Selective serotonin 5-HT1A receptor biased agonists elicit distinct brain activation patterns: a pharmacoMRI study

International audienceSerotonin 1A (5-HT 1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT 1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT 1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT 1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology. 5-HT 1A receptors belong to the family of serotonin receptors, composed of 13 receptor subtypes. 5-HT 1A receptors are known to play a key role in serotonin neurotransmission due to their localization both as pre-synaptic receptors located on serotonin cell bodies in the raphe nuclei (somatodendritic receptors) and as post-synaptic heteroreceptors in forebrain areas that receive serotonergic projections. In such areas, 5-HT 1A receptors are located on pyramidal and GABAergic neurons of the neocortex and limbic system 1,2. Because of their distribution pattern and of their central role in the modulation of the serotoninergic neurotransmission, 5-HT 1A receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target for psychiatric 3 and, more recently, for neurological disorders 4. Indeed, it is now well establish that 5-HT 1A receptors are one of the main targets for the treatment of mood disorders 5 , with different actions that depend strongly on their localization. For example, activation of soma-todendritic receptors by serotonin or 5-HT 1A receptor agonists decreases the firing of serotonin neurons in the raphe, and, consequently decreases its terminal release 6. This decrease is thought to be partially responsible for the delay in onset of the therapeutic action of selective serotonin reuptake inhibitors (SSRI) antidepressants 5. A recent study renewed this concept, showing that expression levels of 5-HT 1A somatodendritic receptors, are critically important for SSRI treatment response by controlling serotoninergic tone 7. On the other hand, the activation of postsynaptic 5-HT 1A receptors seems to be equally important for response to antidepressants 5,8. In a different therapeutic area, 5-HT 1A receptor agonism is also known as an important feature of some atypical antipsychotics including clozapine, aripiprazole, ziprasidone and quetiapine 9–12. Recently, 5-HT 1A receptors have attracted renewed interest as possible targets in neuropharmacology. For example, it was described that blockade of post-synaptic 5-HT 1A receptors, located on pyramidal cells, can improve cognition by enhancing glutamatergic transmission 13. This led to clinical trials using the 5-HT 1A antagonist lecozotan as a procognitive drug in Alzheimer's disease 14,15. Other 5-HT 1A receptor ligands such as sarizotan, buspirone and tandospirone were shown to alleviate dyskinesia in Parkinson's disease patients 16,17. More recently

Noradrenaline and Movement Initiation Disorders in Parkinson’s Disease: A Pharmacological Functional MRI Study with Clonidine

International audienceSlowness of movement initiation is a cardinal motor feature of Parkinson’s disease (PD) and is not fully reverted by current dopaminergic treatments. This trouble could be due to the dysfunction of executive processes and, in particular, of inhibitory control of response initiation, a function possibly associated with the noradrenergic (NA) system. The implication of NA in the network supporting proactive inhibition remains to be elucidated using pharmacological protocols. For that purpose, we administered 150 μg of clonidine to 15 healthy subjects and 12 parkinsonian patients in a double-blind, randomized, placebo-controlled design. Proactive inhibition was assessed by means of a Go/noGo task, while pre-stimulus brain activity was measured by event-related functional MRI. Acute reduction in noradrenergic transmission induced by clonidine enhanced difficulties initiating movements reflected by an increase in omission errors and modulated the activity of the anterior node of the proactive inhibitory network (dorsomedial prefrontal and anterior cingulate cortices) in PD patients. We conclude that NA contributes to movement initiation by acting on proactive inhibitory control via the α2-adrenoceptor. We suggest that targeting noradrenergic dysfunction may represent a new treatment approach in some of the movement initiation disorders seen in Parkinson’s diseas

Bayesian Estimation of the ntPET Model in Single-Scan Competition PET Studies

International audienceThis paper proposes an innovative method, named b-ntPET, for solving a competition model in PET. The model is built upon the state-of-the-art method called lp-ntPET. It consists in identifying the parameters of the PET kinetic model relative to a reference region that rule the steady state exchanges, together with the identification of four additional parameters defining a displacement curve caused by an endogenous neurotransmitter discharge, or by a competing injected drug targeting the same receptors as the PET tracer. The resolution process of lp-ntPET is however suboptimal due to the use of discretized basis functions, and is very sensitive to noise, limiting its sensitivity and accuracy. Contrary to the original method, our proposed resolution approach first estimates the probability distribution of the unknown parameters using Markov-Chain Monte-Carlo sampling, distributions from which the estimates are then inferred. In addition, and for increased robustness, the noise level is jointly estimated with the parameters of the model. Finally, the resolution is formulated in a Bayesian framework, allowing the introduction of prior knowledge on the parameters to guide the estimation process toward realistic solutions. The performance of our method was first assessed and compared head-to-head with the reference method lp-ntPET using well-controlled realistic simulated data. The results showed that the b-ntPET method is substantially more robust to noise and much more sensitive and accurate than lp-ntPET. We then applied the model to experimental animal data acquired in pharmacological challenge studies and human data with endogenous releases induced by transcranial direct current stimulation. In the drug challenge experiment on cats using [18F]MPPF, a serotoninergic 1A antagonist radioligand, b-ntPET measured a dose response associated with the amount of the challenged injected concurrent 5-HT1A agonist, where lp-ntPET failed. In human [11C]raclopride experiment, contrary to lp-ntPET, b-ntPET successfully detected significant endogenous dopamine releases induced by the stimulation. In conclusion, our results showed that the proposed method b-ntPET has similar performance to lp-ntPET for detecting displacements, but with higher resistance to noise and better robustness to various experimental contexts. These improvements lead to the possibility of detecting and characterizing dynamic drug occupancy from a single PET scan more efficiently

Distribution of α 2 -Adrenergic Receptors in the Living Human Brain Using [ 11 C]yohimbine PET

International audienceThe neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [ 11 C]yohimbine in a large sample of subjects (46 healthy volunteers, 23 females, 23 males; aged 20-50) to perform direct quantification of regional alpha 2 adrenergic receptors' (α 2-ARs) availability in the living human brain. The global map shows the highest [ 11 C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe. Moderate binding was found in the parietal lobe, thalamus, parahippocampus, insula, and temporal lobe. Low levels of binding were found in the basal ganglia, the amygdala, the cerebellum, and the raphe nucleus. Parcellation of the brain into anatomical subregions revealed important variations in [ 11 C]yohimbine binding within most structures. Strong heterogeneity was found in the occipital lobe, the frontal lobe, and the basal ganglia, with substantial gender effects. Mapping the distribution of α 2-ARs in the living human brain may prove useful not only for understanding the role of the NA system in many brain functions, but also for understanding neurodegenerative diseases in which altered NA transmission with specific loss of α 2-ARs is suspected

5-HT1A biased agonists induce different hemodynamic responses, a pharmacological MRI study

The pharmacological MRI (phMRI) data were acquired on a 7-Tesla Bruker Biospec MR system camera (CERMEP-Imaging Platform). The modifications of blood oxygen level dependant (BOLD) signal induced by the drugs, indirectly related to changes in neuronal activity, were measured in isoflurane-anesthetized rats. A continuous T2* echo planar imaging (EPI) sequence was used during 1 hour and a repetition time (TR) of 3 seconds. All rats were scanned under four conditions in a randomized order: a saline injection and three increasing doses of 5-HT 1A agonist (0.16-0.32-0.63 mg/kg). The animals were divided in two groups, one for each molecule (n=9 for NLX-112; n=9 for NLX-101). The intraperitoneal injection of agonist or saline was performed 15 minutes after the beginning of the phMRI session, resulting in 300 baseline scans and 900 post-injection scans. A voxel-based analysis of the data was performed at an individual level (for each scan, comparison between different time periods post-injection versus baseline), with the non-specific changes of BOLD signal in ventricles and white matter as regressors of non-interest, followed by a second-level analysis in a block design using a General Linear Model (GLM) approach (comparison between agonists conditions and saline condition) with the software Statistical Parametric Mapping (SPM12, The Wellcome Trust Center for Neuroimaging, London, UK). The statistical significance was set at p<0.001 uncorrected

5-HT1A biased agonists induce different hemodynamic responses, a pharmacological MRI study

The pharmacological MRI (phMRI) data were acquired on a 7-Tesla Bruker Biospec MR system camera (CERMEP-Imaging Platform). The modifications of blood oxygen level dependant (BOLD) signal induced by the drugs, indirectly related to changes in neuronal activity, were measured in isoflurane-anesthetized rats. A continuous T2* echo planar imaging (EPI) sequence was used during 1 hour and a repetition time (TR) of 3 seconds. All rats were scanned under four conditions in a randomized order: a saline injection and three increasing doses of 5-HT 1A agonist (0.16-0.32-0.63 mg/kg). The animals were divided in two groups, one for each molecule (n=9 for NLX-112; n=9 for NLX-101). The intraperitoneal injection of agonist or saline was performed 15 minutes after the beginning of the phMRI session, resulting in 300 baseline scans and 900 post-injection scans. A voxel-based analysis of the data was performed at an individual level (for each scan, comparison between different time periods post-injection versus baseline), with the non-specific changes of BOLD signal in ventricles and white matter as regressors of non-interest, followed by a second-level analysis in a block design using a General Linear Model (GLM) approach (comparison between agonists conditions and saline condition) with the software Statistical Parametric Mapping (SPM12, The Wellcome Trust Center for Neuroimaging, London, UK). The statistical significance was set at p<0.001 uncorrected

CERMEP-IDB-MRXFDG:a database of 37 normal adult human brain [18F]FDG PET, T1 and FLAIR MRI, and CT images available for research

Abstract We present a database of cerebral PET FDG and anatomical MRI for 37 normal adult human subjects (CERMEP-IDB-MRXFDG). Thirty-nine participants underwent static [18F]FDG PET/CT and MRI, resulting in [18F]FDG PET, T1 MPRAGE MRI, FLAIR MRI, and CT images. Two participants were excluded after visual quality control. We describe the acquisition parameters, the image processing pipeline and provide participants’ individual demographics (mean age 38 ± 11.5 years, range 23–65, 20 women). Volumetric analysis of the 37 T1 MRIs showed results in line with the literature. A leave-one-out assessment of the 37 FDG images using Statistical Parametric Mapping (SPM) yielded a low number of false positives after exclusion of artefacts. The database is stored in three different formats, following the BIDS common specification: (1) DICOM (data not processed), (2) NIFTI (multimodal images coregistered to PET subject space), (3) NIFTI normalized (images normalized to MNI space). Bona fide researchers can request access to the database via a short form