Reproducibility via coordinated standardization: a multi-center study in a Shank2 genetic rat model for Autism Spectrum Disorders.

Inconsistent findings between laboratories are hampering scientific progress and are of increasing public concern. Differences in laboratory environment is a known factor contributing to poor reproducibility of findings between research sites, and well-controlled multisite efforts are an important next step to identify the relevant factors needed to reduce variation in study outcome between laboratories. Through harmonization of apparatus, test protocol, and aligned and non-aligned environmental variables, the present study shows that behavioral pharmacological responses in Shank2 knockout (KO) rats, a model of synaptic dysfunction relevant to autism spectrum disorders, were highly replicable across three research centers.

Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism.

Mutations in the family of genes have been consistently identified in genetic and genomic screens of autism spectrum disorder (ASD). The functional overlap of with several other ASD-associated genes suggests synaptic dysfunction as a convergent mechanism of pathophysiology in ASD. Although many ASD-related mutations result in alterations to synaptic function, the nature of those dysfunctions and the consequential behavioral manifestations are highly variable when expressed in genetic mouse models.

The location discrimination reversal task in mice is sensitive to deficits in performance caused by aging, pharmacological and other challenges.

Deficits in hippocampal-mediated pattern separation are one aspect of cognitive function affected in schizophrenia (SZ) or Alzheimer's disease (AD). To develop novel therapies, it is beneficial to explore this specific aspect of cognition preclinically. The location discrimination reversal (LDR) task is a hippocampal-dependent operant paradigm that evaluates spatial learning and cognitive flexibility using touchscreens.

Novel triazines as potent and selective phosphodiesterase 10A inhibitors.

The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket.

5-Cyclic amine-3-arylsulfonylindazoles as novel 5-HT6 receptor antagonists.

Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.

WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one]: a novel dopamine D2 receptor partial agonist/serotonin reuptake inhibitor with preclinical antipsychotic-like and antidepressant-like activity.

The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D(2) receptor (D(2L) K(i), 4.0 nM) and serotonin transporter (K(i), 7.

Tetrahydrocarbazole-based serotonin reuptake inhibitor/dopamine D2 partial agonists for the potential treatment of schizophrenia.

A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.

Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia.

Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats.

Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist.

The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field.

WAY-163909, a 5-HT2C agonist, enhances the preclinical potency of current antipsychotics.

Introduction: 5-HT(2C) agonists, by decreasing mesolimbic dopamine without affecting nigrostriatal dopamine, are predicted to have antipsychotic efficacy with low extrapyramidal side effects (EPS). Combining 5-HT(2C) agonists with low doses of existing antipsychotics could increase treatment efficacy while reducing treatment liabilities such as EPS (typical antipsychotics), and the propensity for weight gain (atypical antipsychotics).

Objectives: The objectives of these studies were to combine WAY-163909, a selective 5-HT(2C) agonist, with either the typical antipsychotic haloperidol, or the atypical antipsychotic clozapine, at doses that were ineffective on their own, with the expectation that a shift in potency in several rodent behavior models predictive of antipsychotic activity would occur.

ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities.

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.

The 5-HT(2C) receptor agonist WAY-163909 decreases impulsivity in the 5-choice serial reaction time test.

Increased impulsivity is observed across a number of neuropsychiatric and neurodegenerative diseases. Preclinical evidence has demonstrated that antagonism of the serotonin 5-HT(2C) receptor may act to increase impulsivity, leading to the hypothesis that an agonist may exert reciprocal effects and attenuate impulsive behavior. The 5-HT(2C) agonist, WAY-163909, was evaluated in the present paper using a variable stimulus duration and inter-trial interval manipulation in the 5-choice serial reaction time test designed to increase impulsivity and decrease attention.

Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test.

Deficits in attention and response inhibition are apparent across several neurodegenerative and neuropsychiatric disorders for which current pharmacotherapy is inadequate. The 5-choice serial reaction time test (5-CSRTT), which originated from the continuous performance test (CPT) in humans, may serve as a useful translational assay for efficacy in these key behavioral domains. The selective norepinepherine reuptake inhibitor, atomoxetine, represents the first non-stimulant based drug approved for Attention Deficit Hyperactivity Disorder (ADHD) and has replaced methylphenidate (Ritalin) as the first line in pharmacotherapy for the treatment of ADHD.