5-HT1B Receptor Research Articles

Recent Developments on Future Antidepressant-related Serotonin Receptors.

Conventional serotonin-enhancing antidepressants including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have shown effectiveness in the treatment of major depression, but their significant limitations such as slowness of action have led to intensive research efforts to develop new antidepressants. Increased synaptic neurotransmission of serotonin (5-hdroxytryptamine; 5-HT) through orchestration of stimulation and blockade of various subtypes of 5-HT receptors is involved in the mechanisms of action of SSRIs. Agonists at the 5-HT1A, 5-HT1B, 5-HT2C, 5-HT4, and 5-HT6 receptors and antagonists at the 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5- HT6, and 5-HT7 receptors have shown antidepressant properties in clinical and preclinical studies. However, paradoxical antidepressant-like effects of both agonists and antagonists at particular 5-HT receptors suggest the need to consider the neurochemical mechanisms of each 5-HT receptor subtype. Therefore, better knowledge of the involvement of individual 5-HT receptors in the mechanisms of action of currently used antidepressants as well as antidepressant effects of selective ligands of 5- HT receptor subtypes will provide opportunities for the development of future antidepressants with more rapid onset of action, fewer side effects, and better efficacy than SSRIs.

Exploring Halogen Bonds in 5-Hydroxytryptamine 2B Receptor-Ligand Interactions.

Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to further explore the opportunity of "designing in" halogen bonding interactions in structure-based ligand design for the 5-HT2B receptor, which not only facilitated the identification of previously uncharacterized halogen bonds in known 5-HT2B ligands but also enabled the rational design of halogen bonding interactions for the optimization of 5-HT2B ligands. As a proof-of-concept, a series of halogen-substituted analogues of doxepin was synthesized and evaluated, which showed improved in vitro and in vivo potency.

Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines: High potency agonists at 5-HT2A receptors

The use of new psychoactive substituted 2,5-dimethoxy-N-benzylphenethylamines is associated with abuse and toxicity in the United States and elsewhere and their pharmacology is not well known. This study compares the mechanisms of action of 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe), 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe), 2-(((4-iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH); and 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) with hallucinogens and stimulants. Mammalian cells heterologously expressing 5-HT1A, 5-HT2A, 5-HT2B or 5-HT2C receptors, or dopamine, serotonin or norepinephrine transporters (DAT, SERT and NET, respectively) were used to assess drug affinities at radioligand binding sites. Potencies and efficacies were determined using [35S]GTPγS binding assays (5-HT1A), inositol-phosphate accumulation assays (5-HT2A, 5-HT2B and 5-HT2C), and uptake and release assays (transporters). The substituted phenethylamines were very low potency and low efficacy agonists at the 5-HT1A receptor. 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOH and 25N-NBOMe had very high affinity for, and full efficacy at, 5-HT2A and 5-HT2C receptors. In the 5-HT2A receptor functional assay, 25D-NBOMe, 25E-NBOMe, 25I-NBOH and 25N-NBOMe had subnanomolar to low nanomolar potencies similar to (+)lysergic acid diethylamide (LSD) while 25H-NBOMe had lower potency, similar to serotonin. At the 5-HT2C receptor, four had very high potencies, similar to LSD and serotonin, while 25H-NBOMe had lower potency. At the 5-HT2B receptor, the compounds had lower affinity, potency and efficacy compared to 5-HT2A or 5-HT2C. The phenethylamines had low to mid micromolar affinities and potencies at the transporters. These results demonstrate that these –NBOMe and –NBOH substituted phenethylamines have a biochemical pharmacology consistent with hallucinogenic activity, with little psychostimulant activity.

Antiallodynic effect induced by [6]‐gingerol in neuropathic rats is mediated by activation of the serotoninergic system and the nitric oxide–cyclic guanosine monophosphate–adenosine triphosphate‐sensitive K+ channel pathway

The present study evaluated the possible antiallodynic effect induced by [6]-gingerol in rats with L5-L6 spinal nerve ligation (SNL). Moreover, we determined the possible mechanism underlying the antiallodynic effect induced by [6]-gingerol in neuropathic rats. The animals underwent L5-L6 SNL for the purpose of developing tactile allodynia. Tactile allodynia was measured with von Frey filaments. Intrathecal administration of [6]-gingerol reversed SNL-induced tactile allodynia. The [6]-gingerol-induced antiallodynic effect was prevented by the intrathecal administration of methiothepin (30μg per rat; nonselective 5-hydroxytryptamine [5-HT] antagonist), WAY-100635 (6μg per rat; selective 5-HT1A receptor antagonist), SB-224289 (5μg per rat; selective 5-HT1B receptor antagonist), BRL-15572 (4μg per rat; selective 5-HT1D receptor antagonist), and SB-659551 (6μg per rat; selective 5-HT5A receptor antagonist), but naloxone (50μg per rat; nonselective opioid receptor antagonist) did not prevent the [6]-gingerol-induced antiallodynic effect. Moreover, intrathecal administration of Nω-nitro-l-arginine methyl ester (100μg per rat; nonselective nitric oxide [NO] synthase inhibitor), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10μg per rat; inhibitor of guanylate cyclase), and glibenclamide (50μg per rat; channel blocker of adenosine triphosphate [ATP]-sensitive K+ channels) prevented the [6]-gingerol-induced antiallodynic effect. These data suggest that the antiallodynic effect induced by [6]-gingerol is mediated by the serotoninergic system involving the activation of 5-HT1A/1B/1D/5A receptors, as well as the NO-cyclic guanosine monophosphate-ATP-sensitive K+ channel pathway but not by the opioidergic system.

CB1 receptors in the paraventricular nucleus of the hypothalamus modulate the release of 5-HT and GABA to stimulate food intake in rats

Endocannabinoids and their receptors not only contribute to the control of natural processes of appetite regulation and energy balance but also have an important role in the pathogenesis of obesity. CB1 receptors (CB1R) are expressed in several hypothalamic nuclei, including the paraventricular nucleus (PVN), where induce potent orexigenic responses. Activation of CB1R in the PVN induces hyperphagia by modulating directly or indirectly orexigenic and anorexigenic signals; however, interaction among these mediators has not been clearly defined. CB1R mRNA is expressed in serotonergic neurons that innervate the PVN, and activation of 5-HT receptors in the PVN constitutes an important satiety signal. Some GABAergic terminals are negatively influenced by 5-HT, suggesting that the hyperphagic effect of CB1R activation could involve changes in serotonergic and GABAergic signaling in the PVN. Accordingly, the present study was aimed to characterize the neurochemical mechanisms related to the hyperphagic effects induced by activation of CB1R in the PVN, studying in vitro and in vivo changes induced by direct activation these receptors. Here, we have found that the neurochemical mechanisms activated by stimulation of CB1 receptors in the PVN involve inhibition of 5-HT release, resulting in a decrease of serotonergic activity mediated by 5-HT1A and 5-HT1B receptors and inducing disinhibition of GABA release to stimulate food intake. In conclusion, these neurochemical changes in the PVN are determinant to the cannabinoid-induced stimulation of food intake. Our findings provide evidence of a functional connection among CB1R and serotonergic and GABAergic systems on the control of appetite regulation mediated by endocannabinoids.

Diverse approaches to understand functional pharmacology—Examples of the 5-HT1B and 5-HT2A receptors

Diverse approaches to understand functional pharmacology—Examples of the 5-HT1B and 5-HT2A receptors

Amphetamine Self-Administration and Its Extinction Alter the 5-HT1B Receptor Protein Levels in Designated Structures of the Rat Brain

Manipulation of the serotonin (5-HT)1B receptors can modify the behavioral effects of amphetamine including its reinforcing properties. Focus of this study was to examine changes in 5-HT1B receptor protein expression in several brain structures linked to substance drug disorder in different stages of amphetamine addiction—single session of amphetamine self-administration, 20 consecutive days of amphetamine self-administration, and 3 and 14 days of extinction from chronic drug intake. “Yoked” procedure was employed to set apart pharmacological and motivational effects of amphetamine intoxication. Immunohistofluorescence was performed on brain slices containing the following regions: nucleus accumbens (NAc) shell and core, globus pallidum (GP) lateral and ventral, hippocampus (HIP), substantia nigra (SN), and ventral tegmental area (VTA). Single amphetamine session decreased the amount of 5-HT1B receptors in SN, VTA, and HIP in active and yoked rats. On the contrary, 20 days of chronic amphetamine exposure triggered elevation of 5-HT1B receptors exclusively in animals that voluntarily administered the drug in NAc core, GP ventral, and HIP. Furthermore, 14-day (but not 3-day) extinction from amphetamine increased the 5-HT1B receptor expression in ventral and lateral GP, HIP, and SN. This study is the first to demonstrate that exposure to amphetamine and its extinction alter the expression of 5-HT1B receptors in various rat brain regions, and those changes seem to be transient and region specific. Importantly, since increased expression of 5-HT1B receptor after chronic amphetamine self-administration was limited only to active group of animals, we suggest that 5-HT1B receptor is linked to motivational aspect of addiction.

Structural determinants of 5-HT2B receptor activation and biased agonism.

Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor-the human 5-HT2B receptor-in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications.

Identification and characterization of stress degradation products of sumatriptan succinate by using LC/Q-TOF-ESI-MS/MS and NMR: Toxicity evaluation of degradation products.

Sumatriptan succinate, a selective 5-HT1B receptor agonist, was subjected to forced degradation studies as per to International Conference on Harmonization-specified conditions. The drug exclusively showed its degradation under basic, photolytic, and oxidative stress conditions, whereas it was found to be stable under acidic, thermal, and neutral conditions. Eight (DP-1 to DP-8) degradation products were identified and characterized by UPLC-ESI/MS/MS experiments combined with accurate mass measurements. The effective chromatographic separation was achieved on Hibar Purospher STAR, C18 (250×4.6mm, 5μm) column using mobile phase consisting of 0.1% formic acid and methanol at a flow rate of 0.6mL/minute in gradient elution method. It is noteworthy that 2 major degradation products DP-3 and DP-7 were isolated using preparative HPLC and characterized by advanced NMR experiments. The degradation pathway of the sumatriptan was established, which was duly justified by mechanistic explanation. In vitro cytotoxicity of isolated DPs was tested on normal human cells such as HEK 293 (embryonic kidney cells) and RWPE-1 (normal prostate epithelial cells). This study revealed that they were nontoxic up to 100μm concentration. Further, in silico toxicity of the drug and its degradation products was determined using ProTox-II prediction tool. This study revealed that DP-4 and DP-8 are predicted for immune toxicity. Amine oxidase A and prostaglandin G/H synthase 1 are predicted as toxicity targets for DP-3, DP-4, and DP-6 whereas DP-1 and DP-2 are predicted for amine oxidase A target.

5-HT release in nucleus accumbens rescues social deficits in mouse autism model.

Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.

Gut-derived serotonin contributes to bone deficits in colitis

Osteoporosis and bone fractures occur at higher frequency in patients with inflammatory bowel disease (IBD), and decreased bone mass is observed in animal models of colitis. Another consistent feature of colitis is increased serotonin (5-HT) availability in the intestinal mucosa. Since gut-derived 5-HT can decrease bone mass, via activation of 5-HT1B receptors on pre-osteoblasts, we tested the hypothesis that 5-HT contributes to bone loss in colitis. Colitis was chronically induced in mice by adding dextran sodium sulfate (DSS) to their drinking water for 21 days. At day 21, circulating 5-HT levels were elevated in DSS-inflamed mice. Micro-computed tomography of femurs showed a decrease in trabecular bone volume fraction, formation, and surface area, due largely to decreased trabecular numbers in DSS-treated mice. The colitis-induced loss of trabecular bone was significantly suppressed in mice treated with the 5-HT synthesis inhibitor, p-chloro-DL-phenylalanine (PCPA; 300 mg/kg/day IP daily), and in mice treated with the 5-HT1B receptor antagonist GR55562 (1 mg/Kg/day SC daily). The 5-HT reuptake transporter (SERT) is critical for moving 5-HT from the interstitial space into enterocytes and from serum into platelets. Mice lacking SERT exhibited significant deficits in trabecular bone mass that are similar to those observed in DSS-inflamed mice, and these deficits were not extensively worsened by DSS-induced colitis in the SERT−/− mice. Taken together, findings from both the DSS and SERT−/− mouse models support a contributing role for 5-HT as a significant factor in bone loss induced by colitis.

Serotonin concentration enhancers at clinically relevant doses reduce [11C]AZ10419369 binding to the 5-HT1B receptors in the nonhuman primate brain

The serotonin (5-HT) system plays an important role in the pathophysiology and treatment of several major psychiatric disorders. Currently, no suitable positron emission tomography (PET) imaging paradigm is available to assess 5-HT release in the living human brain. [11C]AZ10419369 binds to 5-HT1B receptors and is one of the most 5-HT-sensitive radioligands available. This study applied 5-HT concentration enhancers which can be safely studied in humans, and examined their effect on [11C]AZ10419369 binding at clinically relevant doses, including amphetamine (1 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA; 1 mg/kg) or 5-hydroxy-L-tryptophan (5-HTP; 5 mg/kg). Twenty-six PET measurements (14 for amphetamine, 6 for MDMA and 6 for 5-HTP) using a bolus and constant infusion protocol were performed in four cynomolgus monkeys before or after drug administration. Binding potential (BPND) values were determined with the equilibrium method (integral interval: 63–123 min) using cerebellum as the reference region. BPND values were significantly decreased in several examined brain regions after administration of amphetamine (range: 19–31%), MDMA (16–25%) or 5-HTP (13–31%). Reductions in [11C]AZ10419369 binding were greater in striatum than cortical regions after administration of 5-HTP, while no prominent regional differences were found for amphetamine and MDMA. In conclusion, [11C]AZ10419369 binding is sensitive to changes in 5-HT concentration induced by amphetamine, MDMA or 5-HTP. The robust changes in BPND, following pretreatment drugs administered at clinically relevant doses, indicate that the applied PET imaging paradigms hold promise to be successfully used in future human studies.

Effect of Metformin on Metabolic Parameters and Hypothalamic Signaling Systems in Rats with Obesity Induced by a High-Carbohydrate and High-Fat Diet

Metformin (MF), a first-line drug in the treatment of diabetes mellitus, has been used in the recent years to treat obesity. Its therapeutic effect is due not only to the influence on the peripheral tissues, but also on the hypothalamus, which controls food behavior and energy metabolism. The aim was to study the effect of MF therapy (200 mg/kg/day, 8 weeks) in rats with obesity caused by a high-carbohydrate/high-fat diet on the metabolic and hormonal parameters and functional state of the hypothalamic signaling systems. The MF treatment of obese rats (the group ObM) normalized the food behavior, reduced the body and fat weight and the glucose, insulin and leptin levels, increased the sensitivity to glucose and insulin, improved the lipid metabolism, and restored the Ser473-phosphorylation of Akt-kinase in the liver. In the hypothalamus, the stimulating adenylyl cyclase (AC) effects of the agonists of type 4 melanocortin receptor and type 1 dopamine receptor were partially restored, the inhibitory AC effect of the agonists of subtype 1B serotonin receptor (5-HT1BR) was increased, which was associated with an increase in Htr1b gene expression, and the stimulating effect of the 5-HT6R-agonist EMD-386088 was normalized. At the same time, the differences in the activity of the leptin and insulin systems and the ratio of anorexigenic and orexigenic factors in the hypothalamus of the rat groups Ob and ObM were insignificant. Thus, MF treatment changes functional activity of the hypothalamic melanocortin, dopamine and serotonin systems in obese rats, which is one of the reasons to decrease their food intake and to restore the metabolic indicators and insulin sensitivity.

Loren Parsons' contribution to addiction neurobiology.

Loren (Larry) H. Parsons passed away at the age of 51. In spite of his premature departure, Larry much contributed to the drug abuse field. Since his graduate studies for the Ph.D. in Chemistry in J.B. Justice lab, microdialysis is the tread that links Larry's research topics, namely, the role of dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamate and endocannabinoids (eCBs) in drug reinforcement and dependence. Larry was the first to show that abstinence from chronic cocaine reduces extracellular DA in the NAc, consistent with the so called 'dopamine depletion hypothesis' of cocaine addiction. Another Larry's major contributions are the studies on 5-HT and 5-HT receptors' role in cocaine stimulant actions, which resulted in the identification of 5-HT1B receptors as a critical substrate of cocaine reinforcement. By applying mass spectrometry to eCBs analysis in brain dialysates, Larry's lab showed that ethanol, heroin, nicotine and cocaine differentially affect anandamide and 2-arachidonoylglicerol overflow in the NAc shell, a critical site of drugs of abuse DA stimulant actions. Larry also applied microdialysis to study GABA and glutamate's role in ethanol dependence and heroin reinforcement, providing in vivo evidence for a sensitization of corticotropin-releasing factor-dependent release of GABA in the central amygdala in withdrawal from chronic ethanol and for a reduction of GABA transmission in the ventral pallidum in heroin but not cocaine intravenous self-administration. Larry showed the wide possibilities of microdialysis as a general purpose methodology for monitoring neurotransmitters and neuromodulators in the brain extracellular compartment. From this viewpoint, he stands as the best advocate for microdialysis.

Modulation of Kalirin-7 expression by hippocampal CA1 5-HT1B receptors in spatial memory consolidation

Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25 μg/μL) or agonist CP93129 (25 μg/μL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation.

Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go

G-protein-coupled receptors (GPCRs) form the largest family of receptors encoded by the human genome (around 800 genes). They transduce signals by coupling to a small number of heterotrimeric G proteins (16 genes encoding different α-subunits). Each human cell contains several GPCRs and G proteins. The structural determinants of coupling of Gs to four different GPCRs have been elucidated1-4, but the molecular details of how the other G-protein classes couple to GPCRs are unknown. Here we present the cryo-electron microscopy structure of the serotonin 5-HT1B receptor (5-HT1BR) bound to the agonist donitriptan and coupled to an engineered Go heterotrimer. In this complex, 5-HT1BR is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the β2-adrenoceptor (β2AR) 3 or the adenosine A2A receptor (A2AR) 1 in complex with Gs. In contrast to the complexes with Gs, the gap between the receptor and the Gβ-subunit in the Go-5-HT1BR complex precludes molecular contacts, and the interface between the Gα-subunit of Go and the receptor is considerably smaller. These differences are likely to be caused by the differences in the interactions with the C terminus of the Go α-subunit. The molecular variations between the interfaces of Go and Gs in complex with GPCRs may contribute substantially to both the specificity of coupling and the kinetics of signalling.

Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics.

BackgroundPharmacological profiles of new psychoactive substances can be established rapidly in vitro and provide information on potential psychoactive effects in humans. The present study investigated whether specific in vitro monoamine transporter and receptor interactions can predict effective psychoactive doses in humans.MethodsWe correlated previously assessed in vitro data of stimulants and psychedelics with human doses that are reported on the Internet and in books.ResultsFor stimulants, dopamine and norepinephrine transporter inhibition potency was positively correlated with human doses, whereas serotonin transporter inhibition potency was inversely correlated with human doses. Serotonin 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2C receptor affinity was significantly correlated with psychedelic doses, but 5-HT1A receptor affinity and 5-HT2A and 5-HT2B receptor activation potency were not.ConclusionsThe rapid assessment of in vitro pharmacological profiles of new psychoactive substances can help to predict psychoactive doses and effects in humans and facilitate the appropriate scheduling of new psychoactive substances.

5-HT1B receptor agonist CGS12066 presynaptically inhibits glutamate release in rat hippocampus

CGS12066, a 5-hydroxytryptamine 1B (5-HT1B) receptor agonist, has been reported to exhibit antidepressant activity. Considering that glutamatergic dysfunction is implicated in depression, the effect of CGS12066 on glutamate release in rat hippocampal nerve terminals and possible underlying mechanism were investigated. We observed that CGS12066 inhibited 4-aminopyridine (4-AP)-evoked glutamate release, and that a 5-HT1B receptor antagonist blocked this inhibition. Western blot analysis and immunocytochemistry confirmed the presence of presynaptic 5-HT1B receptor proteins. CGS12066-mediated inhibition of 4-AP-evoked glutamate release was completely abolished in the synaptosomes pretreated with inhibitors of Gi/Go-protein, adenylate cyclase (AC), and protein kinase A (PKA), namely pertussis toxin, MDL12330A, and H89, respectively. CGS12066 reduced the elevation of 4-AP-evoked intrasynaptosomal Ca2+ and cyclic AMP (cAMP) levels, but did not affect the synaptosomal membrane potential. Furthermore, in the presence of ω-conotoxin MVIIC, a N- and P/Q-type channel blocker, CGS12066-mediated inhibition of 4-AP-evoked glutamate release was markedly reduced; however, the intracellular Ca2+-release inhibitors dantrolene and CGP37157 did not affect the CGS12066 effect. Furthermore, CGS12066 reduced glutamatergic miniature excitatory postsynaptic current (mEPSC) frequency but did not affect mEPSC amplitude or glutamate-activated currents in hippocampal slices. Our data are the first to suggest that CGS12066 reduces AC/cAMP/PKA activation, through the activation of Gi/Go protein-coupled 5-HT1B receptors present on hippocampal nerve terminals, subsequently reducing Ca2+ entry through voltage-dependent Ca2+ channels and reducing 4-AP-evoked glutamate release. This investigation into the role of 5-HT1B receptors in glutamate release provides crucial information regarding the potential therapeutic role of 5-HT1B receptors for treating depression.

Acneiform eruption associated with the use of vortioxetine

ABSTRACTAcneiform is used to describe eruptions that resemble acne vulgaris, but are not aetiologically similar. A number of drugs that can be responsible for acneiform eruptions exist. Vortioxetine is a multimodal antidepressant molecule that shows an antagonistic effect to the 5HT1D, 5HT3, and 5HT7 receptors, a partial agonistic effect to the 5HT1B receptor and a fully agonistic effect to the 5HT1A receptor, and also is an inhibitor to the serotonin transporter (SERT). In this article, we report a female patient who developed acneiform eruption during vortioxetine treatment.

The preclinical discovery and development of cariprazine for the treatment of schizophrenia

ABSTRACTIntroduction: Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult patients. It is typically administered orally once a day (a dose range 1.5 – 6 mg/day), does require titration, and may be given with or without food. It has a half-life of 2 – 4 days with an active metabolite that has a terminal half-life of 2 – 3 weeks.Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. This article is based on the available literature with respect to the preclinical and clinical findings and product labels of cariprazine.Expert opinion: Cariprazine shows highest affinity toward D3 receptors, followed by D2, 5-HT2B, and 5-HT1A receptors. It also shows moderate affinity toward σ1, 5-HT2A, and histamine H1 receptors. Long-term administration of cariprazine altered the abundance of dopamine, serotonin, and glutamate receptor subtypes in different brain regions. All these mechanisms of cariprazine may contribute toward its unique preclinical profile and its clinically observed benefits in the treatment of schizophrenia, bipolar mania, and possibly other psychiatric disorders.