Spike mutation resilient scFv76 antibody counteracts SARS-CoV-2 lung damage upon aerosol delivery.

The uneven worldwide vaccination coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emergence of variants escaping immunity call for broadly effective and easily deployable therapeutic agents. We have previously described the human single-chain scFv76 antibody, which recognizes SARS-CoV-2 Alpha, Beta, Gamma and Delta variants. We now show that scFv76 also neutralizes the infectivity and fusogenic activity of the Omicron BA.1 and BA.2 variants. Cryoelectron microscopy (cryo-EM) analysis reveals that scFv76 binds to a well-conserved SARS-CoV-2 spike epitope, providing the structural basis for its broad-spectrum activity. We demonstrate that nebulized scFv76 has therapeutic efficacy in a severe hACE2 transgenic mouse model of coronavirus disease 2019 (COVID-19) pneumonia, as shown by body weight and pulmonary viral load data. Counteraction of infection correlates with inhibition of lung inflammation, as observed by histopathology and expression of inflammatory cytokines and chemokines. Biomarkers of pulmonary endothelial damage were also significantly reduced in scFv76-treated mice. The results support use of nebulized scFv76 for COVID-19 induced by any SARS-CoV-2 variants that have emerged so far.

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy.

As of December 2021, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single-chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the Delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Because of their high efficiency, remarkable stability, resilience to nebulization, and low cost of production, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status.

L-Acetylcarnitine causes analgesia in mice modeling Fabry disease by up-regulating type-2 metabotropic glutamate receptors.

Fabry disease (FD) is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3). A hallmark symptom of FD patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. Previous studies have shown that Acetyl-L-carnitine (ALC) has neuroprotective, neurotrophic, and analgesic activity in animal models of neuropathic pain. To study the action of ALC on neuropathic pain associated with FD, we treated α-GalA gene null mice (α-GalA(-/0)) with ALC for 30 days. In α-Gal KO mice, ALC treatment induced acute and long-lasting analgesia, which persisted 1 month after drug withdrawal. This effect was antagonized by single administration of LY341495, an orthosteric antagonist of mGlu2/3 metabotropic glutamate receptors. We also found an up-regulation of mGlu2 receptors in cultured DRG neurons isolated from 30-day ALC-treated α-GalA KO mice. However, the up-regulation of mGlu2 receptors was no longer present in DRG neurons isolated 30 days after the end of treatment. Taken together, these findings suggest that ALC induces analgesia in an animal model of FD by up-regulating mGlu2 receptors, and that analgesia is maintained by additional mechanisms after ALC withdrawal. ALC might represent a valuable pharmacological strategy to reduce pain in FD patients.

Pharmacokinetics, pharmacodynamics and safety assessment of multiple doses of soticlestat in healthy volunteers.

AIMS: Soticlestat, a first-in-class inhibitor of cholesterol 24-hydroxylase (also known as cytochrome P450 46A1), is currently in development for the treatment of developmental and epileptic encephalopathies. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic outcomes from a phase I, randomized, double-blind, placebo-controlled, multiple-rising-dose study of soticlestat in healthy adults. METHODS: Five cohorts of healthy subjects (n = 8 each, randomized 6:2 soticlestat:placebo) received oral soticlestat 100-600 mg once daily (QD) or 300 mg twice daily (BID) for 10-14 days. Serial blood and urine samples were obtained on days 1, 7 (blood only) and 14. RESULTS: Soticlestat in the dose range 100-400 mg/day for up to 14 days was generally well tolerated. In total, 45 treatment-emergent adverse events (TEAEs) were reported; most (91%) were transient and mild in intensity. Two subjects experienced TEAEs leading to discontinuation: one receiving soticlestat 600 mg QD reported a severe event of acute psychosis; another receiving 300 mg BID reported a mild event of confusional state. Steady-state exposure to soticlestat increased in a slightly greater than dose-proportional manner across the dose range 100-400 mg QD. Peak plasma concentrations were reached within 0.33-0.5 hour, and soticlestat elimination half-life was approximately 4 hours. Renal excretion of soticlestat was negligible. Soticlestat 100-400 mg QD reduced 24S-hydroxycholesterol levels by 46.8 (coefficient of variation [CV%] -9.2) to -62.7% (CV% -7.3) at steady state; values of enzymatic inhibition were compatible with antiepileptic effects observed in preclinical models. CONCLUSION: The pharmacokinetic and pharmacodynamic profiles of soticlestat characterized here provided a data-driven rationale for clinical trial dose selection.

Longitudinal study based on a safety registry for malaria patients treated with artenimol-piperaquine in six European countries.

BACKGROUND: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. METHODS: Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013-2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. RESULTS: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). CONCLUSIONS: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942.

Safety, tolerability, pharmacokinetics, pharmacodynamics, bioavailability and food effect of single doses of soticlestat in healthy subjects.

AIMS: Soticlestat is a first-in-class selective inhibitor of cholesterol 24-hydroxylase, the enzyme that converts brain cholesterol to 24S-hydroxycholesterol (24HC), a positive allosteric modulator of N-methyl-D-aspartate receptors. Soticlestat is under development as treatment for rare developmental and epileptic encephalopathies. METHODS: In this first-in-human study, 48 healthy men and women received single ascending doses of soticlestat oral solution or placebo. Subsequently, nine healthy subjects received soticlestat tablets under fed and fasting conditions to assess the relative oral bioavailability and effects of food. Serial blood and urine samples were collected for pharmacokinetic and pharmacodynamic assessments. RESULTS: Soticlestat appeared to be well tolerated up to a single dose of 1350 mg. Adverse events (AEs) were mild in intensity, and dose-dependent increase in AE prevalence was not apparent. Soticlestat administered via oral solution was rapidly absorbed (median time to maximum plasma concentration [Cmax ] 0.250-0.520 h). Mean Cmax and area under plasma concentration-time curve from zero to infinity increased by 183- and 581-fold, respectively, over a 90-fold dose increase. Mean terminal elimination half-life was 0.820-7.16 hours across doses. Renal excretion was negligible. Administration of soticlestat tablets, and with food, lowered Cmax but did not affect overall exposure. Plasma 24HC concentrations generally decreased with increasing dose. CONCLUSIONS: Soticlestat appeared to be well tolerated after a single oral administration of up to 1350 mg and dose-dependently reduced plasma 24HC concentrations. Systemic exposure increased in a greater than dose-proportional manner over the dose range evaluated but was not affected by formulation or administration with food.

An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers.

Chronic administration of antipsychotic drugs has been linked to structural brain changes observed in patients with schizophrenia. Recent MRI studies have shown rapid changes in regional brain volume following just a single dose of these drugs. However, it is not clear if these changes represent real volume changes or are artefacts ("apparent" volume changes) due to drug-induced physiological changes, such as increased cerebral blood flow (CBF). To address this, we examined the effects of a single, clinical dose of three commonly prescribed antipsychotics on quantitative measures of T1 and regional blood flow of the healthy human brain. Males (n = 42) were randomly assigned to one of two parallel groups in a double-blind, placebo-controlled, randomized, three-period cross-over study design. One group received a single oral dose of either 0.5 or 2 mg of risperidone or placebo during each visit. The other received olanzapine (7.5 mg), haloperidol (3 mg), or placebo. MR measures of quantitative T1, CBF, and T1-weighted images were acquired at the estimated peak plasma concentration of the drug. All three drugs caused localized increases in striatal blood flow, although drug and region specific effects were also apparent. In contrast, all assessments of T1 and brain volume remained stable across sessions, even in those areas experiencing large changes in CBF. This illustrates that a single clinically relevant oral dose of an antipsychotic has no detectable acute effect on T1 in healthy volunteers. We further provide a methodology for applying quantitative imaging methods to assess the acute effects of other compounds on structural MRI metrics. Hum Brain Mapp 39:319-331, 2018. © 2017 Wiley Periodicals, Inc.

Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling.

The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6-kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms.

Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies.

RATIONALE: Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve, and vagal afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C fibers and particularly the morphologically distinct, myelinated, nodose-derived mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers or detailed morphologies available for human bronchopulmonary afferent nerves. OBJECTIVES: Morphologic and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans. METHODS: A whole-mount immunofluorescence approach, rarely used in human lung tissue, was used with antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200-kD neurofilament subunit. MEASUREMENTS AND MAIN RESULTS: We have developed a robust technique to visualize fibers consistent with autonomic and C fibers and pulmonary neuroendocrine cells. A group of morphologically distinct, 200-kD neurofilament-immunopositive myelinated afferent fibers, a subpopulation of which did not express PGP9.5, was also identified. CONCLUSIONS: PGP9.5-immunonegative nerves are strikingly similar to myelinated airway afferents, the cough receptor, and smooth muscle-associated airway receptors described in rodents. These have never been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting.

Nicotine-induced structural plasticity in mesencephalic dopaminergic neurons is mediated by dopamine D3 receptors and Akt-mTORC1 signaling.

Although long-term exposure to nicotine is highly addictive, one beneficial consequence of chronic tobacco use is a reduced risk for Parkinson's disease. Of interest, these effects both reflect structural and functional plasticity of brain circuits controlling reward and motor behavior and, specifically, recruitment of nicotinic acetylcholine receptors (nAChR) in mesencephalic dopaminergic neurons. Because the underlying cellular mechanisms are poorly understood, we addressed this issue with use of primary cultures of mouse mesencephalic dopaminergic neurons. Exposure to nicotine (1-10 µM) for 72 hours in vitro increased dendritic arborization and soma size in primary cultures. These effects were blocked by mecamylamine and dihydro-ß-erythroidine, but not methyllycaconitine. The involvement of α4ß2 nAChR was supported by the lack of nicotine-induced structural remodeling in neurons from α4 null mutant mice (KO). Challenge with nicotine triggered phosphorylation of the extracellular signal-regulated kinase (ERK) and the thymoma viral proto-oncogene (Akt), followed by activation of the mammalian target of rapamycin complex 1 (mTORC1)-dependent p70 ribosomal S6 protein kinase. Upstream pathway blockade using the phosphatidylinositol 3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride] resulted in suppression of nicotine-induced phosphorylations and structural plasticity. These effects were dependent on functional DA D3 receptor (D3R), because nicotine was inactive both in cultures from D3R KO mice and after pharmacologic blockade with D3R antagonist trans-N-4-2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethylcyclohexyl-4-quinolinecarboxamide (SB-277011-A) (50 nM). Finally, exposure to nicotine in utero (5 mg/kg/day for 5 days) resulted in increased soma area of DAergic neurons of newborn mice, effects not observed in D3 receptor null mutant mice mice. These findings indicate that nicotine-induced structural plasticity at mesencephalic dopaminergic neurons involves α4ß2 nAChRs together with dopamine D3R-mediated recruitment of ERK/Akt-mTORC1 signaling.

Mathematical modelling of [¹¹C]-(+)-PHNO human competition studies.

The D(2)/D(3) agonist radioligand [(11)C]-(+)-PHNO is currently the most suitable D(3) imaging agent available, despite its limited selectivity for the D(3) over the D(2). Given the collocation of D(2) and D(3) receptors, and generally higher densities of D(2), the separation of D(2) and D(3) information from [(11)C]-(+)-PHNO PET data are somewhat complex. This complexity is compounded by recent data suggesting that [(11)C]-(+)-PHNO PET scans might be routinely performed in non-tracer conditions (with respect to D(3) receptors), and that the cerebellum (used as a reference region) might manifest some displaceable binding signal. Here we present the modelling and analysis of data from two human studies which employed an adequate dose range of selective D(3) antagonists (GSK598809 and GSK618334) to interrogate the [(11)C]-(+)-PHNO PET signal. Models describing the changes observed in the PET volume of distribution (V(T)) and binding potential (BP(ND)) were used to identify and quantify a [(11)C]-(+)-PHNO mass dose effect at the D(3), and displaceable signal in the cerebellum, as well as providing refined estimates of regional D(3) fractions of [(11)C]-(+)-PHNO BP(ND). The dose of (+)-PHNO required to occupy half of the available D(3) receptors (ED(50)(PHNO,D3)) was estimated as 40ng/kg, and the cerebellum BP(ND) was estimated as 0.40. These findings confirm that [(11)C]-(+)-PHNO human PET studies are in fact routinely performed under non-tracer conditions. This suggests that (+)-PHNO injection masses should be minimised and tightly controlled in order to mitigate the mass dose effect. The specific binding detected in the cerebellum was modest but could have a significant effect, for example on estimates of D(3) potency in drug occupancy studies. A range of methods for the analysis of future [(11)C]-(+)-PHNO data, incorporating models for the effects quantified here, were developed and evaluated. The comparisons and conclusions drawn from these can inform the design and analysis of future PET studies with [(11)C]-(+)-PHNO.

Involvement of DA D3 Receptors in Structural Neuroplasticity of Selected Limbic Brain Circuits: Possible Role in Treatment-Resistant Depression.

Structural neuroplasticity in the adult brain is a process involving quantitative changes of the number and size of neurons and of their dendritic arborization, axon branching, spines, and synapses. These changes can occur in specific neural circuits as adaptive response to environmental challenges, exposure to stressors, tissue damage or degeneration. Converging studies point to evidence of structural plasticity in circuits operated by glutamate, GABA, dopamine, and serotonin neurotransmitters, in concert with neurotrophic factors such as Brain Derived Neurotrophic Factor (BDNF) or Insulin Growth Factor 1 (IGF1) and a series of modulators that include circulating hormones. Intriguingly, most of these endogenous agents trigger the activation of the PI3K/Akt/mTOR and ERK1/2 intracellular pathways that, in turn, lead to the production of growth-related structural changes, enhancing protein synthesis, metabolic enzyme functions, mitogenesis for energy, and new lipid-bilayer membrane apposition. The dopamine (DA) D3 receptor has been shown to play a specific role by inducing structural plasticity of the DAergic neurons of the nigrostriatal and mesocorticolimbic circuit, where they are expressed in rodents and humans, via activation of the mTORC1 and ERK1/2 pathways. These effects are BDNF-dependent and require the recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to allow the structural changes. Since in mood disorders, depression and anhedonia have been proposed to be associated with impaired neuroplasticity and reduced DAergic tone in brain circuits connecting prefrontal cortex, ventral striatum, amygdala, and ventral mesencephalon, activation of D3 receptors could provide a therapeutic benefit. Sustained improvements of mood and anhedonia were observed in subjects with an unsatisfactory response to serotonin uptake inhibitors (SSRI) when treated with D3-preferential D2/D3 agonists such as pramipexole and ropinirole. The recent evidence that downstream mTOR pathway activation in human mesencephalic DA neurons is also produced by ketamine, probably the most effective antidepressant currently used in subjects with treatment-resistant depression, further supports the rationale for a D3 receptor activation in mood disorders.

Brain functional connectivity in stimulant drug dependence and obsessive-compulsive disorder.

There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N=18), patients with OCD (N=18) and SDIs (N=18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories.

Pre-synaptic dopamine D(3) receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways.

Exposure to psychostimulants results in neuroadaptive changes of the mesencephalic dopaminergic system including morphological reorganization of dopaminergic neurons. Increased dendrite arborization and soma area were previously observed in primary cultures of mesencephalic dopaminergic neurons after 3-day exposure to dopamine agonists via activation of D(3) autoreceptors (D(3) R). In this work, we showed that cocaine significantly increased dendritic arborization and soma area of dopaminergic neurons from E12.5 mouse embryos by activating phosphorylation of extracellular signal-regulated kinase (ERK) and thymoma viral proto-oncogene (Akt). These effects were dependent on functional D(3) R expression because cocaine did not produce morphological changes or ERK/Akt phosphorylation neither in primary cultures of D(3) R mutant mice nor following pharmacologic blockade with D(3) R antagonists SB-277011-A and S-33084. Cocaine effects on morphology and ERK/Akt phosphorylation were inhibited by pre-incubation with the phosphatidylinositol 3-kinase inhibitor LY294002. These observations were corroborated in vivo by morphometrical assessment of mesencephalic dopaminergic neurons of P1 newborns exposed to cocaine from E12.5 to E16.5. Cocaine increased the soma area of wild-type but not of D(3) R mutant mice, supporting the translational value of primary culture. These findings indicate a direct involvement of D3R and ERK/Akt pathways as critical mediators of cocaine-induced structural plasticity, suggesting their involvement in psychostimulant addiction.

The effects of the dopamine D3 receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects.

The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from pre-clinical studies suggests that D3 receptor antagonists may attenuate the motivational impact of rewarding cues. In this study we examined the acute effects of the D3 receptor antagonist GSK598809 on attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7±3.7, range 27-40 kg/m²) who reported binge and emotional eating. We also determined whether individual differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on both visual probe and food Stroop attentional bias scores was inversely correlated with a measure of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters. Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo, and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to food cues generated by individual differences in eating traits can be modulated by D3 receptor antagonists, warranting further investigation with measures of eating behaviour and weight loss.

Effect of dopamine D3 receptor antagonism on approach responses to food cues in overweight and obese individuals.

The aim of the study was to examine the effect of manipulating the brain dopamine system, using a D3 receptor antagonist, on approach responses to food cues in overweight and obese individuals. Twenty-six healthy overweight and obese participants were randomly assigned to receive either a single dose of dopamine D3 receptor antagonist, GSK598809 (175 mg), or placebo in the first assessment session and vice versa in the second session. Using a stimulus-response compatibility task, approach bias was indexed by response latency to move an image of a manikin towards, versus away from, pictures of food, relative to nonfood stimuli. Data from the first session (which were unaffected by repeated testing) indicated that approach bias scores were significantly reduced in overweight and obese participants who received GSK598809, compared with those who received placebo. Data from the second session were confounded by an effect of treatment order and, consequently, were uninformative for the hypotheses. Between-participant comparison of drug versus placebo conditions indicated that GSK598809 attenuated approach bias to food cues, which is consistent with the reduction in their motivational attractiveness. The findings, albeit preliminary, are in agreement with the view that D3 receptor antagonists may prove useful as therapeutic agents for reducing appetitive responses to food cues in obesity.

Altered brain functional connectivity in relation to perception of scrutiny in social anxiety disorder.

Although the fear of being scrutinized by others in a social context is a key symptom in social anxiety disorder (SAD), the neural processes underlying the perception of scrutiny have not previously been studied by functional magnetic resonance imaging (fMRI). We used fMRI to map brain activation during a perception-of-scrutiny task in 20 SAD patients and 20 controls. A multi-dimensional analytic approach was used. Scrutiny perception was mediated by activation of the medial frontal cortex, insula-operculum region and cerebellum, and the additional recruitment of visual areas and the thalamus in patients. Between-group comparison demonstrated significantly enhanced brain activation in patients in the primary visual cortex and cerebellum. Functional connectivity mapping demonstrated an abnormal connectivity between regions underlying general arousal and attention. SAD patients showed significantly greater task-induced functional connectivity in the thalamo-cortical and the fronto-striatal circuits. A statistically significant increase in task-induced functional connectivity between the anterior cingulate cortex and scrutiny-perception-related regions was observed in the SAD patients, suggesting the existence of enhanced behavior-inhibitory control. The presented data indicate that scrutiny perception in SAD enhances brain activity in arousal-attention systems, suggesting that fMRI may be a useful tool to explore such a behavioral dimension.

Effect of the dopamine D3 receptor antagonist GSK598809 on brain responses to rewarding food images in overweight and obese binge eaters.

The dopamine D(3) receptor is thought to be a potential target for treating compulsive disorders such as drug addiction and obesity. Here, we used functional Magnetic Resonance Imaging (fMRI) to investigate the effects the selective dopamine D(3) receptor antagonist GSK598809 on brain activation to food images in a sample of overweight and obese binge-eating subjects. Consistent with previous studies, processing of food images was associated with activation of a network of reward areas including the amygdala, striatum and insula. However, brain activation to food images was not modulated by GSK598809. The results demonstrate that D(3) receptor manipulation does not modulate brain responses to food images in overweight and obese subjects.

Social withdrawal and neurocognitive correlates in schizophrenia.

Poor neurocognitive performance has been associated with poor functional outcome in schizophrenia (SCZ) in past studies. Nonetheless, the likely association between neurocognition and social withdrawal has never been investigated. The aim of our study was to investigate in a large and heterogeneous sample of SCZ patient cross-sectional associations between neurocognitive domains and social withdrawal. The sample included 761 SCZ patients who completed the baseline visit in the CATIE study. Neurocognition was assessed by a comprehensive battery of tests resulting in five domain scores and a composite score. Social withdrawal was measured by a specific item of the Heinrichs-Carpenter Quality of Life Scale. Social withdrawal was associated with a lower score in the neurocognitive composite score and in 'Verbal memory,' 'Processing speed' and 'Working memory' scores. 'Verbal memory' score showed the strongest association with social withdrawal. Eight percent of the total variance of social withdrawal was explained by these three cognitive domains and additional clinical and sociodemographic factors (education years, PANSS positive symptoms score, and employment). Our results confirmed the wide heterogeneity and specificity of the correlation between neurocognitive domains and indicators of functional outcome in SCZ, underlining the role of certain neurocognitive abilities in social withdrawal.

Synergic action of L-acetylcarnitine and L-methylfolate in Mouse Models of Stress-Related Disorders and Human iPSC-Derived Dopaminergic Neurons.

The epigenetic agents, L-acetylcarnitine (LAC) and L-methylfolate (MF) are putative candidates as add-on drugs in depression. We evaluated the effect of a combined treatment with LAC and MF in two different paradigms of chronic stress in mice and in human inducible pluripotent stem cells (hiPSCs) differentiated into dopaminergic neurons. Two groups of mice were exposed to chronic unpredictable stress (CUS) for 28 days or chronic restraint stress (CRS) for 21 day, and LAC (30 or 100 mg/kg) and/or MF (0.75 or 3 mg/kg) were administered i.p. once a day for 14 days, starting from the last week of stress. In both stress paradigms, LAC and MF acted synergistically in reducing the immobility time in the forced swim test and enhancing BDNF protein levels in the frontal cortex and hippocampus. In addition, LAC and MF acted synergistically in enhancing type-2 metabotropic glutamate receptor (mGlu2) protein levels in the hippocampus of mice exposed to CRS. Interestingly, CRS mice treated with MF showed an up-regulation of NFκB p65, which is a substrate for LAC-induced acetylation. We could also demonstrate a synergism between LAC and MF in cultured hiPSCs differentiated into dopamine neurons, by measuring dendrite length and number, and area of the cell soma after 3 days of drug exposure. These findings support the combined use of LAC and MF in the treatment of MDD and other stress-related disorders.