ABSTRACT
The modulation of genes implicated in synaptic plasticity following administration of antipsychotic drugs has been instrumental in understanding their possible mode of action. Arc (Arg 3.1) is one such gene closely associated with changes in synaptic plasticity. In this study we have investigated the changes in expression of Arc protein following acute and chronic administration of a typical antipsychotic (haloperidol) and an atypical antipsychotic (clozapine) by means of immunohistochemistry compared to the prototypic gene marker c-Fos. In dorsal striatum haloperidol (1 mg/kg) significantly increased Arc expression following both acute and chronic (21 day) administration with evidence of modulation in induction after repeated dosing. No significant changes were observed following either acute or chronic administration of clozapine (20 mg/kg). In the nucleus accumbens shell both clozapine and haloperidol induced Arc expression following acute administration, again with evidence of modulation after chronic dosing. The pattern of induction of Arc expression following haloperidol and clozapine in both dorsal and ventral striatum was similar to that for c-Fos. In medial prefrontal and cingulate cortex, Arc expression was significantly decreased by clozapine but not haloperidol without any indication of modulation following chronic dosing, whereas no significant changes in c-Fos expression were observed with either drug. Since synaptic modulation mediated by Arc is associated with down-regulation of the AMPA glutamate receptor, this study suggests a mechanism whereby enhanced glutamate receptor efficacy in medial cortical areas may be a component of antipsychotic drug action.
Subject(s)
Brain/drug effects , Brain/metabolism , Clozapine/pharmacology , Cytoskeletal Proteins/biosynthesis , Gene Expression Regulation/drug effects , Haloperidol/pharmacology , Nerve Tissue Proteins/biosynthesis , Proto-Oncogene Proteins c-fos/biosynthesis , Animals , Antipsychotic Agents/pharmacology , Clozapine/administration & dosage , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Gyrus Cinguli/drug effects , Gyrus Cinguli/metabolism , Haloperidol/administration & dosage , Male , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Rats , Septum of Brain/drug effects , Septum of Brain/metabolism , Time FactorsABSTRACT
The development of diagnostic assays using highly targeted specific aptamers with existing detection platforms has been an endeavor with few opportunities until now. Many current commercially available diagnostic platforms make use of detection systems employing capture agents composed of modified antigen-specific antibodies coupled with a variety of detection modalities, including radioimmunoassays, fluorescence-based detection assays, electro/chemiluminescence assays, and immunoradiometric assays. In the studies presented here, a novel frequency-modulating technology from BioScale called Acoustic Membrane MicroParticle (AMMP) detection was used to demonstrate a sensitive and reproducible method of incorporating aptamers as capture and detection agents. The method provides a robust and rapid detection of thrombin in human serum while also eliminating the labor-intensive efforts of Western blot analysis and is not affected by the interfering substances found in serum that often affect optical-based detection systems. In addition, we have demonstrated, for the first time, the adaptation of the AMMP platform to exploit aptamers against a clinically relevant target. The AMMP platform is an ideal medium for using aptamers in commercial assay development for application in a clinical setting.
Subject(s)
Aptamers, Nucleotide/chemistry , Immunosorbents/chemistry , Serum/chemistry , Thrombin/analysis , Acoustics , Base Sequence , Biosensing Techniques , Humans , Molecular Sequence Data , Reproducibility of Results , SELEX Aptamer Technique , Sensitivity and Specificity , VibrationABSTRACT
Recent studies have demonstrated a similar acute effect of 3,4- methylenedioxymethamphetamine (MDMA) in blood platelets and brain tissue via action on the serotonin transporter. To investigate the validity of blood serotonin as a peripheral marker for central serotonin in this regard, we administered MDMA (20 mg/kg i.p.) to rats and observed a parallel decrease in serotonin levels in the frontal cortex and blood at 2 h (63% and 46% respectively) with some recovery evident at 8 h (42% and 38%) and more so at 18 h (19% and 24% below control levels). Administration of a tryptophan supplement (82.5 mg/kg p.o.) to naïve rats produced parallel increases in serotonin levels 2 h later in the frontal cortex (39%) and blood (26%). Following MDMA administration, the same dose of tryptophan caused a smaller (26%) rise in brain serotonin whereas in blood it had no effect. We conclude that blood serotonin is a useful marker for brain serotonin levels in the rat following acute administration of MDMA and this finding highlights the possible use of platelet serotonin as a marker for brain serotonin in human studies involving MDMA.
