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The ventral tegmental area (VTA) projection to the nucleus accumbens shell (NAcSh) regulates NAcSh-mediated motivated behaviors in part by modulating the glutamatergic inputs. This modulation is likely to be mediated by multiple substances released from VTA axons, whose phenotypic diversity is illustrated here by ultrastructural examination. Furthermore, we show in mouse brain slices that a brief optogenetic stimulation of VTA-to-NAc projection induced a transient inhibition of excitatory postsynaptic currents (EPSCs) in NAcSh principal medium spiny neurons (MSNs). This inhibition was not accompanied by detectable alterations in presynaptic release properties of electrically-evoked EPSCs, suggesting a postsynaptic mechanism. The VTA projection to the NAcSh releases dopamine, GABA and glutamate, and induces the release of other neuronal substrates that are capable of regulating synaptic transmission. However, pharmacological inhibition of dopamine D1 or D2 receptors, GABAA or GABAB receptors, NMDA receptors, P2Y1 ATP receptors, metabotropic glutamate receptor 5, and TRP channels did not prevent this short-term inhibition. These results suggest that an unknown mechanism mediates this form of short-term plasticity induced by the VTA-to-NAc projection.

5-HT 7 receptors are the most recently discovered serotonergic receptors, for which numerous physiological implications in the central and the peripheral nervous systems as well as the endocrine system are described. A current public health challenge is to propose new and more efficient treatments against neuropsychiatric disorders such as epilepsy or Alzheimer's disease. In this context, 5-HT 7 receptors represent an interesting target for the treatment and prevention of those pathologies, as an alternative or in association with other medicines. Thus, numerous chemical series of agonists and antagonists have been developed. Some of these molecules have shown a therapeutic potential in various in vivo studies. This review aims to present an overview of 5-HT 7 receptors and of the medicinal chemistry programs that led to the identification of new, potent and selective 5-HT 7 receptors ligands. Structure-activity relationships studies based on molecular docking and pharmacophoric approaches are also described., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Stimulation of the serotoninergic system (5-hydroxytryptophan, 50 mg/kg; fluoxetine, 3 mg/kg) induced a significant increase in HR and a reduction in the amplitude of all waves of the heart rhythm variability. Stimulation of the dopaminergic system (L-DOPA and amantadine, 20 mg/kg each) resulted in a moderate increase in HR and amplitudes of low-frequency (LF) and very-low-frequency (VLF) waves of the heart rhythm variability. Successive blockade of nicotinic (hexamethonium, 7 mg/kg) and muscarinic cholinergic receptors (atropine, 1 mg/kg) leads to a significant decrease in the variability of cardiointervals (almost to complete levelling) both under control conditions and after stimulation of the neurotransmitter systems. Serotonin receptor blockade (promethazine, 2 mg/kg) did not affect HR, but reduced the amplitude of LF- and VLF-waves. Under conditions of serotoninergic system stimulation, the blockade of serotonin receptors was followed by a significant HR acceleration without changes in heart rhythm variability; blockade of dopamine receptors (sulpiride, 1 mg/kg) induced HR acceleration and increase in the amplitude of LF- and VLF-waves; blockade of dopamine receptors under conditions of dopamine system stimulation was followed by a significant increase in HR and a decrease in the amplitude of all waves of the heart rhythm variability. It can be hypothesized that serotonin- and dopaminergic systems affect the heart rhythm via cardiomyocyte receptors and via modulation of activity of the adrenergic and cholinergic systems. The effects of serotonin- and dopaminergic systems can be considered as synergic in the CNS, and antagonistic at the periphery.

Whereas the potential role of serotonin for the pathophysiology of irritable bowel syndrome (IBS) has since long been discussed, the possibility that 5-hydroxytryptamine 6 (5-HT 6 ) receptors may serve as targets for the treatment of this condition has as yet not been explored. The aim of the current study was to assess to what extent defecation in rats is influenced by manipulation of 5-HT 6 receptors. Reduced defecation following SB-399885 was observed in non-stressed animals assessed for 7 h after drug administration. While not impacting context-conditioned freezing, three 5-HT 6 receptor antagonists (SB-399885, SB-271046 and SB-258585) also markedly reduced the number of faecal boli produced by rats exposed to context-conditioned fear. In contrast, a 5-HT 6 receptor agonist, WAY-208466, influenced defecation neither in unstressed animals nor in rats experiencing conditioned fear stress. A clinical study on the possible effect of a 5-HT 6 receptor antagonist in IBS with diarrhea appears warranted., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The present paper describes the synthesis and the binding properties for the serotonergic 5-HT 7 and 5-HT 1A receptors of three new series (A-C) of (benzo)thienopyrimidinone derivatives. All series exhibit a basic moiety at the 2-position of the heterocyclic scaffold such as N,N-dialkylaminoalkylthio chain in series A and phenylpiperazine, benzylpiperazine, or benzylpiperidine alkyl chain in series B and C. Compounds endowed with the best binding properties at 5-HT 7 R belong to the B and C types. In particular, derivatives B2 and C1 (RSC4) exhibit notable affinity for 5-HT 7 R (K i  = 9.08 and 0.85 nM, respectively) and selectivity over the 5-HT 1A R (254- and 48-fold, respectively). The structure-affinity relationships for these three new classes of 5-HT 7 R ligands are discussed and, in order to rationalize and deeply investigate the observed results, molecular modeling studies were performed. In particular, the binding poses of the synthesized compounds were studied by docking them in the two receptor proteins suitably built by homology modeling. The calculated binding energies resulted in an excellent agreement with the experimental measured K i , further validating the quality of the models., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The Chinese mitten crab ( Eriocheir sinensis ) is a commercially important crab in China and is usually managed at high stocking densities. Agonistic behavior directly impacts crab integrity, survival, and growth and results in economic losses. In the present study, we evaluated the modulatory effects of serotonin (5-HT) and dopamine (DA) though the 5-HT2 and DA2 receptor-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway on agonistic behavior. The results showed that injection of either 10 -6 mol/crab 5-HT or DA reduced the agonistic behavior of E. sinensis ( P < 0.05), as did 10 -10 mol/crab DA and 10 -8 mol/crab 5-HT and DA ( P < 0.05); however, a dose of 10 -10 mol/crab 5-HT promoted agonistic behavior. 5-HT significantly increased the mRNA expression level of 5-HT7 receptor and reduced that of the DA2 receptor in the cerebral ganglion ( P < 0.05). In contrast to 5-HT, DA significantly decreased 5-HT2B mRNA levels and increased 5-HT7 and DA2 receptor levels in the thoracic ganglia ( P < 0.05). In addition, injections of either 5-HT or DA increased the cAMP and PKA levels in hemolymph ( P < 0.05). By using in vitro culture of the thoracic ganglia, the current study showed that ketanserin (5-HT2 antagonist) and [R(-)-TNPA] (DA2 agonist) had obvious effects on the expression levels of the two receptors ( P < 0.05). In vivo experiments further demonstrated that ketanserin and [R(-)-TNPA] could both significantly reduce the agonistic behavior of the crabs ( P < 0.05). Furthermore, both ketanserin and [R(-)-TNPA] promoted the cAMP and PKA levels ( P < 0.05). The injection of CPT-cAMP (cAMP analogue) elevated the PKA levels and inhibited agonistic behavior. In summary, this study showed that 5HT-2B and DA2 receptors were involved in the agonistic behavior that 5-HT/DA induced through the cAMP-PKA pathway in E. sinensis .

The presence of dominant active compounds in standardised methanol extract from the leaves of Stizolophus balsamita ( S. balsamita ) was examined using HPLC with a diode-array detector. The extract and three dominant parthenolide derivatives were tested with Serotonin Research ELISA for their ability to inhibit the serotonin release from platelets. The antiserotonin effect of the extract was compared with that of parthenolide, a compound with proven antiserotonin and antimigraine effects. This study aimed to evaluate the ability of natural parthenolide derivatives to inhibit serotonin release from platelets. Izospiciformin, stizolin and stizolicin were analysed along with the standardised alcohol extract of S. balsamita leaves, which also contained four other parthenolide derivatives. All the analysed substances were found to inhibit serotonin release from platelets as compared with the control sample, which had 100% of serotonin released. Izospiciformin had the most significant impact (97.98% serotonin release inhibition). The effect of the methanol extract of S. balsamita on the serotonin release inhibition was also statistically significant.

Purpose: Like other psychedelics, D-lysergic acid diethylamide (LSD) affects numerous serotonin receptors, and according to the current dogma, the 5-HT 2A receptors are considered the main target for its hallucinogenic effects. LSD, however, also displays agonistic activity at the 5-HT 5A receptors, which mediate some of LSD-induced behavioural effects., Methods: Using male Sprague Dawley rats, we examined the effects of 5-HT 2A and 5-HT 5A receptor antagonists on LSD-induced stimulus control in the two-lever drug discrimination test using a FR10 schedule of reinforcement., Results: In animals trained to discriminate 0.08 mg/kg LSD from vehicle 15 minutes after injection, LSD produced dose-related increases in response, with an ED50 (±95% confidence limits) of 0.0384 (± 0.025-0.051) mg/kg). LSD-like responses were observed when the training dose of LSD was given 5-30 but not 90 minutes before the test. Confirming earlier reports, the 5-HT antagonist ketanserin (2 mg/kg) attenuated the LSD response in 50% of rats, and due to pretreatment with 0.2 and 2 mg/kg MDL 100907, 63% and 67% of animals, respectively, failed to select the LSD lever. We then investigated the effects of two 5-HT 5A receptor antagonists, and we found that 56% and 60% of rats pretreated with 3 and 10 mg/kg SB 699551, respectively, failed to select the LSD lever. Due to pretreatment with 0.01 mg/kg ASP 5736, 58% of rats did not select the LSD lever. This dose also reduced the response rate but not the number of rats failing to complete the test., Conclusions: The present results suggest that antagonists of the 5-HT 5A receptor may inhibit subjective effects of LSD in rats.

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT 2A R and dopamine receptors D 2 R and stimulate 5-HT 1A R directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT 1A R, 5-HT 2A R and D 2 R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT 1A R antagonist WAY-100635, risperidone + 5-HT 2A/2C R agonist DOI, risperidone + D 2 R agonist quinpirole). Risperidone, 5-HT 1A R agonism with 8-OH-DPAT, 5-HT 2A R antagonism with M100907, and D 2 R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT 2A R with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT 1A R agonism and 5-HT 2A R antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D 2 R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT 1A (compound 18, K i  = 4 nM - antagonist mode) and D 2 (compound 15, K i  = 7 nM - antagonist mode) receptor, and in some cases also 5-HT 7 receptor (compound 17, K i  = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Key Points: Functional disorders (i.e. interstitial cystitis/painful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel, respectively. Various non-5-HT 3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5-HT. Whilst 5-HT 3 receptors were not detected in mouse urothelium, 5-HT 3 receptors expressed on bladder sensory neurons plays a role in bladder afferent excitability both under normal conditions and in a mouse model of chronic visceral hypersensitivity. These data suggest that the role 5-HT 3 receptors play in bladder afferent signalling warrants further study as a potential therapeutic target for functional bladder disorders., Abstract: Serotonin (5-HT) is an excitatory mediator that in the gastrointestinal (GI) tract plays a physiological role in gut-brain signalling and is dysregulated in functional GI disorders such as irritable bowel syndrome (IBS). Patients suffering from IBS frequently suffer from urological symptoms characteristic of interstitial cystitis/painful bladder syndrome, which manifests due to cross-sensitization of shared innervation pathways between the bladder and colon. However, a direct modulatory role of 5-HT in bladder afferent signalling and its role in colon-bladder neuronal crosstalk remain elusive. The aim of this study was to investigate the action of 5-HT on bladder afferent signalling in normal mice and mice with chronic visceral hypersensitivity (CVH) following trinitrobenzenesulfonic acid-induced colitis. Bladder afferent activity was recorded directly using ex vivo afferent nerve recordings. Expression of 14 5-HT receptor subtypes, the serotonin transporter (SERT) and 5-HT-producing enzymes was determined in the urothelium using RT-PCR. Retrograde labelling of bladder-projecting dorsal root ganglion neurons was used to investigate expression of 5-HT 3 receptors using single cell RT-PCR, while sensory neuronal and urothelial responses to 5-HT were determined by live cell calcium imaging. 5-HT elicited bladder afferent firing predominantly via 5-HT 3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5-HT bioavailability. Granisetron, a 5-HT 3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5-HT exerts a direct effect on bladder afferents to enhance signalling. 5-HT 3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

The present study was designed to evaluate the therapeutic effectiveness and mechanism of acute intermittent hypoxia on respiratory function at distinct injury stages following mid-cervical spinal contusion. In the first experiment, adult male rats received laminectomy or unilateral contusion at 3rd-4th cervical spinal cord at 9 weeks of age. The ventilatory behavior in response to mild acute intermittent hypercapnic-hypoxia (10 episodes of 5 min of hypoxia [10% O 2 , 4% CO 2 , 86% N 2 ] with 5 min of normoxia intervals) was measured by whole-body plethysmography at the acute (∼3 days), subchronic (∼2 weeks), and chronic (∼8 weeks) injury stages. The minute ventilation of contused animals is significantly enhanced following acute intermittent hypercapnic-hypoxia due to an augmentation of the tidal volume at all time-points post-injury. However, acute intermittent hypercapnia-hypoxia-induced ventilatory long-term facilitation was only observed in uninjured animals at the acute stage. During the second experiment, the effect of acute intermittent hypercapnic-hypoxia on respiration was examined in contused animals after a blockade of serotonin receptors, or adenosine 2A receptors. The results demonstrated that acute intermittent hypercapnic-hypoxia-induced enhancement of minute ventilation was attenuated by a serotonin receptor antagonist (methysergide) but enhanced by an adenosine 2A receptor antagonist (KW6002) at the subchronic and chronic injury stages. These results suggested that acute intermittent hypercapnic-hypoxia can induce respiratory recovery from acute to chronic injury stages. The therapeutic effectiveness of intermittent hypercapnic-hypoxia is dampened by the inhibition of serotonin receptors, but a blockade of adenosine 2A receptors enhanced respiratory recovery induced by intermittent hypercapnic-hypoxia.

Introduction: Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss., Aim: To understand possible mechanisms by which flibanserin may produce weight loss., Methods: A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management., Main Outcome Measures: Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss., Results: Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT 2A receptors and factors such as improved mood and improved sleep., Conclusion: Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT 2A receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss. Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575-586., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Lurasidone is an atypical mood-stabilizing antipsychotic with a unique receptor-binding profile, including 5-HT 7 receptor antagonism; however, the detailed effects of 5-HT 7 receptor antagonism on various transmitter systems relevant to schizophrenia, particularly the thalamo-insular glutamatergic system and the underlying mechanisms, are yet to be clarified., Experimental Approach: We examined the mechanisms underlying the clinical effects of lurasidone by measuring the release of l-glutamate, GABA, dopamine, and noradrenaline in the reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) and insula of freely moving rats in response to systemic injection or local infusion of lurasidone or MK-801 using multiprobe microdialysis with ultra-HPLC., Key Results: Systemic MK-801 (0.5 mg·kg -1 ) administration increased insular release of l-glutamate, dopamine, and noradrenaline but decreased GABA release. Systemic lurasidone (1 mg·kg -1 ) administration also increased insular release of l-glutamate, dopamine, and noradrenaline but without affecting GABA. Local lurasidone administration into the insula (3 μM) did not affect MK-801-induced insular release of l-glutamate or catecholamine, whereas local lurasidone administration into the MDTN (1 μM) inhibited MK-801-induced insular release of l-glutamate and catecholamine, similar to the 5-HT 7 receptor antagonist SB269970., Conclusions and Implications: The present results indicate that MK-801-induced insular l-glutamate release is generated by activation of thalamo-insular glutamatergic transmission via MDTN GABAergic disinhibition resulting from NMDA receptor inhibition in the MDTN and RTN. Lurasidone inhibited this MK-801-evoked insular l-glutamate release through inhibition of excitatory 5-HT 7 receptor in the MDTN. These effects on thalamo-insular glutamatergic transmission may contribute to the antipsychotic and mood-stabilizing actions of lurasidone., (© 2019 The British Pharmacological Society.)

The present study investigated a possible antidepressant-like effect of ((4-tert-butylcyclohexylidene)methyl) (4-methoxystyryl) sulfide (BMMS) by using the forced swimming test (FST) and the tail suspension test (TST) in Swiss mice. The contribution of serotoninergic, glutamatergic and nitrergic systems in the antidepressant-like activity of BMMS was evaluated. We also examined the involvement of monoamine oxidase (MAO)-A, MAO-B and Na + , K + -ATPase activities in prefrontal cortex of mice. BMMS, (0.1-10 mg/kg, intragastrically (i.g.)) and fluoxetine (32 mg/kg, i.g.) decreased the immobility time in the FST and TST. The anti-immobility effect of BMMS (10 mg/kg, i.g.) in the TST was prevented by the pretreatment of mice with WAY100635 (0.1 mg/kg, subcutaneously (s.c.), a 5-HT 1A receptor antagonist), ketanserin (5 mg/kg, intraperitoneal (i.p.), a 5-HT 2A/2C receptor antagonist), and partially blocked by ondansetron (1 mg/kg, i.p., a 5-HT 3 receptor antagonist). The anti-immobility effect of BMMS (10 mg / kg, i.g.) was not avoided by pretreatment with MK-801 (0.01 mg/kg, s.c. a non-competitive N-methyl D-Aspartate (NMDA) receptor) in the TST. Pretreatment with L-arginine (500 mg/kg, i.p., a nitric oxide precursor) reversed partially the reduction in the immobility time elicited by BMMS (10 mg/kg, i.g.) in TST. BMMS altered Na + ,K + -ATPase and MAO-A activities in prefrontal cortex of mice, but was not able to change the MAO-B activity. In conclusion, BMMS exerted an antidepressant-like effect in mice and serotonergic and nitrergic systems are involved in the antidepressant-like action of compound. BMMS modulated MAO-A and Na + , K + - ATPase activities in prefrontal cortex of mice.

A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT 6 R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT 6 R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT 6 R and very high selectivity over 5-HT 1A , 5-HT 2A , 5-HT 7 and D 2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential., (Copyright © 2019. Published by Elsevier Masson SAS.)

This research has provided the most active 5-HT 6 R agents among 1,3,5-triazine derivatives investigated to date and has also identified the world's first selenium-containing 5-HT 6 R ligands. The studies are focused on design, synthesis, biological evaluation and docking-supported SAR analysis for novel 5-HT 6 R agents as derivatives of lead structure 4-(4-methylpiperazin-1-yl)-6-(phenoxymethyl)-1,3,5-triazin-2-amine (7). The lead modifications included an introduction of: (i) various small substituents at benzene ring, (ii) a branched ether linker or (iii) the ether oxygen replacement with other chalcogen (S, Se) or sulfonyl moiety. Hence, a series of new compounds (7-24) was synthesized and examined on their affinities for 5-HT 6 R and selectivity, in respect to the 5-HT 1A R, 5-HT 2A R, 5-HT 7 R and dopamine D 2 receptor, in the radioligand binding assays. For representative most active compounds functional bioassays and toxicity profile in vitro and antidepressant-like activity in vivo were examined. The 2-isopropyl-5-methylphenyl derivative (10) was found as the most active triazine 5-HT 6 R antagonist (K i  = 11 nM). SAR analysis indicated, that an exchange of oxygen to selenium (7 vs. 22), and especially, to sulfur (7 vs. 19) was beneficial to increase both affinity and antagonistic action for 5-HT 6 R. Surprisingly, an introduction of SO 2 caused a drastic decrease of the 5-HT 6 R affinity, which was explained at a molecular level based on docking studies. All in vivo tested compounds (10, 18 and 21) did not show any risk of toxicity in the safety studies in vitro., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Serotonin (5-HT) in the central nervous system regulates a variety of biological functions, from the basic homeostatic control to higher brain functions, by acting on fourteen known receptor subtypes. However, it is still usually unclear which receptor subtype is responsible for a specific function due to the lack of highly selective ligands for most of these receptors. Although 5-HT receptor knockout mice are useful, the brain-wide distribution of various receptors makes it difficult to dissect receptor functions in specific and brain regions and cell types. Recent advances in CRISPR/Cas9-mediated in vivo genome editing technology may overcome this problem. In this study, we constructed a viral vector expressing a single guide (sg)RNA targeting Htr1a (sgHtr1a) and Cre recombinase under the control of a neuron-specific promoter. Injection of the viral vector into the dorsal raphe nucleus (DRN) of Cre-dependent Cas9 knock-in mice induced Cre-dependent Cas9 expression mainly in DRN serotonin and GABA neurons. Mismatch cleavage assay and Sanger sequencing showed insertion or deletion formation at the target site. 5-HT 1A receptor agonist-induced hypothermia was attenuated and antidepressant effect of a selective serotonin reuptake inhibitor (SSRI) was enhanced by microinjection of the viral vector expressing sgHtr1a into the DRN of Cre-dependent Cas9 knock-in mice. These results suggest that this in vivo CRISPR/Cas9-mediated 5-HT receptor gene knockout strategy provides a reliable and low-cost method for elucidating 5-HT receptor functions in specific cell types and brain regions. Further, we demonstrate that the neuronal 5-HT 1A receptor in the DRN regulates body temperature and antidepressant effect of SSRI., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study was performed to investigate the effect of ondansetron, a serotonin receptor (5-HT3) antagonist, in the alleviation of diclofenac-induced kidney injuries. NMRI mice were randomly divided into six groups and treated with (A) untreated control group, (B) diclofenac (100 mg/kg), (C) ondansetron (1 mg/kg), (D to F) ondansetron (0.1, 0.5, and 1 mg/kg, respectively) and diclofenac (100 mg/kg) for last 3 days of experiment. The oxidative stress tests strongly demonstrated the negative synergistic effects of diclofenac and ondansetron, regarding the observation of dose-dependent enhancement of malondialdehyde concentration, and reduction of glutathione content, and superoxide dismutase and catalase activity. Histopathological analyses revealed dose-dependent tubular epithelial cells degeneration, outstanding mononuclear cells infiltration, clear necrosis at the papillary region of kidney, dilation, and vascular hyperemia in mice kidney tissues treated with ondansetron and diclofenac. Conclusively, these findings suggested the possible ondansetron-diclofenac interaction through the induction of oxidative stress., (© 2019 Wiley Periodicals, Inc.)

Chemogenetic strategies have emerged as reliable tools for remote control of neuronal activity. Among these, designer receptors exclusively activated by designer drugs (DREADDs) have become the most popular chemogenetic approach used in modern neuroscience. Most studies deliver the ligand clozapine-N-oxide (CNO) using a single intraperitoneal injection, which is suitable for the acute activation/inhibition of the targeted neuronal population. There are, however, only a few examples of strategies for chronic modulation of DREADD-controlled neurons, the majority of which rely on the use of delivery systems that require surgical intervention. Here, we expand on two non-invasive strategies for delivering the ligand CNO to chronically manipulate neural population in mice. CNO was administered either by using repetitive (daily) eye-drops, or chronically through the animal's drinking water. These non-invasive paradigms result in robust activation of the designer receptors that persisted throughout the CNO treatments. The methods described here offer alternatives for the chronic DREADD-mediated control of neuronal activity and may be useful for experiments designed to evaluate behavior in freely moving animals, focusing on less-invasive CNO delivery methods.

The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

More than 300 million people are suffering from depression, one of the civilization diseases in the 21st century. Serotonin 5-HT 1A R and dopamine D 2 R play an important role in the treatment and pathogenesis of depression. Moreover, in recent years, the efficacy of dual 5-HT 1A /D 2 receptors ligands has been demonstrated in the fight against depression. In this work the new bulky arylpiperazine derivatives (LCAP) were synthesized in microwave radiation field. The affinities for the selected serotonin (5-HT 1A ,5-HT 2A ,5-HT 6 ,5-HT 7 ) and dopamine (D 2 ) receptors have been evaluated in vitro. Compounds 5.3a, 5.4, 5.1c, 5.3d, 5.2a are promising dual 5-HT 1A R/D 2 R ligands. The SAR analysis were additionally supported with molecular docking studies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Acacetin, a natural flavonoid, possesses broad spectrum of pharmacological and biochemical activities, such as neuroprotection, antinociception and inhibition of monoamine oxidase. The current work aimed to investigate the antidepressant-like activity of acacetin in mice and explore the underlying mechanism(s). Chronic, but not acute, acacetin treatment (5, 15 or 45 mg/kg, p.o., once per day for three weeks) exerted in mice dose-dependently antidepressant-like activity, assessed by forced swim test (FST) and tail suspension test (TST). Although acacetin-treated mice showed normal circadian hypothalamo-pituitary-adrenal (HPA) axis activity, their endocrine responsivity to both acute restraint stress and intracerebroventricular injection of corticotropin-releasing factor (CRF) was buffered. The acacetin-triggered antidepressant-like activities are serotonergically dependent, since its impacts on behavior and stress responsivity were totally abolished by chemical depletion of brain serotonin by PCPA. Consistently, acacetin-treated mice showed escalated levels of brain monoamines especially serotonin and depressed activity of monoamine oxidase. Moreover, the acacetin-evoked anti-depression was preferentially counteracted by co-administration of 5-HT 1A receptor antagonist WAY-100635, but potentiated by 5-HT 1A receptor agonist 8-OH-DPAT and sub-effective dose of serotonergic antidepressant fluoxetine, suggesting a pivotal engagement of 5-HT 1A related serotonergic system. In vitro, acacetin (1-100 nM) increased the Emax of 8-OH-DPAT. Collectively, these findings confirm that chronic acatetin administration to mice engenders antidepressant-like efficacy on both behavior and stress axis responsivity, with serotonergic system that preferentially couples with 5-HT 1A receptors being critically involved., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Serotonin (5-HT) is a key regulator of spinal respiratory motor plasticity. For example, spinal 5-HT receptor activation is necessary for the induction of phrenic long-term facilitation (pLTF), a form of respiratory motor plasticity triggered by moderate acute intermittent hypoxia (mAIH). mAIH-induced pLTF is blocked by cervical spinal application of the broad-spectrum 5-HT-receptor antagonist, methysergide. However, methysergide does not allow distinctions between the relative contributions of different 5-HT receptor subtypes. Intravenous administration of the Gq protein-coupled 5-HT 2A/2C receptor antagonist ketanserin blocks mAIH-induced pLTF when administered before, but not after, mAIH; thus, 5-HT 2 receptor activation is necessary for the induction but not maintenance of mAIH-induced pLTF. However, systemic ketanserin administration does not identify the site of the relevant 5-HT 2A/2C receptors. Furthermore, this approach does not differentiate between the roles of 5-HT 2A versus 5-HT 2C receptors, nor does it preclude involvement of other Gq protein-coupled metabotropic 5-HT receptors capable of eliciting long-lasting phrenic motor facilitation, such as 5-HT 2B receptors. Here we tested the hypothesis that mAIH-induced pLTF requires cervical spinal 5-HT 2 receptor activation and determined which 5-HT 2 receptor subtypes are involved. Anesthetized, paralyzed, and ventilated adult male Sprague Dawley rats were pretreated intrathecally with cervical (~C3-C5) spinal injections of subtype selective 5-HT 2A/2C , 5-HT 2B , or 5-HT 2C receptor antagonists before mAIH. Whereas cervical spinal 5-HT 2C receptor inhibition had no impact on mAIH-induced pLTF, pLTF was no longer observed after pretreatment with either 5-HT 2A/2C or 5-HT 2B receptor antagonists. Furthermore, spinal pretreatment with an MEK/ERK MAPK inhibitor blocked phrenic motor facilitation elicited by intrathecal injections of 5-HT 2A but not 5-HT 2B receptor agonists. Thus, mAIH-induced pLTF requires concurrent cervical spinal activation of both 5-HT 2A and 5-HT 2B receptors. However, these distinct receptor subtypes contribute to phrenic motor facilitation via distinct downstream signaling cascades that differ in their requirement for ERK MAPK signaling. The demonstration that both 5-HT 2A and 5-HT 2B receptors make unique contributions to mAIH-induced pLTF advances our understanding of mechanisms that underlie 5-HT-induced phrenic motor plasticity. NEW & NOTEWORTHY Moderate acute intermittent hypoxia (mAIH) triggers a persistent enhancement in phrenic motor output, an effect termed phrenic long-term facilitation (pLTF). mAIH-induced pLTF is blocked by cervical spinal application of the broad-spectrum serotonin (5-HT) receptor antagonist methysergide, demonstrating the need for spinal 5-HT receptor activation. However, the exact type of 5-HT receptors required for initiation of pLTF remains unknown. To the best of out knowledge, the present study is the first to demonstrate that 1 ) spinal coactivation of two distinct Gq protein-coupled 5-HT 2 receptor subtypes is necessary for mAIH-induced pLTF, and 2 ) these receptors contribute to pLTF via cascades that differ in their requirement for ERK MAPK signaling.

In light of the multifactorial origin of neurodegenerative disorders and some body of evidence indicating that pharmacological blockade of serotonin 5-HT 6 and dopamine D 3 receptors might be beneficial for cognitive decline, we envisioned ( S )-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1 H -pyrrolo[3,2- c ]quinoline (CPPQ), a neutral antagonist of 5-HT 6 R, as a chemical template for designing dual antagonists of 5-HT 6 /D 3 receptors. As shown by in vitro experiments, supported by quantum chemical calculations and molecular dynamic simulations, introducing alkyl substituents at the pyrrolidine nitrogen of CPPQ, fulfilled structural requirements for simultaneous modulation of 5-HT 6 and D 3 receptors. The study identified compound 19 (( S )-1-((3-chlorophenyl)sulfonyl)- N -(1-isobutylpyrrolidin-3-yl)-1 H -pyrrolo[3,2- c ]quinolin-4-amine), which was classified as a dual 5-HT 6 /D 3 R antagonist ( K i(5-HT6) = 27 nM, K i(D3) = 7 nM). Compound 19 behaved as a neutral antagonist at G s signaling and had no influence on receptor-operated, cyclin-dependent kinase 5 (Cdk5)-dependent neurite growth. In contrast to the well characterized 5-HT 6 R antagonist intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage induced by doxorubicin, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an index of cell membrane disruption. This feature is of particular importance considering the involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. Biological results obtained for 19 in in vitro tests, translated into procognitive properties in phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in rats.

We remember our lives as sequences of events, but it is unclear how these memories are controlled during retrieval. In rats, the medial prefrontal cortex (mPFC) is positioned to influence sequence memory through extensive top-down inputs to regions heavily interconnected with the hippocampus, notably the nucleus reuniens of the thalamus (RE) and perirhinal cortex (PER). Here, we used an hM4Di synaptic-silencing approach to test our hypothesis that specific mPFC→RE and mPFC→PER projections regulate sequence memory retrieval. First, we found non-overlapping populations of mPFC cells project to RE and PER. Second, suppressing mPFC activity impaired sequence memory. Third, inhibiting mPFC→RE and mPFC→PER pathways effectively abolished sequence memory. Finally, a sequential lag analysis showed that the mPFC→RE pathway contributes to a working memory retrieval strategy, whereas the mPFC→PER pathway supports a temporal context memory retrieval strategy. These findings demonstrate that mPFC→RE and mPFC→PER pathways serve as top-down mechanisms that control distinct sequence memory retrieval strategies., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The proprioceptive sensory inputs from neurons in the mesencephalic trigeminal nucleus (MesV) to masseter motoneurons (MMNs) play an important role in regulating masseter muscle activity during mastication. Several histological studies have shown that serotonin (5-HT) fibers densely innervate both the MesV and the trigeminal motor nucleus. However, the functional roles of 5-HT in the regulation of the excitatory synaptic inputs from MesV afferents to MMNs remain to be clarified. Thus, using the whole-cell recording technique in brainstem slice preparations from juvenile Wistar rats aged between postnatal days 8 and 12, we examined the effects of 5-HT on the excitatory synaptic inputs from MesV afferents to MMNs. Bath application of 5-HT reduced the peak amplitude of excitatory postsynaptic potentials evoked in MMNs by electrical stimulation of the MesV afferents (eEPSPs), and this inhibitory effect of 5-HT on eEPSPs was replicated with the 5-HT 1B receptor agonist CP-93129 but not by the 5-HT 1A receptor agonist 8-OH-DPAT. Moreover, the 5-HT 1B receptor antagonist SB-224289 but not the 5-HT 1A receptor antagonist WAY-100635 antagonized the inhibitory effect of 5-HT on eEPSPs. CP-93129 increased the paired-pulse ratio and decreased the frequency of miniature excitatory postsynaptic currents (mEPSCs), while it did not alter the mEPSC amplitude. These results suggest that presynaptic 5-HT 1B receptors are involved in the inhibition of the excitatory synaptic inputs from MesV afferents to MMNs. Such inhibition may regulate MesV afferent activity during mastication., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rationale: 2-Amino-6-chloro-3,4-dihydroquinazoline (e.g., A6CDQ) represents a novel putative antidepressant originally thought to act through a 5-HT 3 serotonin receptor antagonist mechanism. Here, we investigated this further by examining a positional isomer of A6CDQ (i.e., A7CDQ)., Materials and Methods: 5-HT 3 receptor and transporter activity (uptake-1 and uptake-2) were investigated using a variety of in vitro assays and the in vivo mouse tail suspension test (TST)., Results: Although A7CDQ binds at 5-HT 3 receptors with low affinity (K i  = 1975 nM) compared to A6CDQ (K i  = 80 nM), it retained 5-HT 3 receptor antagonist action (IC 50  = 5.77 and 0.26 μM, respectively). In the mouse TST A7CDQ produced antidepressant-like actions (ED 50  = 0.09 mg/kg) comparable to that of A6CDQ. In addition, A6CDQ was found to be a 5-HT releasing agent (K m  = 2.8 μM) at hSERT and a reuptake inhibitor (IC 50  = 1.8 μM) at hNET, whereas A7CDQ was a weak reuptake inhibitor (K m  = 43.6 μM) at SERT but a releasing agent (EC 50  = 3.3 μM) at hNET. Moreover, A6CDQ and A7CDQ were potent inhibitors of uptake-2 (e.g.; OCT3 IC 50  = 3.9 and 5.9 μM, respectively)., Conclusions: A simple shift of a substituent in a common quinazoline scaffold from one position to another (i.e., a chloro group from the 6- to the 7-position) resulted in a common action in the TST but via a somewhat different mechanism. A6CDQ and A7CDQ might represent the first members of a new class of potential antidepressants with a unique multi-modal mechanism of action.

Serotonin 5-HT 6 receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5-HT 6 antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease-modifying effect. Combining BuChE inhibition, 5-HT 6 antagonism, and antioxidant properties may result in multitarget-directed ligands providing cognition-enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5-HT 6 antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5-HT 6 receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K i and K b values against 5-HT 6 receptors of 41.8 and 74 nM, respectively, an IC 50 value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti-Alzheimer's agents., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

In this article, we propose, based on a clinical case, the potential antitumor effect related to the inhibition of serotonin in neuroendocrine tumors (NETs). Currently, the only drug that exists for the symptomatic treatment of carcinoid syndrome refractory to somatostatin analogues is telotristat, based on its pivotal study, the TELESTAR trial. Based on the existing preclinical rationale, it seems that the inhibition of serotonin may have an antitumoral role in NETs. Briefly, serotonin may act as an autocrine growth factor of NETs, and it may also play an immunomodulatory role by enhancing macrophage polarization to an immunotolerant M2 phenotype. To our knowledge, this rationale for the possible antitumor effect of serotonin in NETs has not yet been published in the literature., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Repeated cycles of binge-like alcohol consumption and abstinence change the activity of several neurotransmitter systems. Some of these changes are consolidated following prolonged alcohol use and are thought to play an important role in the development of dependence. We have previously shown that systemic administration of the dual beta-adrenergic antagonist and 5-HT 1A/1B partial agonist pindolol selectively reduces long-term but not short-term binge-like consumption of ethanol and alters excitatory postsynaptic currents in basolateral amygdala (BLA) principal neurons. The aim of this study was to investigate the effects of pindolol microinfusions in the BLA on long-term ethanol intake using the drinking-in-the-dark paradigm in mice. We also microinfused RU24969 (5-HT 1A/1B receptor partial agonist) and CGP12177 (β 1/2 adrenergic antagonist) following long-term ethanol intake and determined the densities of 5-HT 1A/1B receptors and β 1/2 adrenergic in the BLA following short-term (4 weeks) and long-term ethanol (12 weeks) consumption. We show that intra-BLA infusion of pindolol (1000 pmol/0.5 μl), RU24969 (0.3 and 3 pmol/0.5 μl) and CGP12177 (500 pmol/0.5 μl) produce robust decreases in long-term ethanol consumption. Additionally, we identified reduced β 1/2 adrenergic receptor expression and no change in 5-HT 1A/1B receptor density in the BLA of long-term ethanol-consuming mice. Collectively, our data highlight the effects of pindolol on voluntary, binge-like ethanol consumption behavior following long-term intake., (© 2018 Society for the Study of Addiction.)

G protein-coupled receptors (GPCRs) represent the largest class of receptors involved in signal transduction across cell membranes and are major drug targets in all clinical areas. Endocytosis of GPCRs offers a regulatory mechanism for sustaining their signaling within a stringent spatiotemporal regime. In this work, we explored agonist-induced endocytosis of the human serotonin 1A receptor stably expressed in HEK-293 cells and the cellular machinery involved in receptor internalization and intracellular trafficking. The serotonin 1A receptor is a popular GPCR implicated in neuropsychiatric disorders such as anxiety and depression and serves as an important drug target. In spite of its pharmacological relevance, its mechanism of endocytosis and intracellular trafficking is less understood. In this context, we have utilized a combination of robust population-based flow cytometric analysis and confocal microscopic imaging to address the path and fate of the serotonin 1A receptor during endocytosis. Our results, utilizing inhibitors of specific endocytosis pathways and intracellular markers, show that the serotonin 1A receptor undergoes endocytosis predominantly via the clathrin-mediated pathway and subsequently recycles to the plasma membrane via recycling endosomes. These results would enhance our understanding of molecular mechanisms of GPCR endocytosis and could offer novel insight into the underlying mechanism of antidepressants that act via the serotonergic pathway. In addition, our results could be relevant in understanding cell (or tissue)-specific GPCR endocytosis.

Most studies on discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) have been conducted using a relatively low dose (1.5 mg/kg), and those studies have invariably implicated serotonergic mechanisms. In contrast, dopaminergic mechanisms mediate the discriminative stimulus effects of amphetamine (AMPH). Some studies have suggested that the discriminative stimulus effects of a higher (3.0 mg/kg) dose of MDMA might rely on both serotonergic and dopaminergic mechanisms. This study aimed to determine effects of selective dopamine (DA) and serotonin (5HT) antagonists on the discriminative stimulus properties of AMPH (0.5 mg/kg) and MDMA (3.0 mg/kg). Separate groups of rats were trained to discriminate AMPH (0.5 mg/kg) or MDMA (3.0 mg/kg) from saline using a food-reinforced drug-discrimination procedure. Effects of DA (SCH 23390: 0.003-0.03 mg/kg and eticlopride: 0.03-0.3 mg/kg) or 5HT (ritanserin: 1.0-10.0 mg/kg, WAY-100635: 0.3-1.0 mg/kg and GR129375: 1.0-3.0 mg/kg) antagonists on the discriminative stimulus effects of both drugs were determined. Both DA antagonists dose-dependently decreased the AMPH but not the MDMA discrimination. None of the 5HT antagonists altered the discriminative stimulus effects of either drug. The MDMA (3.0 mg/kg) stimulus comprises both a DAergic and 5HTergic response, and the results suggest that either one is sufficient, but not required, to maintain the stimulus effects.

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has well documented prosocial effects and is currently under clinical investigation as a treatment for patients with PTSD, autism, and other conditions. Early clinical trials have found that MDMA-assisted therapy may have robust long-lasting therapeutic effects, yet the mechanism by which acute treatments produce these long-term effects is unclear. Sensitization to certain behavioral drug effects is a common rodent model used to assess long-lasting neurobiological adaptations induced by acute drug treatments. Nine independent experiments were undertaken to investigate if and how mice sensitize to the prosocial effects of MDMA. When treated with 7.8 mg/kg MDMA and paired every other day for a week, MDMA-induced social interaction increased precipitously across treatment sessions. This previously unreported phenomenon was investigated and found to be heavily influenced by a social context and 5-HT 2A R activation. Social sensitization did not appear to develop if mice were administered MDMA in isolation, and pretreatment with MDL100907, a selective 5-HT 2A R antagonist, inhibited the development of social sensitization. However, when MDL100907 was administered to mice that had already been sensitized, it did not attenuate social interaction, suggesting that 5-HT 2A R activity may be necessary for the development of social sensitization but not the expression of MDMA-induced social behavior. Additional investigation is warranted to further explore the phenomenon of social sensitization and to determine the underlying neurobiological mechanisms., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Current theories of deliberative decision making suggest that deliberative decisions arise from imagined simulations that require interactions between the prefrontal cortex and hippocampus. In rodent navigation experiments, hippocampal theta sequences advance from the location of the rat ahead to the subsequent goal. To examine the role of the medial prefrontal cortex (mPFC) on the hippocampus, we disrupted the mPFC with DREADDs (designer receptors exclusively activated by designer drugs). Using the Restaurant Row foraging task, we found that mPFC disruption resulted in decreased vicarious trial and error behavior, reduced the number of theta sequences, and impaired theta sequences in hippocampus. mPFC disruption led to larger changes in the initiation of the hippocampal theta sequences that represent the current location of the rat rather than to the later portions that represent the future outcomes. These data suggest that the mPFC likely provides an important component to the initiation of deliberative sequences and provides support for an episodic-future thinking, working memory interpretation of deliberation. NEW & NOTEWORTHY The medial prefrontal cortex (mPFC) and hippocampus interact during deliberative decision making. Disruption of the mPFC impaired hippocampal processes, including the local and nonlocal representations of space along each theta cycle and the initiation of hippocampal theta sequences, while sparing place cell firing characteristics and phase precession. mPFC disruption reduced the deliberative behavioral process vicarious trial and error and improved economic behaviors on this task.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory impairment and synaptic loss. Long-term potentiation (LTP), a type of synaptic plasticity, is impaired during AD. Serotonin type 6 receptor (5-HT6R) inactivation is proposed as a therapeutic target for AD. This study examined the effects of chronic administration of the 5-HT6R antagonist, SB-258585, on cognitive, memory, and hippocampal plasticity in a rat model of AD. Abeta neurotoxicity was induced in rats using Aβ (1.35 pmol intracerebroventricular [ICV] injection). The following groups were formed: control sustained surgery and saline-treated, Aβ+saline (1 μL ICV for 30 days), and Aβ+SB-258585 (0.024 mg/kg, ICV for 30 days). The learning and memory were tested using the novel object recognition and passive avoidance tests. Next, anesthetized rats were placed in a stereotaxic apparatus. The population spike (PS) amplitude and the slope of the excitatory postsynaptic potentials (fEPSPs) of the LTP were measured following high-frequency stimulation in the dentate gyrus. The Aβ injection reduced step-through latency in the passive avoidance test and decreased the discrimination index in the novel object test. Aβ diminished both the amplitude of hippocampal neuron population spikes and the slope of excitatory postsynaptic potentials, compared to the control group. The administration of SB-258585 in rats receiving Aβ attenuated the Aβ-induced deficits in cognition, memory, and LTP in comparison with the Aβ group. It can be concluded that chronic treatment with SB-258585 antagonist can prevent Aβ-related deficiencies in learning and memory performance by improving neuronal plasticity. SB-258585 can prevent the progression of AD., (Copyright © 2019. Published by Elsevier B.V.)

Administration of 5-HT receptor antagonist to snails trained in conditioned food aversion prior to reminding of the conditioning stimulus caused amnesia. At the early period of amnesia (day 3), injections of protein synthesis inhibitor cycloheximide without reminder or reminder alone were ineffective. At the same time, injections of the inhibitor combined with reminder led to memory recovery; this effect in most animals persisted for at least 10 days. In the rest snails, aversive responses to presentations of the conditioning stimulus persisted for 2 days. Cycloheximide injection and reminder in 10 days after induction of amnesia did not affect its development or caused a transient memory recovery (2 days). We hypothesized that amnesia is an active process unfolding in time. One of mechanism of this process is reminder-induced and protein synthesis-depended reactivation of amnesia. Inhibitor of protein synthesis disturbed this reactivation and led to recovery of the initial memory of conditioned food aversion.

The antidepressant-like effects of zinc (Zn) have been documented in some animal models of depression. In addition, antidepressants may reduce the abuse potential of opioids by affecting their rewarding effect. Hence, this study was performed to investigate the effect of Zn on the expression of morphine-induced conditioned place preference (CPP) in male rats. We used an unbiased CPP paradigm for investigating the effect of Zn. The intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations of Zn (5-20 mg/kg, i.p., and 10 nmol/rat, respectively) with or without morphine did not induce conditioned place aversion (CPA) or CPP during acquisition phase. However, the same i.p. and i.c.v. administrations of Zn induced morphine-like CPP in the expression phase. Pre-treatment with dopamine receptor antagonists (SCH23390, sulpiride, and haloperidol) and serotonin receptor antagonists (WAY100135, ketanserin, and ondansetron) reversed the enhancement effect of Zn on the expression of morphine-induced CPP (especially 20mg/kg, i.p. and 10 nmol/rat, i.c.v.). These findings suggest that acute i.p. and i.c.v administration of Zn might enhance the rewarding properties of morphine through involvement with dopaminergic and serotonergic neuronal systems.

Rationale: Fear conditioning is an important factor in the etiology of anxiety disorders. Previous studies have demonstrated a role for serotonin (5-HT) 1A receptors in fear conditioning. However, the relative contribution of somatodendritic 5-HT 1A autoreceptors and post-synaptic 5-HT 1A heteroreceptors in fear conditioning is still unclear., Objective: To determine the role of pre- and post-synaptic 5-HT 1A receptors in the acquisition and expression of cued and contextual conditioned fear., Methods: We studied the acute effects of four 5-HT 1A receptor ligands in the fear-potentiated startle test. Male Wistar rats were injected with the 5-HT 1A receptors biased agonists F13714 (0-0.16 mg/kg, IP), which preferentially activates somatodendritic 5-HT 1A autoreceptors, or F15599 (0-0.16 mg/kg, IP), which preferentially activates cortical post-synaptic 5-HT 1A heteroreceptors, with the prototypical 5-HT 1A receptor agonist R(+)8-OH-DPAT (0-0.3 mg/kg, SC) or the 5-HT 1A receptor antagonist WAY100,635 (0-1.0 mg/kg, SC)., Results: F13714 (0.16 mg/kg) and R(+)-8-OH-DPAT (0.03 mg/kg) injected before training reduced cued fear acquisition. Pre-treatment with F15599 or WAY100,635 had no effect on fear learning. In the fear-potentiated startle test, F13714 (0.04-0.16 mg/kg) and R(+)-8-OH-DPAT (0.1-0.3 mg/kg) reduced the expression of cued and contextual fear, whereas F15599 had no effect. WAY100,635 (0.03-1.0 mg/kg) reduced the overall startle response., Conclusions: The current findings indicate that activation of somatodendritic 5-HT 1A autoreceptors reduces cued fear learning, whereas 5-HT 1A receptors seem not involved in contextual fear learning. Moreover, activation of somatodendritic 5-HT 1A autoreceptors may reduce cued and contextual fear expression, whereas we found no evidence for the involvement of cortical 5-HT 1A heteroreceptors in the expression of conditioned fear.

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT 2A R) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT 2A R antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.

Credit should be granted to medicinal chemists with a solid background in organic chemistry and computational chemistry, able to read, understand, and discuss the biological data, in order to design new and more efficient therapeutic approaches for Alzheimer's disease.

Background: Cisplatin is a highly emetogenic antineoplastic drug and induces peripheral neuropathy when given in cycles. Granisetron, a 5-HT 3 antagonist, is clinically used to prevent chemotherapy-induced nausea/emesis and abdominal pain in irritable bowel syndrome. The effects of cisplatin on visceral sensitivity and those of granisetron in the context of cancer chemotherapy are not well known., Methods: Adult male Wistar rats received two intraperitoneal injections 30 minutes apart: granisetron (1 mg kg -1 )/vehicle and cisplatin (6 mg kg -1 )/vehicle. Thereafter, nausea-like behavior was measured as bedding intake for 4 hours, and gastric dysmotility was measured radiographically for 8 hours. Gastric weight and size were determined ex vivo and samples of the forestomach, corpus, ileum, and colon were obtained for histological analysis at 4 and 30 hours after cisplatin/vehicle. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation 2 hours after cisplatin/vehicle., Key Results: Cisplatin-induced bedding intake and gastric dysmotility, and granisetron blocked these effects, which occurred in the absence of frank mucositis. Visceral sensitivity was reduced to a similar extent by both drugs alone or in combination., Conclusions and Inferences: Cisplatin-induced bedding intake and gastric dysmotility were blocked by granisetron, confirming the involvement of serotonin acting on 5-HT 3 receptors. Unexpectedly, visceral sensitivity to colonic distension was reduced, to the same extent, by cisplatin, granisetron, and their combination, suggesting important mechanistic differences with nausea and gastric dysmotility that warrant further investigation., (© 2018 John Wiley & Sons Ltd.)

Objectives: Insomnia and loss of appetite are the most common side effects of methylphenidate in patients with attention deficit/hyperactivity disorder (ADHD). The adverse effects may limit optimal dosing and patients' compliance with treatment leading to the discontinuation of treatment. This research evaluates the preventive effects of cyproheptadine on sleeping and appetite disorders induced by methylphenidate in ADHD children., Methods: During this exploratory, randomised, double-blinded, placebo-controlled clinical trial, forty patients with ADHD diagnosis who had received methylphenidate randomly were assigned to participate in the cyproheptadine or the placebo group. Patients' weight and Pittsburgh Sleep Quality Index (PSQI) score were recorded at baseline, after four, six and eight weeks of treatment. The ADHD Parent Rating Scale-V score was also defined at the beginning and the end of study for each patient., Results: There was no significant difference between the cyproheptadine and the placebo groups regarding their weight, rate of growth and PSQI score in the monthly assessment. In addition, there was no significant difference in response to the therapy between the two groups., Conclusions: Based on our findings, cyproheptadine does not have any considerable preventive effect on sleeping and appetite disorders induced by methylphenidate in ADHD children.

Rationale: The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused., Objective: Direct-acting 5-HT 2A/2C receptor agonists and antagonists and D 1-3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT 2A/2C and D 1-3 receptor antagonists were examined in both groups., Methods: Male Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N = 24) or a high dose of 3.2 mg/kg mephedrone (N = 11) from saline., Results: In the low training-dose group, mephedrone, MDMA, methamphetamine, d-amphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates., Conclusions: A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine, whereas a higher training dose of mephedrone requires a discriminative stimulus that was only mimicked by MDMA. Dopaminergic or serotoninergic antagonists failed to produce significant blockade of mephedrone at either training dose.

Psychedelics exert unique effects on human consciousness. The thalamic filter model suggests that core effects of psychedelics may result from gating deficits, based on a disintegration of information processing within cortico-striato-thalamo-cortical (CSTC) feedback loops. To test this hypothesis, we characterized changes in directed (effective) connectivity between selected CTSC regions after acute administration of lysergic acid diethylamide (LSD), and after pretreatment with Ketanserin (a selective serotonin 2A receptor antagonist) plus LSD in a double-blind, randomized, placebo-controlled, cross-over study in 25 healthy participants. We used spectral dynamic causal modeling (DCM) for resting-state fMRI data. Fully connected DCM models were specified for each treatment condition to investigate the connectivity between the following areas: thalamus, ventral striatum, posterior cingulate cortex, and temporal cortex. Our results confirm major predictions proposed in the CSTC model and provide evidence that LSD alters effective connectivity within CSTC pathways that have been implicated in the gating of sensory and sensorimotor information to the cortex. In particular, LSD increased effective connectivity from the thalamus to the posterior cingulate cortex in a way that depended on serotonin 2A receptor activation, and decreased effective connectivity from the ventral striatum to the thalamus independently of serotonin 2A receptor activation. Together, these results advance our mechanistic understanding of the action of psychedelics in health and disease. This is important for the development of new pharmacological therapeutics and also increases our understanding of the mechanisms underlying the potential clinical efficacy of psychedelics., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

The aim of the present study was to investigate and compare the ability of three novel 5-HT 6 and/or 5-HT 7 receptor antagonists as follows: PZ-668-a preferential 5-HT 6 antagonist; PZ-1433-a preferential 5-HT 7 antagonist; and ADN-1184-a monoaminergic ligand with potent 5HT 6/7 antagonist properties, to augment the effect of antidepressant drugs with different mechanisms of action (escitalopram, reboxetine, and bupropion) in the forced swim test in rats. In neurochemical ex vivo experiments, the influence of the tested compounds on levels of monoamines and their metabolites were determined in the rat frontal cortex, in addition to behavioral experiments. The results of our investigations revealed the differences in action of the tested compounds. PZ-668 strongly affected dopaminergic and faintly noradrenergic system, PZ-1433 induced a significant elevation in dopamine, noradrenaline, serotonin, and their metabolite levels, while ADN-1184 appeared to act mostly through dopaminergic transmission. The agent with 5-HT 6 antagonistic properties (PZ-668) revealed an anti-immobility action of bupropion (primarily) and reboxetine in interaction studies. PZ-1433, the 5-HT 7 preferential antagonist facilitated antidepressant effects of escitalopram and, to a lesser extent, bupropion, while ADN-1184, a multireceptor ligand, potentiated the effectiveness of escitalopram, reboxetine, and bupropion. The presented findings may contribute to further investigations of more effective and safer antidepressant drugs, and may help selecting optimal augmentation therapy in treatment-resistant depression., (Copyright © 2018 Elsevier B.V. All rights reserved.)

When dopamine was identified as a primary target for schizophrenia, the dopamine antagonists, now referred to as first-generation antipsychotics, were added to our pharmacopeia. In the 1990s, with the discovery of risperidone and clozapine, the mechanism of dopamine receptor antagonism was paired with serotonin receptor antagonism to give rise to second-generation antipsychotics. A decade later these mechanisms were further refined to selective dopamine receptors antagonism and serotonin receptors antagonism and agonism to create a modulation or stabilization of dopamine nerve firing in differential ways. This new wave may be referred to as the third generation. The current article reviews the pharmacodynamics and pharmacokinetics of these dopamine modulators. [Journal of Psychosocial Nursing and Mental Health Services, 57(2), 7-11.]., (Copyright 2019, SLACK Incorporated.)

Objectives: Somatostatin analogs (SSAs) are standard for symptomatic patients with neuroendocrine tumors (NETs). However, most patients experience tachyphylaxis, and limited options exist for this so-called "refractory carcinoid syndrome." Recently, 5-HT 3 antagonist ondansetron has been associated with reduction of bowel movement in a small series. The aim of this analysis was to assess effectiveness of ondansetron for symptomatic treatment of carcinoid syndrome., Design and Patients: We have analyzed patients given ondansetron as bridging therapy for refractory carcinoid syndrome. The dose was 2 × 8 mg for 5 days, followed by reduction to 1 × 8 mg in case of benefit., Results: A total of 14 patients with small bowel NETs metastatic to the liver were identified. All patients had been treated with SSAs for a median time of 18 months before aggravation of diarrhea. One patient had to be excluded because of an underlying infectious cause of diarrhea. The median number of daily bowel movements was 7 (range, 5-13) before initiation of therapy. At this time, seven patients had stable disease, whereas six patients showed radiological progression with symptomatic breakthrough. All 13 patients were scheduled for salvage therapy. Remarkably, in 85% (11/13) ondansetron resulted in a clinically relevant decrease of bowel movements to a median of 3 (1-4). The median time of ondansetron intake was 29 days (7 days to 29 months). In four patients, diarrhea recurred after initial improvement at an interval of 22-43 days, whereas the remaining seven had an ongoing benefit, including two long-term responders who refused further therapy because of pronounced decrease of symptoms (ondansetron for 14+ and 29+ months)., Conclusion: Ondansetron offers symptomatic relief in the majority of patients. Although there was no influence on 5-HIAA levels, evidence from two patients suggests prolonged benefit., Implications for Practice: Somatostatin analogs are standard treatment in patients with carcinoid syndrome and have an overall response rate of up to 50%. This symptomatic benefit, however, is lost in many patients because of the development of tachyphylaxis or tumor progression. Patients with this "refractory carcinoid syndrome" pose a therapeutic challenge and are sometimes faced with a detrimental effect on quality of life. In this article, the authors suggest the 5-HT 3 receptor antagonist ondansetron as potential symptomatic therapy for patients with refractory diarrhea due to carcinoid syndrome. Although the number of patients in this retrospective series is limited, treatment was easily applicable, feasible, and safe and resulted in an ongoing symptomatic benefit in 85% of patients, including two long-term responders., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Research in Alzheimer's disease is going through a big turnaround. New palliative therapies are being reconsidered for the effective management of disease because of setbacks in the development of disease-modifying therapies. Serotonin 6 (5-HT6) receptor has long been pursued as a potential target for the symptomatic treatment of Alzheimer's disease. SUVN-502 is a novel 5-HT6 receptor antagonist (Ki=2.04 nmol/l) with high receptor affinity and high degree of selectivity. SUVN-502 at doses ranging from 1 to 10 mg/kg, per os (p.o.) demonstrated procognitive effects in various behavioral animal models (object recognition task, water maze, and radial arm maze), and it acts on three phases of cognition, viz., acquisition, consolidation, and retention (object recognition task). SUVN-502 (3 and 10 mg/kg, p.o.) modulated glutamate levels when administered alone (microdialysis). At doses ranging from 1 to 10 mg/kg p.o., SUVN-502 potentiated the effects of donepezil (microdialysis). SUVN-502 [1 mg/kg, intravenous (i.v.)] also potentiated pharmacological effects of memantine (1 mg/kg, i.v.) and/or donepezil (0.3 mg/kg, i.v.) (θ modulation). The beneficial effects of SUVN-502 on learning and memory might be mediated through the modulation of cholinergic and/or glutamatergic neurotransmission in relevant brain regions. In summary, behavioral, neurochemical, and electrophysiological outcomes indicate that SUVN-502 may augment the beneficial effects of donepezil and memantine combination.

5-HT 7 receptors have been suggested to play a role in the regulation of psychiatric disorders. The experimental literature however is not fully consistent on this possibility. Two selective 5-HT 7 receptor antagonists, DR-4004 and SB-269970, were evaluated in mouse models used to detect drugs used to treat anxiety, depression, or schizophrenia. A 5-HT-induced hypothermia assay was used to define the doses of DR-4004 and SB-269970 predicted to impact 5-HT 7 receptors in the brain in vivo. 5-HT produced hypothermia in wildtype mice by either i.p. or i.c.v. routes but did not in 5-HT 7 receptor knockout mice. 5-HT-induced hypothermia was not attenuated by drugs selectively blocking alpha1 or 5-HT 1A receptors. Doses of DR-4004 and SB-269970 that blocked 5-HT-induced hypothermia, did not display significant anxiolytic-like (elevated plus maze; vogel conflict) or antidepressant-like efficacy (tail-suspension test) in mouse models. These compounds did demonstrate some antipsychotic-like properties in the PCP-induced hyperactivity assay and anxiolytic/anti-stress effects in the stress-induced cGMP assay. Negative findings were substantiated by positive control drugs that were active in each assay system. We conclude that 5-HT-induced hypothermia can be used to estimate blockade of central 5-HT 7 receptors. Effects of DR-4004 and SB-269970 in animal models are generally consistent with the experimental literature that the evidence is mixed or not robust regarding the potential efficacy of 5-HT 7 receptor antagonism in the treatment of anxiety, depression, or schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)