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Scalp seborrheic dermatitis, or dandruff, is thought to worsen during the winter when there is later sunrise and less daylight. This study investigates trends in search engine interest for the term "dandruff" as they relate to changes in daylight, sunrise, and seasonality. We investigated the search interest in several countries of varying latitudes over a five-year period, and we explore the effect of daylight saving time on disease interest within two cities in the United States. We discuss our findings in the context of hormonal changes and skincare/behavior.

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT 1B R activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of ( R )-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo , increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT 2C R antagonist (SB242084), but not by the 5-HT 1B R antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, ( R )-MDMA is predicted to have prosocial effects and low abuse potential., Competing Interests: CONFLICT OF INTERESTS B.D.H. is on the scientific advisory boards of Journey Clinical and Osmind, and is a paid consultant to Arcadia Medicine, Inc. N.E. is a paid consultant for Boehringer Ingelheim. R.C.M. is now on leave from Stanford, functioning as Chief Scientific Officer at Bayshore Global Management. R.C.M. is on the scientific advisory boards of MapLight Therapeutics, Bright Minds, MindMed, and Aelis Farma.

Nucleus accumbens (NAc) deep brain stimulation (DBS) has been increasingly explored as a treatment modality for refractory neuropsychiatric disorders. Uncovering the accumbens network that is engaged by DBS is a critical step forward in understanding how modulating this important node impacts the broader mesocorticolimbic circuit. Using whole-brain clearing and unbiased, brain-wide neural activity mapping, we found that NAc DBS increases neural activity in a coordinated mesocorticolimbic network in mice. Simultaneous intracranial electrophysiology recordings from the human NAc and brief stimulation epochs of homologous mesocorticolimbic nodes revealed similar connectivity. Altogether, these results identify specific connectivity conserved across species within the mesocorticolimbic circuit that may underlie mechanisms of NAc DBS.

Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. It is unclear whether naltrexone blocks a direct effect of ketamine at ORs, or whether normal functioning of the OR system is required to realize the full antidepressant effects of treatment. In mice, the effect of ketamine on locomotion, but not analgesia or the forced swim test, was sensitive to naltrexone and was therefore used as a behavioral readout to localize the effect of naltrexone in the brain. We performed whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, and identified the central amygdala (CeA) as the area with greatest difference in cFos intensity. CeA neurons expressing both μOR (MOR) and PKCμ were strongly activated by naltrexone but not ketamine, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine. These data suggest that MORs expressed in CeA neurons gate behavioral effects of ketamine but are not direct targets of ketamine., Competing Interests: DECLARATION OF INTERESTS B.D.H. is a Scientific Advisor to Osmind Mental Health and Journey Clinical and has been a consultant to Vine Ventures LLC and Clairvoyant Therapeutics. R.C.M. is on the scientific advisory boards of MapLight Therapeutics, Bright Minds Biosciences, and MindMed. He is currently on leave from Stanford functioning as the Chief Scientific Officer at Bayshore Global Management.

The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged iDISCO+ cleared tissue with light sheet fluorescence microscopy (LSFM) to examine the impact of environmental context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed clusters of neural activity associated with main effects of context and psilocybin-treatment, which were validated with c-Fos + cell density measurements. Psilocybin increased c-Fos expression in subregions of the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while it decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum in a predominantly context-independent manner. To gauge feasibility of future mechanistic studies on ensembles activated by psilocybin, we confirmed activity- and Cre-dependent genetic labeling in a subset of these neurons using TRAP2 +/- ;Ai14 + mice. Network analyses treating each psilocybin-sensitive cluster as a node indicated that psilocybin disrupted co-activity between highly correlated regions, reduced brain modularity, and dramatically attenuated intermodular co-activity. Overall, our results indicate that main effects of context and psilocybin were robust, widespread, and reorganized network architecture, whereas context×psilocybin interactions were surprisingly sparse., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Blockade of the serotonin 5-HT 2A G protein-coupled receptor (5-HT 2A R) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HT 2A R by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT 2A R agonists, however, often bind other receptors, and standard 5-HT 2A R antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT 2A R-dependent effects of these compounds and the general neurobiological function of 5-HT 2A Rs. This review discusses the limitations and strengths of currently available "selective" 5-HT 2A R antagonists, the molecular determinants of antagonist selectivity at 5-HT 2A Rs, and the utility of molecular pharmacology and computational methods in guiding the discovery of novel unambiguously selective 5-HT 2A R antagonists., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Purpose: The 5-HT receptor subtypes 5-HT 2A and 5-HT 2C are important neurotherapeutic targets, though, obtaining selectivity over 5-HT 2B and H 1 receptors is challenging. Here, we delineated molecular determinants of selective binding to 5-HT 2A and 5-HT 2C receptors for novel 4-phenyl-2-dimethylaminotetralins (4-PATs)., Experimental Approach: We synthesized 42 novel 4-PATs with halogen or aryl moieties at the C(4)-phenyl meta-position. Affinity, function, molecular modeling and 5-HT 2A receptor mutagenesis studies were performed to understand structure-activity relationships at 5-HT 2 -type and H 1 receptors. Lead 4-PAT-type 5-HT 2A /5-HT 2C receptor inverse agonists were compared with pimavanserin, a selective 5-HT 2A /5-HT 2C receptor inverse agonist approved to treat Parkinson's disease-related psychosis, in the mouse head twitch response and locomotor activity assays, models relevant to antipsychotic drug development., Key Results: Most 4-PAT diastereomers in the (2S,4R)-configuration bound non-selectively to 5-HT 2A , 5-HT 2C and H 1 receptors, with >100-fold selectivity over 5-HT 2B receptors, whereas diastereomers in the (2R,4R)-configuration bound preferentially to 5-HT 2A over 5-HT 2C receptors and had >100-fold selectivity over 5-HT 2B and H 1 receptors. Results suggest that G238 5.42 and V235 5.39 in 5-HT 2A receptors (conserved in 5-HT 2C receptors) are important for high affinity binding, whereas interactions with T194 5.42 and W158 4.56 determine H 1 receptor affinity. The 4-PAT analog (2S,4R)-4-(4'-(dimethylamino)-[1,1'-biphenyl]-3-yl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, (2S,4R)-2k, a potent and selective 5-HT 2A /5-HT 2C receptor inverse agonist, had activity like pimavanserin in the mouse head twitch response assay but was distinct in not suppressing locomotor activity., Conclusions and Implications: The novel 4-PAT chemotype can yield selective 5-HT 2A /5-HT 2C receptor inverse agonists for antipsychotic drug development by optimizing ligand-receptor interactions in transmembrane domain 5. Chirality can be exploited to attain selectivity over H 1 receptors, which may circumvent sedative effects., (© 2021 The British Pharmacological Society.)

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clinically by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD. Serotonergic neurons directly innervate and modulate the activity of neurobiological circuits altered in both disorders, providing a rationale for investigating serotonin receptors (5-HTRs) as targets for FXS and ASD drug discovery. Previously we unveiled an orally active aminotetralin, ( S )-5-(2'-fluorophenyl)- N,N -dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), that exhibits partial agonist activity at 5-HT 1A Rs, 5-HT 2C Rs, and 5-HT 7 Rs and that reduces repetitive behaviors and increases social approach behavior in wild-type mice. Here we report that in an Fmr1 knockout mouse model of FXS and ASD, FPT is prophylactic for audiogenic seizures. No FPT-treated mice displayed audiogenic seizures, compared to 73% of vehicle-treated mice. FPT also exhibits anxiolytic-like effects in several assays and increases social interactions in both Fmr1 knockout and wild-type mice. Furthermore, FPT increases c-Fos expression in the basolateral amygdala, which is a preclinical effect produced by anxiolytic medications. Receptor pharmacology assays show that FPT binds competitively and possesses rapid association and dissociation kinetics at 5-HT 1A Rs and 5-HT 7 Rs, yet has slow association and rapid dissociation kinetics at 5-HT 2C Rs. Finally, we reassessed and report FPT's affinity and function at 5-HT 1A Rs, 5-HT 2C Rs, and 5-HT 7 Rs. Collectively, these observations provide mounting support for further development of FPT as a pharmacotherapy for common neuropsychiatric symptoms in FXS and ASD., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

The serotonin 5-HT 7 G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT 7 . We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT 7 GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT 1A GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure-affinity relationship (3D-QSAR) at the human 5-HT 7 receptor for comparison with similar studies at the highly homologous 5-HT 1A receptor. We report 35 new 5-SAT ligands, some with very high affinity (K i  ≤ 1 nM) and stereoselectivity at 5-HT 7 + or 5-HT 1A receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT 7 , and, several ligands with high selectivity (up to 40-fold) at the 5-HT 1A receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT 7 over 5-HT 1A receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT 1A selectivity. In silico receptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT 7 vs. 5-HT 1A GPCRs, as may be required for successful clinical translation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D 2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D 2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D 2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects, which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D 2 receptor binding kinetics, have significantly lower risk of movement side effects but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology, characterized by its unique agonist activity at dopamine D 2 and D 3 and serotonin 5-HT 1A receptors, as well as antagonist activity at serotonin 5-HT 2A receptors, translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.