Velusetrag rescues GI dysfunction, gut inflammation and dysbiosis in a mouse model of Parkinson's disease.

In patients with Parkinson's disease (PD), constipation is common, and it appears in a prodromal stage before the hallmark motor symptoms. The present study aimed to investigate whether Velusetrag, a selective 5‑HT4 receptor agonist, may be a suitable candidate to improve intestinal motility in a mouse model of PD. Five months old PrP human A53T alpha-synuclein transgenic (Tg) mice, which display severe constipation along with decreased colonic cholinergic transmission already at 3 months, were treated daily with the drug for 4 weeks.

Wearable Devices for Assessing Function in Alzheimer's Disease: A European Public Involvement Activity About the Features and Preferences of Patients and Caregivers.

Alzheimer's Disease (AD) impairs the ability to carry out daily activities, reduces independence and quality of life and increases caregiver burden. Our understanding of functional decline has traditionally relied on reports by family and caregivers, which are subjective and vulnerable to recall bias. The Internet of Things (IoT) and wearable sensor technologies promise to provide objective, affordable, and reliable means for monitoring and understanding function.

Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome.

Kabuki syndrome (KS) is a rare cause of intellectual disability primarily caused by loss-of-function mutations in lysine-specific methyltransferase 2D (), which normally adds methyl marks to lysine 4 on histone 3. Previous studies have shown that a mouse model of KS ( ) demonstrates disruption of adult neurogenesis and hippocampal memory. Proof-of-principle studies have shown postnatal rescue of neurological dysfunction following treatments that promote chromatin opening; however, these strategies are non-specific and do not directly address the primary defect of histone methylation.

Functional Neuroimaging of Nociceptive and Pain-Related Activity in the Spinal Cord and Brain: Insights From Neurovascular Coupling Studies.

Spinal cord and brain processes underlie pain perception, which produces systemic cardiovascular changes. In turn, the autonomic nervous system regulates vascular function in the spinal cord and brain in order to adapt to these systemic changes, while neuronal activity induces local vascular changes. Thus, autonomic regulation and pain processes in the brain and spinal cord are tightly linked and interrelated.

Statistical power and prediction accuracy in multisite resting-state fMRI connectivity.

Connectivity studies using resting-state functional magnetic resonance imaging are increasingly pooling data acquired at multiple sites. While this may allow investigators to speed up recruitment or increase sample size, multisite studies also potentially introduce systematic biases in connectivity measures across sites. In this work, we measure the inter-site effect in connectivity and its impact on our ability to detect individual and group differences.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients.

Estimating multivariate similarity between neuroimaging datasets with sparse canonical correlation analysis: an application to perfusion imaging.

An increasing number of neuroimaging studies are based on either combining more than one data modality (inter-modal) or combining more than one measurement from the same modality (intra-modal). To date, most intra-modal studies using multivariate statistics have focused on differences between datasets, for instance relying on classifiers to differentiate between effects in the data. However, to fully characterize these effects, multivariate methods able to measure similarities between datasets are needed.

Pharmacological targeting of dopamine D3 receptors: Possible clinical applications of selective drugs.

Dopamine D3 receptors have been pharmacologically engaged in humans since the development of the first antipsychotics and ergot-derivative dopamine (DA) agonists, even without knowing it. These agents were generally non-selective, developed primarily to target D2 receptors. In the last 10 years the understanding of the clinical implication of D3 receptors has been progressing also due to the identification of D3 gene polymorphisms, the use of more selective PET ligands such as [(11)C]-(+)-PHNO and the learning regarding the clinical use of the D3-preferential D2/D3 agonists ropinirole and pramipexole.

Association between amygdala reactivity and a dopamine transporter gene polymorphism.

Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli.

Amygdala-frontal couplings characterizing SSRI and placebo response in social anxiety disorder.

Unlabelled: In patients with social anxiety disorder (SAD) it has been reported that selective serotonin reuptake inhibitors (SSRIs) and placebo induce anxiolytic effects by attenuating neural activity in overlapping amygdala subregions, i.e. left basolateral and right ventrolateral amygdala.

Inhibition of glycine transporter-1 reduces cue-induced nicotine-seeking, but does not promote extinction of conditioned nicotine cue responding in the rat.

Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats.

Biomarkers for antipsychotic therapies.

Molecular biomarkers for antipsychotic treatments have been conceptually linked to the measurements of dopamine functions, mostly D(2) receptor occupancy, either by imaging using selective PET/SPECT radioactive tracers or by assessing plasma prolactin levels. A quest for novel biomarkers was recently proposed by various academic, health service, and industrial institutions driven by the need for better treatments of psychoses. In this review we conceptualize biomarkers within the Translational Medicine paradigm whose goal was to provide support to critical decision-making in drug discovery.

Amygdala subregions tied to SSRI and placebo response in patients with social anxiety disorder.

The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments. Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported.

GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs.

Ghrelin is a 28-amino-acid polypeptide expressed in the stomach and hypothalamus that stimulates GH secretion, increases food intake (FI) and promotes body weight (BW) gain most likely via activation of the growth hormone secretagogue receptor type 1a (GHSR1a). GSK1614343 is a novel selective and potent GHSR antagonist with no partial agonist properties, recently characterized as GH secretion inhibitor by Sabbatini et al. [Chem Med Chem 2010;5:1450-1455].

Neuroimaging evidence of altered fronto-cortical and striatal function after prolonged cocaine self-administration in the rat.

Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme.

Central nervous system effects of the interaction between risperidone (single dose) and the 5-HT6 antagonist SB742457 (repeated doses) in healthy men.

What Is Already Known About This Subject: • Several lines of evidence suggest a possible role of 5-HT(6) receptor antagonists in dementia or cognitive dysfunction of schizophrenia. SB-742457 is a potent 5-HT(6) antagonist and has shown efficacy in different animal models of cognitive impairment. It is currently in development as a cognitive enhancer.

Plasma nociceptin/orphanin FQ levels in response to the hyperventilation test in healthy subjects.

In vitro and in vivo studies demonstrated that nociceptin/orphanin FQ inhibits norepinephrine release, while the effects of norepinephrine on nociceptin/orphanin FQ release remain unknown. Previous studies in healthy and hypertensive subjects showed that prolonged and forced hyperventilation induces different blood pressure (BP) responses depending on changes in plasma catecholamine levels. We investigated whether the effects of hyperventilation on the sympatho-adrenergic system involve nociceptin/orphanin FQ release.

Plasma nociceptin/orphanin FQ levels rise after spontaneous episodes of angina, but not during induced myocardial ischemia.

The aim of our study was to evaluate the effects of repeated episodes of angina and induced myocardial ischemia on plasma nociceptin/orphanin FQ (N/OFQ) levels. Patients with unstable angina (23 with new onset severe angina or accelerated angina and 18 with subacute angina at rest) who had had repeated spontaneous episodes of chest pain in the last week before the study underwent myocardial perfusion single-photon emission computed tomography using adenosine infusion. Twenty subjects without clinical symptoms of angina matched for age, sex and cardiac risk factors served as a control group.

Genotype over-diagnosis in amygdala responsiveness: affective processing in social anxiety disorder.

Background: Although the amygdala is thought to be a crucial brain region for negative affect, neuroimaging studies do not always show enhanced amygdala response to aversive stimuli in patients with anxiety disorders. Serotonin (5-HT)-related genotypes may contribute to interindividual variability in amygdala responsiveness. The short (s) allele of the 5-HT transporter linked polymorphic region (5-HTTLPR) and the T variant of the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene have previously been associated with amygdala hyperresponsivity to negative faces in healthy controls.

A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety.

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period.

Functional coupling of the amygdala in depressed patients treated with antidepressant medication.

The amygdala plays a central role in various aspects of affect processing and mood regulation by its rich anatomical connections to other limbic and cortical regions. It is plausible that depressive disorders, and response to antidepressant drugs, may reflect changes in the physiological coupling between the amygdala and other components of affect-related large-scale brain systems. We explored this hypothesis by mapping the functional coupling of right and left amygdalae in functional magnetic resonance imaging data acquired from 19 patients with major depressive disorder and 19 healthy volunteers, each scanned twice (at baseline and 8 weeks later) during performance of an implicit facial affect processing task.

A longitudinal functional magnetic resonance imaging study of verbal working memory in depression after antidepressant therapy.

Background: Impairments in the neural circuitry of verbal working memory are evident in depression. Factors of task demand and depressive state might have significant effects on its functional neuroanatomy.

Methods: Two groups underwent functional magnetic resonance imaging while performing a verbal working memory task of varying cognitive load (n-back).

Neural responses to happy facial expressions in major depression following antidepressant treatment.

Objective: Processing affective facial expressions is an important component of interpersonal relationships. However, depressed patients show impairments in this system. The present study investigated the neural correlates of implicit processing of happy facial expressions in depression and identified regions affected by antidepressant therapy.

Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo.

Background: Evidence is accumulating that pharmacological blockade of the substance P preferring neurokinin-1 (NK1) receptor reduces anxiety. This study compared the effects of an NK1 receptor antagonist, citalopram, and placebo on brain activity and anxiety symptoms in social phobia.

Methods: Thirty-six patients diagnosed with social phobia were treated for 6 weeks with the NK1 antagonist GR205171 (5 mg), citalopram (40 mg), or matching placebo under randomized double-blind conditions.