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1.
Neuropharmacology ; 72: 187-96, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23643748

ABSTRACT

Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 h following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin.


Subject(s)
Child Development Disorders, Pervasive/complications , Oxytocin/therapeutic use , Social Behavior Disorders/drug therapy , Stereotyped Behavior/drug effects , Analysis of Variance , Animals , Child Development Disorders, Pervasive/drug therapy , Choice Behavior/drug effects , Cohort Studies , Disease Models, Animal , Exploratory Behavior/drug effects , Female , Impulsive Behavior/drug therapy , Impulsive Behavior/etiology , Male , Mice , Mice, Inbred BALB C , Sex Factors , Social Behavior , Social Behavior Disorders/etiology , Species Specificity , Time Factors
2.
Bioconjug Chem ; 24(2): 215-23, 2013 Feb 20.
Article in English | MEDLINE | ID: mdl-23297747

ABSTRACT

Fluorescent biosensors based on environmentally sensitive dyes enable visualization and quantification of endogenous protein activation within living cells. Merocyanine dyes are especially useful for live cell imaging applications, as they are extraordinarily bright, have long wavelengths of excitation and emission, and can exhibit readily detectable fluorescence changes in response to environment. We sought to systematically examine the effects of structural features on key photophysical properties, including dye brightness, environmental responsiveness, and photostability, through the synthesis of a library of 25 merocyanine dyes, derived from combinatorial reaction of 5 donor and 5 acceptor heterocycles. Four of these dyes showed optimal properties for specific imaging applications and were subsequently prepared with reactive side chains and enhanced aqueous solubility using a one-pot synthetic method. The new dyes were then applied within a biosensor design for Cdc42 activation, where dye mero60 showed a remarkable 1470% increase in fluorescence intensity on binding activated Cdc42 in vitro. The dye-based biosensors were used to report activation of endogenous Cdc42 in living cells.


Subject(s)
Fluorescent Dyes/analysis , Fluorescent Dyes/metabolism , Pyrimidinones/analysis , Pyrimidinones/metabolism , cdc42 GTP-Binding Protein/analysis , cdc42 GTP-Binding Protein/metabolism , Animals , Biosensing Techniques/methods , Cell Survival , Enzyme Activation , Fluorescent Dyes/chemistry , Mice , Models, Molecular , NIH 3T3 Cells , Photobleaching , Protein Binding , Pyrimidinones/chemistry
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