ABSTRACT
To explore pathophysiology of schizophrenia, this study analyzed the regulation mechanisms that are associated with cystine/glutamate antiporter (Sxc), group-II (II-mGluR), and group-III (III-mGluR) metabotropic glutamate-receptors in thalamo-cortical glutamatergic transmission of MK801-induced model using dual-probe microdialysis. L-glutamate release in medial pre-frontal cortex (mPFC) was increased by systemic- and local mediodorsal thalamic nucleus (MDTN) administrations of MK801, but was unaffected by local administration into mPFC. Perfusion into mPFC of activators of Sxc, II-mGluR, and III-mGluR, and into the MDTN of activators of Sxc, II-mGluR, and GABAA receptor inhibited MK801-evoked L-glutamate release in mPFC. Perfusion of aripiprazole (APZ) into MDTN and mPFC also inhibited systemic MK801-evoked L-glutamate release in mPFC. Inhibition of II-mGluR in mPFC and MDTN blocked inhibitory effects of Sxc-activator and APZ on MK801-evoked L-glutamate release; however, their inhibitory effects were blocked by the inhibition of III-mGluR in mPFC but not in MDTN. These results indicate that reduced activation of the glutamate/NMDA receptor (NMDAR) in MDTN enhanced L-glutamate release in mPFC possibly through GABAergic disinhibition in MDTN. Furthermore, MDTN-mPFC glutamatergic transmission receives inhibitory regulation of Sxc/II-mGluR/III-mGluR functional complex in mPFC and Sxc/II-mGluR complex in MDTN. Established antipsychotic, APZ inhibits MK801-evoked L-glutamate release through the activation of Sxc/mGluRs functional complexes in both MDTN and mPFC.
Subject(s)
Antiporters/metabolism , Aripiprazole/pharmacology , Dizocilpine Maleate/pharmacology , Glutamic Acid/metabolism , N-Methylaspartate/antagonists & inhibitors , Prefrontal Cortex/physiopathology , Synaptic Transmission/drug effects , Thalamus/physiopathology , Acetylcysteine/pharmacology , Animals , Aripiprazole/administration & dosage , Dizocilpine Maleate/administration & dosage , Male , Models, Biological , Perfusion , Prefrontal Cortex/drug effects , Rats, Sprague-Dawley , Receptors, GABA-A/metabolism , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Receptors, Metabotropic Glutamate/metabolism , Thalamus/drug effectsABSTRACT
The aim of this study was to design a novel carrier for enhancing the bioavailability of the poorly water-soluble drug, aripiprazole (ARP). Silicosan, the applied carrier, was obtained by chemical interaction between tetraethyl orthosilicate (TEOS) and chitosan HCl. Different ARP-loaded silicosan particles were successfully prepared in absence and presence of one of the following surfactants; Tween 80, Poloxamer 407 and cetyltrimethylammonium bromide (CTAB). The prepared ARP-loaded silicosan particles were thoroughly investigated for their structures using FTIR, XRD, and DSC analysis as well as their particle size, zeta potential, flowability, drug content, and in vitro drug release efficiencies. The prepared ARP-loaded silicosan particles were characterized by amorphous structure, high drug entrapment efficiency and a remarkable improvement in the release of aripiprazole in simulated gastric fluid. SEM and EDX revealed that the morphology and silica atom content in the prepared ARP-loaded silicosan particles were affected by the used surfactant in their formulations. The selected ARP-loaded silicosan particles were subjected to in vivo study using rabbits. The obtained pharmacokinetic results showed that the relative bioavailability for orally administered ARP-loaded silicosan particles (SC-2-CTAB) was 66% higher relative to the oral suspension (AUC0-10h was 16.38 ± 3.21 and 27.23 ± 2.35 ng.h/mL for drug powder and SC-2-CTAB formulation, respectively). The obtained results suggested the unique-structured silicosan particles to be used as successful vehicle for ARP.
Subject(s)
Aripiprazole/chemical synthesis , Aripiprazole/metabolism , Particle Size , Silicon Dioxide/chemical synthesis , Silicon Dioxide/metabolism , Administration, Oral , Animals , Antidepressive Agents/administration & dosage , Antidepressive Agents/chemical synthesis , Antidepressive Agents/metabolism , Aripiprazole/administration & dosage , Biological Availability , Cross-Over Studies , Drug Evaluation, Preclinical/methods , Drug Liberation/physiology , Male , Rabbits , Silicon Dioxide/administration & dosage , Spectroscopy, Fourier Transform Infrared/methods , Surface-Active Agents/chemistry , X-Ray Diffraction/methodsABSTRACT
The present study was designed to evaluate the combined effect of lithium and aripiprazole supplemented with omega-3 fatty acids in methylphenidate (MPD)-induced manic mice. Swiss albino mice were administered with MPD or saline for 14 days, and based on changes in behavioral activities animals were treated with lithium, aripiprazole, and omega-3 fatty acids from the 8th day. Behavioral patterns were analyzed by video tracking. Thyroxine, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were assayed in serum using ELISA kits. The levels of neurotransmitters in the whole brain were analyzed spectrofluorometrically. Glycogen synthase kinase 3ß (GSK3ß) mice brain mRNA expression levels and phosphorylated Akt (pAkt) protein levels were measured using RT-PCR and western blot, respectively. Results indicated that the administration of MPD alters the behavioral activity, thyroid hormones, FSH, LH, and testosterone levels. Lithium, aripiprazole, and omega-3 fatty acids alone significantly reduced MPD-induced behavior, hormonal, and neurotransmitter abnormalities. However, GSK3ß and pAkt in the brain showed no significant differences in the level of expression. These results reveal that the combination of lithium and aripiprazole supplemented with omega-3 fatty acids provide protective effects against MPD-induced neuroendocrine system and multiple neurochemical abnormalities.
Subject(s)
Antipsychotic Agents/administration & dosage , Aripiprazole/administration & dosage , Bipolar Disorder/drug therapy , Fatty Acids, Omega-3/administration & dosage , Lithium Compounds/administration & dosage , Animals , Bipolar Disorder/metabolism , Brain/drug effects , Brain/metabolism , Disease Models, Animal , Drug Therapy, Combination , Glycogen Synthase Kinase 3 beta/genetics , Hormones/blood , Male , Mice , Neurotransmitter Agents/metabolism , Proto-Oncogene Proteins c-akt/genetics , RNA, Messenger/metabolismSubject(s)
Antipsychotic Agents/pharmacology , Aripiprazole/pharmacology , Bipolar Disorder/drug therapy , Obsessive-Compulsive Disorder/drug therapy , Antipsychotic Agents/administration & dosage , Aripiprazole/administration & dosage , Bipolar Disorder/chemically induced , Child , Female , Humans , Obsessive-Compulsive Disorder/chemically induced , Plant Preparations/adverse effects , Vitiligo/drug therapySubject(s)
Antipsychotic Agents/pharmacology , Aripiprazole/pharmacology , Asperger Syndrome/therapy , Eye Movement Desensitization Reprocessing/methods , Mutism/therapy , Stress Disorders, Post-Traumatic/therapy , Antipsychotic Agents/administration & dosage , Aripiprazole/administration & dosage , Asperger Syndrome/epidemiology , Child , Combined Modality Therapy , Comorbidity , Humans , Male , Mutism/epidemiology , Stress Disorders, Post-Traumatic/epidemiologyABSTRACT
The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a central role in folate metabolism. Many studies have demonstrated an association between MTHFR C677 T variant with depression, schizophrenia and bipolar disorder as one of them being comorbid to other. This has justified the use of folate supplement in psychiatric disorders mainly depression but still not in various other comorbid complex psychiatric disorders. Here we have tried to show how the l-methylfolate in conjunction with the conventional psychotropic drugs can be useful in a state of such complex psychiatric phenomenon and comorbid diagnosis with genetic polymorphism of MTHFR C677 T mutation.