Simulations of the effect of smectite-to-illite transition in shales on permeability and overpressures using a stochastic approach, a Norwegian margin case study

The smectite-illite transition in shales due to subsidence, temperature changes and diagenesis influences many processes in a sedimentary basin that can contribute to overpressure build up like reducing the shale permeability. The smectite-rich layers can form sealing barriers to fluid flows that will influence pore pressure prognosis for drilling campaigns, contribute to sealing caprocks for possible CO2 storage and to sealing of plugging and abandonment wells. In this work, we have included the diagenetic smectite-illite transition into a three-dimensional pressure simulation model to simulate its effect on pressure build-up due to reduced shale permeabilities over geological time scale. We have also tested effect of thermal history and potassium concentration on the process of smectite-illite transition and the associated smectite-illite correction on permeability. A new smectite-illite correction has been introduced, to mimic how shale permeability will vary dependent on the smectite-illite transition. Stochastic Monte Carlo simulations have been carried out to test the sensitivity of the new correction parameters. Finally, a 3D Monte Carlo pore pressure simulation with 1000 drawings has been carried out on a case study covering Skarv Field, and Dønna Terrace offshore Mid-Norway. The simulated mean overpressures are in range with observed overpressures from exploration wells in the area for the Cretaceous sandy Lysing Formation and for the two Cretaceous Intra Lange Formation sandstones. The simulated smectite content versus depth is in line with published XRD dataset from wells. The corresponding modelled present-day permeabilities for the shales including the smectite-illite transition are two magnitudes higher than measured permeabilities on small samples in the laboratory using transient decay method. The measured permeabilities are in the range of 2.66·10−18 to 3.94·10−22 m2 (2695 to 0.39 nD) for the North Sea database and represent the end members for shales-permeabilities with the lowest values, since the small samples are selected with no or minor natural fractures. This work shows that by upscaling shale permeabilities from mm-scale to km scale, natural fractures and sedimentary heterogeneities will increase the shale permeabilities with a factor of two and that by including permeability correction controlled by the smectite fraction, pressure ramp can be simulated due to diagenesis effect in shales.publishedVersio

Discriminative stimulus properties of 1.25 mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors

The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug dis- crimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25 mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4- (1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl) piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 re- ceptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the dis- criminative stimulus properties of 1.25 mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus

Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

ABSTRACT Brexpiprazole piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT 1A ) and D 2/3 receptors, combined with potent antagonist effects on 5-HT 2A , a 1B -, and a 2C -adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED 50 = 6.0 mg/kg), apomorphine-or D-amphetamine-induced hyperactivity (ED 50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED 50 = 2.9) in rats at clinically relevant D 2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED 50 = 20) well above clinically relevant D 2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D 2 occupancies. In the NOR test

Bifeprunox and aripiprazole suppress in vivo VTA dopaminergic neuronal activity via D2 and not D3 dopamine autoreceptor activation

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Mitral valve analysis adding a virtual semi-transparent annulus plane for detection of prolapsing segments

Background We hypothesized that a novel three-dimensional virtual semi-transparent annulus plane (3D VSAP) presented on a holographic screen can be used to visualize the prolapsing tissue in degenerative mitral valve disease and furthermore, provide us with geometrical data of the mitral valve apparatus. Phantom and patient studies were designed to demonstrate the feasibility of creating a semi-automatic, semi-transparent mitral annulus plane visualized on a holographic display. Methods Ten pipe cleaners mimicking the mitral annulus with different shapes and three types of annuloplasty rings served as phantoms. We obtained 3D transoesophageal examination of the phantoms in a special designed box filled with water. Recordings were converted to the holographic display and a 3D VSAP was created. The ratio of the major and minor axes as well as the non-planar angles were calculated and compared with direct measures of the phantoms. Forty patients with degenerative mitral valve disease were then analyzed with 3D transthoracic echocardiography (TTE) and a 3D VSAP was created on the holographic display. A total of 240 segments were analyzed by two independent observers, one echo expert (observer I), and the other novice with limited echo experience (observer II). The two observers created the 3D VSAP in each patient before suggesting the valve pathology. Results The major/minor axes ratio and non-planar angles by 3D VSAP correlated with direct measurements by r = 0.65, p < 0.02 and r = 0.99, p < 0.0001, respectively. The sensitivity and specificity of the 3D VSAP method in patients was 81 and 97 %, respectively (observer I) and for observer II 77 and 96 %, respectively. The accuracy and precisions were 93.9 and 89.4 %, respectively (observer I), 92.3 and 85.1 % (observer II). Mitral valve analysis adding a 3D VSAP was feasible with high accuracy and precision, providing a quick and less subjective method for diagnosing mitral valve prolapse. This novel method may improve preoperative diagnostics and may relieve a better understanding of the pathophysiology of mitral valve disease. Thus, based on the specific findings in each patient, a tailored surgical repair can be planned and hopefully enhance long-term repair patency in the future

The antipsychotic drug brexpiprazole reverses phencyclidine-induced disruptions of thalamocortical networks

Brexpiprazole (BREX), a recently approved antipsychotic drug in the US and Canada, improves cognitive dysfunction in animal models, by still largely unknown mechanisms. BREX is a partial agonist at 5‐HT1A and D2 receptors and antagonist at α1B- and α2C-adrenergic and 5-HT2A receptors all with a similar potency. The NMDA receptor antagonist phencyclidine (PCP), used as pharmacological model of schizophrenia, activates thalamocortical networks and decreases low frequency oscillations (LFO; <4 Hz). These effects are reversed by antipsychotics. Here we assessed the ability of BREX to reverse PCP-induced hyperactivity of thalamocortical circuits, and the involvement of 5-HT1A receptors in its therapeutic action. BREX reversed PCP-induced neuronal activation at a lower dose in centromedial/mediodorsal thalamic nuclei (CM/MD; 0.5 mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2 mg/kg), perhaps due to antagonism at α1B-adrenoceptors, abundantly expressed in the thalamus. Conversely, a cumulative 0.5 mg/kg dose reversed a PCP-induced LFO decrease in mPFC but not in CM/MD. BREX reduced LFO in both areas, yet with a different dose-response, and moderately excited mPFC neurons. The latter effect was reversed by the 5-HT1A receptor antagonist WAY-100635. Thus, BREX partly antagonizes PCP-induced thalamocortical hyperactivity, differentially in mPFC versus CM/MD. This regional selectivity may be related to the differential expression of α1B-, α2C-adrenergic and 5-HT2A receptors in both regions and/or different neuronal types. Furthermore, the pro-cognitive properties of BREX may be related to the 5-HT1A receptor-mediated increase in mPFC pyramidal neuron activity. Overall, the present data provide new insight on the brain elements involved in BREX's therapeutic actions.Work supported by a contract Grant from Lundbeck and grants SAF2015-68346-P (MINECO, FEDER EU) and (PI1200156 and PI1600287) Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness), co-financed by ERDF (European Regional Development Fund), “A way to build Europe”. The contribution of the following funds is also acknowledged: 2014SGR 798 (Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya), CERCA Programme/Generalitat de Catalunya; Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM.Peer reviewe

Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown-a model of mania

RATIONALE: Bipolar disorder (BD) is a unique mood disorder defined by periods of depression and mania. The defining diagnosis of BD is the presence of mania/hypomania, with symptoms including hyperactivity and risk-taking. Since current treatments do not ameliorate cognitive deficits such as risky decision-making, and impulsivity that can negatively affect a patient's quality of life, better treatments are needed. OBJECTIVES: Here, we tested whether acute treatment with brexpiprazole, a serotonin-dopamine activity modulator with partial agonist activity at D2/3and 5-HT1Areceptors, would attenuate the BD mania-relevant behaviors of the dopamine transporter (DAT) knockdown mouse model of mania. METHODS: The effects of brexpiprazole on DAT knockdown and wild-type littermate mice were examined in the behavioral pattern monitor (BPM) and Iowa gambling task (IGT) to quantify activity/exploration and impulsivity/risk-taking behavior respectively. RESULTS: DAT knockdown mice exhibited hyper-exploratory behavior in the BPM and made fewer safe choices in the IGT. Brexpiprazole attenuated the mania-like hyper-exploratory phenotype and increased safe choices in risk-preferring DAT knockdown mice. Brexpiprazole also reduced safe choices in safe-preferring mice irrespective of genotype. Finally, brexpiprazole reduced premature (impulsive-like) responses in both groups of mice. CONCLUSIONS: Consistent with earlier reports, DAT knockdown mice exhibited hyper-exploratory, risk-preferring, and impulsive-like profiles consistent with patients with BD mania in these tasks. These behaviors were attenuated after brexpiprazole treatment. These data therefore indicate that brexpiprazole could be a novel treatment for BD mania and/or risk-taking/impulsivity disorders, since it remediates some relevant behavioral abnormalities in this mouse model