clues to structural requirements that govern drug selectivity at DAT vs SERT.

Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target., (Copyright © 2015 Elsevier Inc. All rights reserved.)