pimavanserin nuplazid  (ACADIA Pharmaceuticals)

Journal: bioRxiv

Article Title: Serotonergic neuron-glioma interactions drive high-grade glioma pathophysiology

doi: 10.64898/2025.12.10.693579

Figure Lengend Snippet: A. Proliferation index (EdU⁺/DAPI⁺) of monocultures of a patient-derived DMG line treated with varying doses of 5HT. One-way ANOVA with Tukey’s post hoc test; ***p < 0.001, **p < 0.01, *p < 0.05, ns: non-significant. Data are presented as mean ± SEM. n=five to six independent experiments, each with three wells per condition; each data point represents the mean of three wells per condition for a given experiment. B. Proliferation index (EdU⁺/DAPI⁺) of monocultures of a patient-derived adult glioblastoma line treated with varying doses of 5HT. One-way ANOVA with Tukey’s post hoc test; ***p < 0.001, **p < 0.01, *p < 0.05, ns: non-significant. Data are presented as mean ± SEM. n=five to six independent experiments, each with three wells per condition; each data point represents the mean of three wells per condition for a given experiment. C. Confocal micrographs showing proliferating glioblastoma cells in vitro . DAPI (blue), EdU (red). Scale bars = 50 µm. D. Schematic of the experimental paradigm for fiber photometry recordings of PsychLight2.0 fluorescence in cortical glioblastoma cells. Human glioblastoma cells (SF232) were transduced in vitro with PsychLight2.0 and used for xenografting. Four-week-old NSG mice (P28–30) received retro-orbital injections of rAAVPHP.eB-Tph2::eYFP or rAAVPHP.eB-Tph2::ChRmine-eYFP, followed three weeks later by xenografting of SF232-PsychLight2.0 cells into the M2 cortex. Optical ferrules were implanted into the dorsal raphe (DR) and the cortical tumor site. Fiber photometry recordings, combined with optogenetic stimulation, were performed six weeks after glioblastoma engraftment. E. Fiber photometry recordings showing averaged PsychLight2.0 fluorescence in M2 cortical glioblastoma cells with simultaneous mock (n=4 mice), DR (n=6 mice), and MR (n=4 mice) stimulation. F. Heatmap of normalized serotonergic receptor gene expression in a single cell sequencing dataset from human DMG samples, stratified by anatomical location (pons, thalamus, and spinal cord). G. Dot plot showing serotonergic receptor gene expression in human glioblastoma samples, depicting the proportion of glioma cells expressing each gene and the average expression level. H. Spatial transcriptomic data from human H3K27M and glioblastoma patient samples showing HTR2A expression patterns. I. Schematic of the experimental paradigm for xenografting 5HT 2A -knockout DMG cells (SU-DIPG17-5HT 2A KO) with optogenetic stimulation of the DR in immunodeficient mice. Four-week-old NSG mice (P28–30) were retro-orbitally injected with rAAVPHP.eB-Tph2::eYFP or rAAVPHP.eB-Tph2::ChRmine-eYFP, followed three weeks later by xenografting of patient-derived SU-DIPG17-5HT 2A KO cells into the ventral pons. After five weeks of tumor growth, optical ferrules were implanted into the DR, and optogenetic stimulation was performed one week later. Mice were perfused 24 hours after stimulation. J. Confocal micrographs showing proliferating HNA + DMG cells in the ventral pons of DR-stimulated mice xenografted with either wildtype DIPG17 (‘DIPG17-Cas9’) or 5HT 2A knockout cells (‘DIPG17-5HT 2A KO’). HNA: green, EdU: red. Scale bars = 50 µm. K. Proliferation index (EdU + /HNA + ) of ventral pontine xenografts in mice either stimulated in DR (“ChRmine”) or mock-stimulated (“eYFP”) with wildtype DIPG (‘DIPG17-Cas9’) or 5HT 2A knockout cells (‘DIPG17-5HT 2A KO’) (n=3-5 mice/group). One-way analysis of variance (ANOVA) with Tukey’s post hoc analysis; **p < 0.01, ns: non-significant. Data=mean ± SEM. L. Schematic of the experimental paradigm for xenografting with 5HT 2A antagonist treatment (pimavanserin). Four-week-old NSG mice (P28–30) were xenografted either into the ventral pons with patient-derived DMG cells (SU-DIPG6 or SU-DIPG13P) or into the M2 cortex with patient-derived glioblastoma cells (UKE3). Chronic 5HT 2A antagonist treatment (i.p. 10 mg/kg) was initiated at time points specific to each cell line. M. Proliferation index (EdU⁺/GFP⁺) of ventral pontine xenografts in mice treated with the 5HT 2A antagonist pimavanserin or vehicle control ( n = 5 mice/group). Unpaired two-tailed Welch’s t -test; **p < 0.01. Data are presented as mean ± SEM. N. Survival curves of ventral pontine xenografts (SU-DIPG13P, top) and M2 cortical xenografts (UKE3, bottom) in mice treated with either the 5HT 2A antagonist pimavanserin or vehicle control. Log-rank test.

Article Snippet: Mice received daily intraperitoneal injections of pimavanserin (10 mg kg−1; Tocris, #7667) formulated in 10% DMSO (Sigma), 10% Tween 80 (Sigma), and PBS, or vehicle control.

Techniques: Derivative Assay, In Vitro, Fluorescence, Gene Expression, Sequencing, Expressing, Knock-Out, Injection, Control, Two Tailed Test

Journal: bioRxiv

Article Title: Serotonergic neuron-glioma interactions drive high-grade glioma pathophysiology

doi: 10.64898/2025.12.10.693579

Figure Lengend Snippet: A. Schematic of the experimental paradigm for psilocybin treatment in glioma xenograft models. Four-week-old NSG mice (P28-30) were xenografted into the M2 cortex with patient-derived glioblastoma cells or into the ventral pons with patient-derived DMG cells. Mice received intraperitoneal injections of psilocybin (2 mg/kg body weight) at 8 weeks post-xenograft (cohort 1) or 6 weeks post-xenograft (cohort 2) and were perfused either 24 hours later (cohort 1) or 2 weeks later (cohort 2). B. Proliferation index (Ki67⁺/HNA⁺) of M2 cortical xenografts from patient-derived glioblastoma cells (SF232) in mice treated with psilocybin (‘Psi’) or vehicle control (‘Vehicle’) ( n = 5 mice/group). One-way analysis of variance (ANOVA) with Tukey’s post hoc test; ***p < 0.001, *p < 0.05. Data are presented as mean ± SEM. C. Proliferation index (Ki67⁺/HNA⁺) of ventral pontine xenografts from patient-derived DMG cells (SU-DIPG17) in mice treated with psilocybin (‘Psi’) or vehicle control (‘Vehicle’) (‘Vehicle’, n = 7 mice; ‘Psi 24h’ and ‘Psi 2 weeks’, n = 5 mice/group). One-way ANOVA with Tukey’s post hoc test; **p < 0.01, *p < 0.05. Data are presented as mean ± SEM. D. Confocal micrographs showing proliferating HNA + DMG cells in ventral pons in vehicle-treated (upper image) and psilocybin-treated (bottom image) mice. HNA: green, Ki67: red, scale bars = 50µm. E. Fiber photometry recordings showing averaged PsychLight2.0 fluorescence in cortical glioblastoma cells (SF232-PsychLight2.0) at 30 minutes and 2 weeks after injection of either psilocybin or vehicle. F. Fiber photometry recordings showing averaged GCaMP6s-labeled calcium transients in cortical glioblastoma cells (GBM39-GCaMP6s) at 30 minutes and 2 weeks after injection of either psilocybin or vehicle. G. Schematic of the experimental paradigm for psilocybin treatment in glioma xenograft models. Four-week-old NSG mice (P28-30) were xenografted into the M2 cortex with patient-derived glioblastoma cells or into the ventral pons with patient-derived DMG cells. Mice received intraperitoneal injections of psilocybin (2 mg/kg body weight) at 8 weeks post-xenograft (cohort 1) or 6 weeks post-xenograft (cohort 2), and were perfused either 24 hours later (cohort 1) or 2 weeks later (cohort 2). H. Proliferation index (Ki67⁺/HNA⁺) of ventral pontine xenografts from patient-derived DMG cells either wildtype (SU-DIPG17 WT) or 5HT 2A knockout (SU-DIPG17-5HT 2A KO) in mice treated with psilocybin (‘Psi’) (‘WT’, n = 4 mice; ‘5HT 2A KO’, n = 5 mice). Unpaired two-tailed Welch’s t -test; **p < 0.01. Data are presented as mean ± SEM. I. Proliferation index (Ki67⁺/HNA⁺) of ventral pontine xenografts from patient-derived DMG cells either wildtype (SU-DIPG13fl WT) or NTRK2 knockout (SU-DIPG13fl-NTRK2 KO) in mice treated with psilocybin (‘Psi’) or vehicle control (‘vehicle’) (‘WT vehicle’, ‘WT Psi 24h’, and ‘NTRK2-KO vehicle’, n = 4 mice; ‘NTRK2-KO psi 24h’, n = 5 mice). One-way analysis of variance (ANOVA) with Tukey’s post hoc test; *p<0.05, **p < 0.01, ns: non-significant. Data are presented as mean ± SEM. J. Quantification of DMG cell proliferation (EdU⁺/DAPI⁺) following psilocybin treatment with or without co-administration of a 5HT2A receptor antagonist (pimavanserin) or a TrkB antagonist (ANA-12). One-way analysis of variance (ANOVA) with Tukey’s post hoc analysis; *p < 0.05, ns: non-significant. Data=mean ± SEM; n=four independent experiments, each with three wells per condition; each data point represents the mean of three wells per condition for a given experiment. K. Representative confocal micrographs showing glioma cell proliferation following treatment with vehicle control, psilocybin, 5HT 2A receptor antagonist (pimavanserin), or TrkB antagonist (ANA-12). Ki67: red, GFP: green, scale bar = 50 µm. L. Quantification of DMG cell proliferation (EdU⁺/DAPI⁺) following treatment with psychedelics compared to vehicle control. One-way analysis of variance (ANOVA) with Tukey’s post hoc analysis; **p < 0.01, *p < 0.05. Data=mean ± SEM; n=four independent experiments, each with three wells per condition; each data point represents the mean of three wells per condition for a given experiment.

Article Snippet: Mice received daily intraperitoneal injections of pimavanserin (10 mg kg−1; Tocris, #7667) formulated in 10% DMSO (Sigma), 10% Tween 80 (Sigma), and PBS, or vehicle control.

Techniques: Derivative Assay, Control, Fluorescence, Injection, Labeling, Knock-Out, Two Tailed Test

Journal: Nature Neuroscience

Article Title: Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain

doi: 10.1038/s41593-025-02068-0

Figure Lengend Snippet: a , Experimental timeline of 5-HT 1A (WAY) and 5-HT 2A (Pima) receptor blockade before PSIL or VC injection in SNI mice. b , Normalized hindlimb withdrawal thresholds in saline ( n = 5), Pima ( n = 5) or Pima VC ( n = 4) groups. Pima blocks the restorative effect of psilocybin on mechanical hypersensitivity compared with saline-injected mice ( P = 0.003 on day 28 and day 40). c , d , Pima blocks psilocybin-induced increase in EPM open arm time ( c ; n = 5, P > 0.999) and decrease in FST immobile time ( d ; n = 5, P > 0.999). Similar trends were observed in mice receiving Pima followed by VC injection. e , Normalized hindlimb withdrawal thresholds in saline ( n = 5), WAY ( n = 6) or WAY VC ( n = 5) groups. WAY blocks psilocybin-induced changes in mechanical hypersensitivity compared with saline mice ( P < 0.0001 on day 28 and day 40). f , g , WAY also blocks psilocybin-induced increases in EPM open arm time ( f ; n = 5, P > 0.05) and decreases in FST immobile time ( g ; n = 5, P > 0.05). WAY followed by VC injection showed no changes. Data are presented as mean ± s.e.m. * ***P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05. Detailed statistics are reported in Supplementary Table . Pima, pimavanserin; WAY, WAY-100635.

Article Snippet: In Fig. , SNI mice received either pimavanserin (Selleck Chemicals, S8183; 1 mg kg −1 i.p. dose) or WAY-100635 (Selleck Chemicals, S2663; 1 mg kg −1 i.p. dose) 30 min before psilocybin (0.5 mg kg −1 ).

Techniques: Injection, Saline

Journal: Nature Neuroscience

Article Title: Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain

doi: 10.1038/s41593-025-02068-0

Figure Lengend Snippet: a , b , Psilocybin injection ( a ) induces the prototypical rotational ‘wet-dog’ head-twitch response, which was blocked by pimavanserin administration ( b ) before psilocybin. The cartoons in a and b (left) are created with BioRender.com .

Article Snippet: In Fig. , SNI mice received either pimavanserin (Selleck Chemicals, S8183; 1 mg kg −1 i.p. dose) or WAY-100635 (Selleck Chemicals, S2663; 1 mg kg −1 i.p. dose) 30 min before psilocybin (0.5 mg kg −1 ).

Techniques: Injection