Dataset Information

Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

ABSTRACT: The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement preparation. Psilocin (2 mg/kg or 0.03 mg/kg i.v.) or vehicle was administered to rats (N=6/group) during either phMRI scanning or concurrent imaging of cortical blood flow and recording of local field potentials. Compared to vehicle controls psilocin (2 mg/kg) evoked phMRI signal increases in a number of regions including olfactory and limbic areas and elements of the visual system. PhMRI signal decreases were seen in other regions including somatosensory and motor cortices. Investigation of neurovascular coupling revealed that whilst neuronal responses (local field potentials) to sensory stimuli were decreased in amplitude by psilocin administration, concurrently measured haemodynamic responses (cerebral blood flow) were enhanced. The present findings show that psilocin evoked region-specific changes in phMRI signals in the rat, confirming recent human data. However, the results also suggest that the haemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. This highlights the importance of understanding the neurovascular effects of pharmacological manipulations for interpreting haemodynamic neuroimaging data.

SUBMITTER: Spain A

PROVIDER: S-EPMC4655865 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

Spain Aisling A Howarth Clare C Khrapitchev Alexandre A AA Sharp Trevor T Sibson Nicola R NR Martin Chris C

Neuropharmacology 20150717

The development of pharmacological magnetic resonance imaging (phMRI) has presented the opportunity for investigation of the neurophysiological effects of drugs in vivo. Psilocin, a hallucinogen metabolised from psilocybin, was recently reported to evoke brain region-specific, phMRI signal changes in humans. The present study investigated the effects of psilocin in a rat model using phMRI and then probed the relationship between neuronal and haemodynamic responses using a multimodal measurement ...[more]

PMID: 26192543

Similar Datasets

Project description:PurposeTo assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.MethodsAlbino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections.ResultsA five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice.ConclusionsIntraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation.

Project description:There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20-80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [(11)C]WAY100635 and [(18)F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (V(T)) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age(2), sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004-0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05-0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03-0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults <50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex-hormone-serotonin receptor relationships.

Project description:BACKGROUND:The circumventricular organs (CVOs) are blood-brain-barrier missing structures whose activation through lipopolysaccharide (LPS) is a starting point for TLR-driven (Toll-like receptors) neuroinflammation. The aim of this study was to evaluate in the CVO area postrema (AP), subfornical organ (SFO), and median eminence (ME), the inflammatory response to two TLR4 agonists: LPS from Escherichia coli (EC-LPS), the strongest endotoxin molecule described, and LPS from Porphyromonas gingivalis (PG-LPS), a pathogenic bacteria present in the periodontium related to neuroinflammation in neurodegenerative/psychiatric diseases. The response to LPS from the cyanobacteria Rhodobacter sphaeroides (RS-LPS), a TLR4 antagonist with an interesting anti-inflammatory potential, was also assessed. METHODS:LPSs were intraperitoneally administered to Wistar rats and, as indicatives of neuroinflammation in CVOs, the cellular localization of the nuclear factor NF-κB was studied by immunofluorescence, and microglia morphology was quantified by fractal and skeleton analysis. RESULTS:Data showed that EC-LPS increased NF-κB nuclear translocation in the three CVOs studied and PG-LPS only induced NF-κB nuclear translocation in the ME. RS-LPS showed no difference in NF-κB nuclear translocation compared to control. Microglia in the three CVOs showed an ameboid-shape after EC-LPS exposure, whereas PG-LPS only elicited a mild tendency to induce an ameboid shape. On the other hand, RS-LPS produced a markedly elongated morphology described as "rod" microglia in the three CVOs. CONCLUSIONS:In conclusion, at the doses tested, EC-LPS induces a stronger neuroinflammatory response than PG-LPS in CVOs, which might be related to their different potency as TLR4 agonists. The non-reduction of basal NF-κB activation and induction of rod microglia by RS-LPS, a cell morphology only present in severe brain injury and infections, suggests that this molecule must be carefully studied before being proposed as an anti-inflammatory treatment for neuroinflammation related to neurodegenerative/psychiatric diseases.

Dataset Information

Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

Publications

Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets