Selective 5-HT1A Receptor Research Articles

Lysergic acid diethylamide (LSD) promotes social behaviour through 5-HT2A and ampa in the medial prefrontal cortex (MPFC)

IntroductionAutism Spectrum Disorder and Social Anxiety Disorder are mental illnesses characterized by a dysfunction in social behavior (SB); a phenomenon largely mediated by the medial prefrontal cortex (mPFC). Clinical studies have demonstrated that lysergic acid diethylamide (LSD), a partial agonist of the 5-HT2A receptor, can promote SB. However, its mechanism of action on SB is unknown.ObjectivesTo assess the effects of repeated LSD administration on social behavior in mice and to identify which mPFC receptors mediate LSD’s behavioral effects.MethodsEight-week-old C57BL/6J male mice received vehicle or repeated LSD (30 μg/kg/day i.p. for 7 days) as well the selective 5-HT2A receptor antagonist MDL, or the AMPA receptor antagonist NBQX. Twenty-four hours following the last injection, mice underwent the Direct Social Interaction Test and the Three-Chamber Test (TCT) to assess sociability and preference for social novelty. in vivo electrophysiological recordings were performed in mice treated with vehicle or LSD using multi-barrelled electrodes for microiontophoretic ejections of the selective 5-HT2A receptor agonist DOI or the selective AMPA receptor agonist quisqualate on mPFC pyramidal neurons.ResultsRepeated treatment with low doses of LSD increased the interaction time in the DSI as well as sociability and social novelty indices in the TCT. These pro-social effects were blocked by the intra-PFC administration of both 5-HT2A and AMPA antagonists. LSD also potentiated, in a current-dependent manner, the excitatory response of mPFC neurons to 5-HT2Aand AMPA agonists.ConclusionsRepeated, low doses of LSD increases social behavior via a mechanism of action that is mediated by 5-HT2A and AMPA in the mPFC.

The selective 5-HT2A receptor agonist 25CN-NBOH does not affect reversal learning in mice.

Psychedelic 5-hydroxytryptamine 2A receptor (5-HT2AR) agonists are showing promise in the treatment of psychiatric disorders, such as treatment-resistant depression and anxiety. Human studies suggest that enhanced cognitive flexibility may contribute to their clinical efficacy. Both improvement and impairment of cognitive flexibility has been reported with 5-HT2AR ligands, making the link between 5-HT2AR pharmacology and cognitive flexibility equivocal. We tested the selective 5-HT2AR agonist 25CN-NBOH in healthy male C57BL/6JOlaHsd mice in a touchscreen-based mouse reversal learning test. No effects were observed on acquisition of the new stimulus-reward contingency, learning errors, or perseverative responses during reversal. Our results suggest that 25CN-NBOH does not affect reversal learning in the schedule used in this study.

Behavioral arrest and a characteristic slow waveform are hallmark responses to selective 5-HT2A receptor activation

Perception, emotion, and mood are powerfully modulated by serotonin receptor (5-HTR) agonists including hallucinogens. The 5-HT2AR subtype has been shown to be central to hallucinogen action, yet the precise mechanisms mediating the response to 5-HT2AR activation remain unclear. Hallucinogens induce the head twitch response (HTR) in rodents, which is the most commonly used behavioral readout of hallucinogen pharmacology. While the HTR provides a key behavioral signature, less is known about the meso level changes that are induced by 5-HT2AR activation. In response to administration of the potent and highly selective 5-HT2AR agonist 25I-NBOH in mice, we observe a disorganization of behavior which includes frequent episodes of behavioral arrest that consistently precede the HTR by a precise interval. By combining behavioral analysis with electroencephalogram (EEG) recordings we describe a characteristic pattern composed of two distinctive EEG waveforms, Phase 1 and Phase 2, that map onto behavioral arrest and the HTR respectively, with the same temporal separation. Phase 1, which underlies behavioral arrest, is a 3.5–4.5 Hz waveform, while Phase 2 is slower at 2.5–3.2 Hz. Nicotine pretreatment, considered an integral component of ritualistic hallucinogen practices, attenuates 25I-NBOH induced HTR and Phase 2 waveforms, yet increases behavioral arrest and Phase 1 waveforms. Our results suggest that in addition to the HTR, behavioral arrest and characteristic meso level slow waveforms are key hallmarks of the response to 5-HT2AR activation. Increased understanding of the response to serotonergic hallucinogens may provide mechanistic insights into perception and hallucinations, as well as regulation of mood.

Abstract 16343: Sarpogrelate, a Selective Serotonin 2a Receptor Antagonist, Suppresses Pressure Overlaod-induced Cardiac Hypertrophy and Systolic Dysfunction Through Inhibiting Erk1/2/gata4 Pathway

Introduction: Serotonin (5-HT), a neurohormone involved in a wide range of physiological functions, has generated much interest in recent years regarding its potential role in cardiac function. It is reported that sarpogrelate, a selective 5-HT2A receptor antagonist, possesses cardioprotective effect against myocardial infarction, however, the precise molecular mechanism of the effect is still unclear. In this study, we examined the effect of sarpogrelate on pressure overload-induced development of heart failure, another heart failure model. Methods: First, primary cultured cardiomyocytes were treated with 1 μM sarpogrelate and then stimulated with various hypertrophic stimuli. Cardiomyocytes were stained with anti-actinin antibody and the surface area of the cells were measured. The phosphorylation levels of ERK1/2 and GATA4 were assessed by western blotting. Next, C57BL/6j male mice were subjected to a transverse aortic constriction (TAC) and sham operation. One day after the operation, the mice were randomly divided into 3 groups: sarpogrelate at 1 mg/kg or 5 mg/kg, and vehicle as a control. Daily oral administration was repeated for 8 weeks. Results: Sarpogrelate significantly suppressed an increase in the surface area of cardiomyocytes induced not only by 5-HT, but also by phenylephrine, angiotensin II and ET-1. Sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. In a mice model of heart failure, echocardiographic analysis showed that 5 mg/kg sarpogrelate significantly prevented a TAC-induced increase in posterior left ventricular wall thickness and a decrease in fractional shortening at 8 weeks after the operation. One mg/kg sarpogrelate also suppressed TAC-induced increase in HW/BW ratio, myocardial cell diameter and the mRNA levels of ANF and BNP. Moreover, 1 mg/kg sarpogrelate significantly suppressed TAC-induced phosphorylation of ERK1/2. Conclusions: These results indicate that sarpogrelate significantly suppresses cardiomyocyte hypertrophy and the development of heart failure via at least, in part, by inhibition of ERK1/2/GATA4 pathway. These findings suggest that sarpogrelate may be an effective agent for heart failure therapy.

Increased behavioral and neuronal responses to a hallucinogenic drug after adolescent toluene exposure in mice: Effects of antipsychotic treatment

Toluene has been characterized as a non-classical hallucinogen drug through activation of 5-HT2A receptors and antagonism of NMDA receptors. It remains unclear whether psychotic symptoms after long-term and intense toluene exposure are associated with abnormalities in 5-HT2A receptor function. The present study examined whether the responses to a hallucinogenic 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) were altered in a mouse model of toluene psychosis. Male NMRI mice were subchronically treated with toluene during adolescence. Reciprocal social interaction test and novel object recognition test were conducted to confirm the persistent behavioral deficits in adulthood. Subsequently, DOI-induced head twitch, c-Fos and Egr-2 expression, field potentials in the medial prefrontal cortex (mPFC), and the levels of 5-HT2A, 5-HT1A and mGlu2 receptors in the mPFC were monitored. Toluene exposure during adolescence produced social and memory impairments and enhanced DOI–induced behavioral, molecular and electrophysiological responses, but did not change the levels of 5-HT2A, 5-HT1A or mGlu2 receptors in the mPFC. Moreover, the effects of haloperidol and risperidone on the behavioral deficits and hyper-responsiveness to DOI after adolescent toluene exposure were compared. When administered after adolescent toluene exposure, risperidone could reverse social withdrawal, cognitive impairment and hypersensitivity to DOI, whereas haloperidol was only beneficial for social withdrawal. These findings suggest that increased functionality of 5-HT2A receptors may play a critical role in solvent-induced psychosis and recommend the antipsychotics with more selective 5-HT2A receptor antagonism as the first-line treatment for solvent-induced psychosis.

Effects of Stress Exposure during Adolescent Period on Inflammatory Pain Response, Psychoemotional Behavior, and Action of Antidepressants in Prenatally Stressed Adult Male Rats.

We studied the effects of stress exposure during the adolescent period of development (SAPD) on the parameters of inflammatory painful response and the level of depression-like behavior in prenatally stressed adult male rats. In addition, we analyzed the effects of selective serotonin (5-HT) reuptake inhibitor fluoxetine and 5-HT1A receptor agonist buspirone injected chronically to pregnant mothers for correction of behavioral disturbances caused by prenatal stress in their adult male progeny. In the formalin test, SAPD decreased integrated at the supraspinal level pain-like response that was increased by prenatal stress; under these conditions, buspirone and fluoxetine were ineffective in contrast to their antinociceptive action on spinally integrated pain-like response increased by SAPD. In the forced swimming test, SAPD had no effect on the level of depression-like behavior in prenatally stressed males; no differences in plasma corticosterone level were found in these animals.

Serotonin 5HT2A receptor antagonism mediated anti-inflammatory and anti-fibrotic effect in adriamycin-induced CKD in rats.

A selective 5-HT2A receptor antagonist ketanserin has been used preclinically to improve renal blood flow because of its beneficial effect on autoregulation in various chronic kidney disease models. Ketanserin might be able to turn down adriamycin-induced chronic kidney disease, which is characterized by renal fibrosis, inflammation and structural and functional changes in glomeruli. In the present study, we investigated whether ketanserin suppresses these renal alterations or not. Wistar rats were administered with a single dose of adriamycin (6mg/kg/i.v), which leads to development of severe tubulointerstitial fibrosis with altered renal function. Subsequent ketanserin treatment (5mg/kg/p.o) for 4weeks shown significant change in oxidative stress, serum and urine parameters in adriamycin-induced chronic kidney disease rats. Additionally, results showed that mRNA expression of TGF-β and collagen IV, which are known to promote fibrosis via various signaling pathways involved in the progression of renal disease, was suppressed by ketanserin treatment. Furthermore, expression levels of 5-HT2A and pro-inflammatory marker IL-6 have also been reduced significantly after ketanserin administration in adriamycin-treated animals. Moreover, histopathological studies also reveal the considerable structural changes after ketanserin treatment, and these results are further supported via data obtained from the percentage of glomeruli size changes. In conclusion, ketanserin reduces renal fibrosis and inflammation in adriamycin-induced chronic kidney disease by suppressing 5-HT2A, IL-6, TGF-β and collagen IV expression in renal tissue.

The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH

The remarkable effects exhibited by classical psychedelics in recent clinical trials have spawned considerable interest in 5-HT2A receptor (5-HT2AR) activation as a treatment strategy for several psychiatric/cognitive disorders. In this study we have continued our development of 25CN-NBOH, one of the most 5-HT2AR-selective agonists reported to date, as a pharmacological tool for exploration of 5-HT2AR expression and functions. The importance of the 2′ and 3′ positions in 25CN-NBOH as structural hotspots for its 5-HT2AR activity was investigated by synthesis and pharmacological characterization of six novel analogs at 5-HT2AR and 5-HT2CR in binding and functional assays. While the 5-HT2AR activity of 25CN-NBOH was retained in 3′-methyl, 2′,3′-chroman, 2′,3′-dihydrofuran and 2′,3′-furan analogs, the 3′-methoxy and 3′-ethyl analogs displayed substantially lower binding affinities and agonist potencies than 25CN-NBOH. Interestingly, the 2′,3′-substitution pattern was also a key determinant of agonist efficacy, as all six analogs exhibited low-efficacy partial agonism or de facto antagonism at the 5-HT2AR in the functional assays. Systemic administration of 25CN-NBOH and its close structural analog 25CN-NBMD induced robust head-twitch response in mice, a well-established behavioural effect of 5-HT2AR activation in vivo, and 25CN-NBOH mediated robust reductions in the activity of mice in an anxiety-related marble burying assay, which supports the proposed beneficial effects of 5-HT2AR activation on disorders characterized by cognitive rigidity. Finally, tritiated 25CN-NBOH exhibited high 5-HT2AR binding affinity (KD ~1 nM) and selectivity against 5-HT2BR and 5-HT2CR in equilibrium and kinetic binding studies of the recombinant receptors, and in concordance [3H]25CN-NBOH displayed substantial specific, ketanserin-sensitive binding to cortex and small levels of binding to choroid plexus in rat brain slices in autoradiography studies. In conclusion, this work delineates the subtle molecular determinants of the 5-HT2AR activity in 25CN-NBOH, substantiates the potential in this compound and its analogs as tools for in vivo studies of the 5-HT2AR, and introduces a novel selective agonist radioligand as another potentially valuable tool for future explorations of this receptor.

Spiroxatrine derivatives towards 5-HT1A receptor selectivity.

In our previous work, spiroxatrine was taken as reference compound to develop selective NOP ligands. Therefore, several triazaspirodecanone derivatives were synthesized. Here, we verify their selectivity towards other 5-HT1 receptor subtypes and with respect to α2-AR (Adrenergic Receptors). Binding affinities were determined on cells expressing human cloned receptors for 5-HT1A/B/D and α2A/B/C subtypes. The Ki values were determined for those with at least 50% radioligand inhibition. All our derivatives show a moderate affinity for α2 subtypes, spanning from 5 to 7.5 pKivalues. Moreover, they show affinity values in a μM-nM range at the 5-HT1A receptor, while they are practically inactive at 5-HT1B and 5-HT1D subtypes. Compound 11, the best of the series, has a 5-HT1A pKi value of 8.43 similar to spiroxatrine but, notably, it has a 5-HT1A favorable selectivity ratio of 52, 8 and 29, respectively over α2A, α2B and α2C adrenoceptor subtypes. In this SAR study, a 5-HT1A selective ligand has been identified in which a tetralone moiety replaced the 1,4-benzodioxane of spiroxatrine and the methylene linker to the triazaspirodecanone portion was maintained in position 2.

DARK Classics in Chemical Neuroscience: NBOMes.

N-Benzylphenethylamines, commonly known as NBOMes, are synthetic psychedelic compounds derived from the phenethylamine class of psychedelics (2C-X compounds), which originally have been derived from the naturally occurring alkaloid mescaline. Analogously to their parent compounds and other classical psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), NBOMes are believed to exert their main pharmacological effects through activation of serotonin 2A (5-HT2A) receptors. Since their introduction as New Psychoactive Substances (NPSs) in 2010, NBOMes have been widely used for recreational purposes; this has resulted in numerous cases of acute toxicity, sometimes with lethal outcomes, leading to the classification of several NBOMes as Schedule I substances in 2013. However, in addition to their recreational use, the NBOMe class has yielded several important biochemical tools, including [11C]Cimbi-36, which is now being used in positron emission tomography (PET) studies of the 5-HT2A and 5-HT2C receptors in the mammalian brain, and 25CN-NBOH, one of the most selective 5-HT2A receptor agonists developed to date. In this Review, the history, chemistry, structure-activity relationships, ADME (absorption, distribution, metabolism, and excretion) properties, and safety profiles of NBOMes will be outlined and discussed.

Risperidone Treatment after Transient Ischemia Induces Hypothermia and Provides Neuroprotection in the Gerbil Hippocampus by Decreasing Oxidative Stress.

Compelling evidence from preclinical and clinical studies has shown that mild hypothermia is neuroprotective against ischemic stroke. We investigated the neuroprotective effect of post-risperidone (RIS) treatment against transient ischemic injury and its mechanisms in the gerbil brain. Transient ischemia (TI) was induced in the telencephalon by bilateral common carotid artery occlusion (BCCAO) for 5 min under normothermic condition (37 ± 0.2 °C). Treatment of RIS induced hypothermia until 12 h after TI in the TI-induced animals under uncontrolled body temperature (UBT) compared to that under controlled body temperature (CBT) (about 37 °C). Neuroprotective effect was statistically significant when we used 5 and 10 mg/kg doses (p < 0.05, respectively). In the RIS-treated TI group, many CA1 pyramidal neurons of the hippocampus survived under UBT compared to those under CBT. In this group under UBT, post-treatment with RIS to TI-induced animals markedly attenuated the activation of glial cells, an increase of oxidative stress markers [dihydroethidium, 8-hydroxy-2′ -deoxyguanosine (8-OHdG), and 4-Hydroxynonenal (4-HNE)], and a decrease of superoxide dismutase 2 (SOD2) in their CA1 pyramidal neurons. Furthermore, RIS-induced hypothermia was significantly interrupted by NBOH-2C-CN hydrochloride (a selective 5-HT2A receptor agonist), but not bromocriptine mesylate (a D2 receptor agonist). Our findings indicate that RIS-induced hypothermia can effectively protect neuronal cell death from TI injury through attenuation of glial activation and maintenance of antioxidants, showing that 5-HT2A receptor is involved in RIS-induced hypothermia. Therefore, RIS could be introduced to reduce body temperature rapidly and might be applied to patients for hypothermic therapy following ischemic stroke.

Year in Review: Applying Top Research to the Practice of PALTC Medicine

Year in Review: Applying Top Research to the Practice of PALTC Medicine

Effect of Equol on Vasocontractions in Rat Carotid Arteries Treated with High Insulin.

Previous research has indicated that high insulin affects vascular function. Equol is an active metabolite of daidzein, an isoflavone produced from soy by intestinal microbial flora, with beneficial effects on the vascular system. This study investigated whether equol was beneficial for vascular function under high insulin conditions. Using organ culture techniques, rat carotid arteries were treated for 23 ± 1 h with a vehicle, high insulin (100 nM), or equol (100 µM) plus high insulin (100 nM). Vascular isometric forces were measured by the organ bath technique. In each endothelium-intact ring, the contractions induced by high-K+, noradrenaline, or by serotonin (5-HT) were similar for the vehicle, insulin, and equol + insulin treatments. Contractions induced by a selective 5-HT2A receptor agonist (TCB2) increased with insulin treatment (vs. vehicle), but less so with equol + insulin. Under basal conditions, a selective 5-HT2B receptor agonist (BW723C86) did not induce contraction; following precontraction by a thromboxane analog, it induced contraction but not relaxation. These responses were similar across the three treatments. Acetylcholine-induced relaxations were also similar for the three treatments. In the endothelium-denuded preparations, 5-HT-induced contraction was augmented with insulin treatment (vs. vehicle) but less so by equol + insulin treatment. These differences in 5-HT-induced contractions were eliminated by iberiotoxin, a large-conductance calcium-activated K+ channel (BKCa) inhibitor. These results suggest that equol exerts a preventive effect on the enhancement of 5-HT-induced contraction by high insulin (possibly mediated by the 5-HT2A receptor), and that these effects may be attributed to the activation of BKCa channels in vascular smooth muscle.

Protective Effects of 5-HT1A Receptor Inhibition and 5-HT2A Receptor Stimulation Against Streptozotocin-Induced Apoptosis in the Hippocampus.

IntroductionIntracerebroventricular administration of streptozotocin (icv-STZ) induced apoptosis changes in neurons similar to Alzheimer’s disease. The serotonergic system via its receptor involved in survival of neurons. The present study examined the ability of selective 5-HT1A receptor antagonist (NAD-299) and 5-HT2A receptor agonist (TCB-2) to attenuate the apoptosis caused by the icv-STZ in the rat.MethodsThe icv-STZ (3 mg/kg, 10 μL, twice) induced neuronal loss in the hippocampus of adult male rats. Animals were divided into naive control, sham-operated, STZ+saline (1 μL, icv), STZ+NAD-299 (5 μg/μL, icv), STZ+TCB-2 (5 μg/μL, icv), and STZ+NAD-299+TCB-2 (5 μg/μL of any agent, icv) groups. Following the 35 days’ treatment period, neuronal apoptosis was detected using the Tunnel. Cells with morphological features of apoptotic cell were contended by microscopy.ResultsTCB-2 and NAD-299 administration decreased number of apoptotic neurons in the treatment group compared with the STZ group. Combined treatment of STZ rat with NAD+TCB more decreased number of apoptotic cells in compare to TCB-2 or NAD-299 treated STZ groups.ConclusionTreatment with 5-HT1A receptor antagonist or 5-HT2A receptor agonist diminished apoptosis. The beneficial effect of 5HT1A receptor inhibition was potentiated with activation of 5-HT2A receptor in prevention of apoptosis in hippocampus.

The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.

Serotonin 2A and Sigma 1 Receptor Antagonists Synergize to Block the Acute Toxicity of Methamphetamine

Currently there are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public‐health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH.Determine whether antagonism of serotonin 2A (5‐HT2A) and sigma 1 (σ1) alone or in combination attenuates METH‐induced lethality, hyperthermia, convulsions, and seizures.Male, Swiss Webster mice received intraperitoneal injections of the selective 5‐HT2A receptor antagonist M100907 (1–10 mg/kg), the selective σ1 receptor antagonist BD 1047 (10–30 mg/kg), and a combination of M100907/BD 1047 (1:10 mg/kg) prior to treatment with METH (78 mg/kg ‐ LD67). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography.M100907 and BD 1047 administered alone had no significant effect on METH‐induced lethality. However, combined antagonism of 5‐HT2A and σ1 receptors eliminated lethality in all mice tested (a reduction from LD67 to LD0). Similarly, only the combination of 5‐HT2A and σ1 receptor antagonism eliminated seizure activity. All three treatments decreased tonic‐clonic convulsions as measured on a modified Racine scale. None of the treatments decreased METH‐induced hyperthermia.This research suggests that reducing METH‐induced seizures may be critical for reducing METH‐induced lethality. These data support the continued investigation of the role of 5‐HT2A and σ1 receptors in METH overdose, including their potential to yield emergency reversal agents.Support or Funding InformationThese studies were supported by the National Institutes on Drug Abuse [NS100512] and by funding from the Mercer University College of Pharmacy (Murnane KS‐ Principal Investigator; Canal CE– Principal Investigator)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT2A receptor activation

The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 – but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB – and a significant and selective up-regulation of serotonin 5-HT2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT2 receptor antagonist ketanserin (1–3 mg kg−1, IP), as well as the selective 5-HT2A receptor blocker MDL-100,907 (volinanserin, 0.1–0.3 mg kg−1, IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT2A receptor activation as a key mechanism for the ontogeny of this condition.This article is part of the Special Issue entitled ‘The neuropharmacology of social behavior: from bench to bedside’.

Can pimavanserin help patients with Parkinson disease psychosis?

Pimavanserin is a first-in-class selective serotonin 5-HT2A receptor inverse agonist approved for the treatment of Parkinson disease psychosis. This article discusses pimavanserin's mechanism of action, which patients are appropriate candidates for therapy, adverse reactions, and appropriate dosing.

Functional mode of action of ASP5736, a selective 5-HT5A receptor antagonist for treatment of cognitive dysfunction in schizophrenia

Docosahexaenoic acid (DHA) is an omega-3 long-chain polyunsaturated fatty acid that accumulates in neural tissues during intrauterine development, particularly in the frontal lobes of the brain. The frontal lobes are responsible for a suite of cognitive abilities referred to as ‘executive functions.’ Executive function skills include attention, working memory (the ability to mentally manipulation information), and inhibitory control (the ability to control or supress inappropriate actions).In this chapter, we briefly review the development of the human brain and the accumulation of DHA in the brain. The main focus is on summarizing the evidence from randomized controlled trials that have supplemented pregnant women with DHA and measured the effects on children’s executive functions. We provide details of the different assessments of executive function that have been used in trials, and summarize the evidence base with respect to dose of DHA used in trials and age when executive functions are measured. We conclude with some recommendations for future trials in this area.

5-HT2A blockade for dyskinesia and psychosis in Parkinson’s disease: is there a limit to the efficacy of this approach? A study in the MPTP-lesioned marmoset and a literature mini-review

Virtually every patient affected by Parkinson's disease (PD) eventually requires treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), which leads to complications such as dyskinesia and psychosis. Whereas blockade of serotonin 2A (5-HT2A) receptors appears to be an effective way to reduce both dyskinesia and psychosis, whether it has the potential to eliminate the two phenomena remains to be determined. In a previous study, we showed that highly selective 5-HT2A receptor blockade with EMD-281,014, at plasma levels comparable to those achieved in the clinic, reduced dyskinesia and psychosis-like behaviours (PLBs), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine whether further increasing the dose would result in greater therapeutic benefit or if maximal effectiveness was achieved at lower doses. Six MPTP-lesioned marmosets with stable dyskinesia and PLBs were administered EMD-281,014 (0.1, 1 and 10mg/kg) or vehicle in combination with L-DOPA and the effect on dyskinesia, PLBs and parkinsonism was assessed. Administration of EMD-281,014 (0.1, 1 and 10mg/kg) in combination with L-DOPA resulted in a significant reduction in the severity of dyskinesia, by up to 63%, 64% and 61% (each P < 0.001), when compared to L-DOPA/vehicle. Similarly, the addition of EMD-281,014 (0.1, 1 and 10mg/kg) to L-DOPA also significantly decreased the severity of PLBs, by up to 54%, 55% and 53% (each P < 0.001), when compared to L-DOPA/vehicle. Our results suggest that there might be a ceiling to the reduction of dyskinesia and psychosis that can be achieved through antagonism of 5-HT2A receptors.