Repeated administration of imipramine attenuates glutamatergic transmission in rat frontal cortex.
ABSTRACT The effects of repeated administration of a tricyclic antidepressant, imipramine, lasting 14 days (10 mg/kg p.o., twice daily), were studied ex vivo in rat frontal cortex slices prepared 48 h after last dose of the drug. In slices prepared from imipramine-treated animals the mean frequency, and to a lesser degree the mean amplitude, of spontaneous excitatory postsynaptic currents recorded from layer II/III pyramidal neurons, were decreased. These effects were accompanied by a reduction of the initial slope ratio of pharmacologically isolated N-methyl-D-aspartate to AMPA/kainate receptor-mediated stimulation-evoked excitatory postsynaptic currents. Imipramine treatment also resulted in a decrease of extracellular field potentials evoked in layer II/III by stimulation of underlying sites in layer V. These results indicate that chronic treatment with imipramine results in an attenuation of the release of glutamate and an alteration in the postsynaptic reactivity of ionotropic glutamate receptors in rat cerebral cortex.
Article: Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders.[show abstract] [hide abstract]
ABSTRACT: Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way 'involved' in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways. This article is part of a Special Issue entitled 'Anxiety and Depression'.Neuropharmacology 08/2011; 62(1):63-77. · 4.81 Impact Factor
Article: Protection of SH-SY5Y neuronal cells from glutamate-induced apoptosis by 3,6'-disinapoyl sucrose, a bioactive compound isolated from Radix Polygala.[show abstract] [hide abstract]
ABSTRACT: The neuroprotective effects of 3,6'-disinapoyl sucrose (DISS) from Radix Polygala against glutamate-induced SH-SY5Y neuronal cells injury were evaluated in the present study. SH-SY5Y neuronal cells were pretreated with glutamate (8 mM) for 30 min followed by cotreatment with DISS for 12 h. Cell viability was determined by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide (MTT) assay, and apoptosis was confirmed by cell morphology and flow cytometry assay, evaluated with propidium iodide dye. Treatment with DISS (0.6, 6, and 60 μmol/L) increased cell viability dose dependently, inhibited LDH release, and attenuated apoptosis. The mechanisms by which DISS protected neuron cells from glutamate-induced excitotoxicity included the downregulation of proapoptotic gene Bax and the upregulation of antiapoptotic gene Bcl-2. The present findings indicated that DISS exerts neuroprotective effects against glutamate toxicity, which might be of importance and contribute to its clinical efficacy for the treatment of neurodegenerative diseases.Journal of Biomedicine and Biotechnology 01/2012; 2012:1-5. · 2.44 Impact Factor
Chapter: Metabotropic Approaches to Anxiety[show abstract] [hide abstract]
ABSTRACT: Current therapies for anxiety disorders neither fully serve the efficacy needs of patients nor are they free of adverse effects. Both preclinical and clinical findings have implicated the excitatory amino acid glutamate in the pathogenesis of anxiety disorders. While a number of review papers were published in recent years describing the anxiolytic effect of mGlu receptor ligands, in this short review we try to explain the mechanisms responsible for the antianxiety actions of specific mGlu receptors ligands, which have been reported to be potent anxiolytics. As the amygdala is the structure integrating the behaviors connected with fear and anxiety, the schema of amygdalar nuclei is shown together with the placement of mGu receptors in that structure. Furthermore, the anxiolytic effect of different mGlu receptor ligands in the context of their activity within specific amygdalar nuclei is proposed. The interactions between the anxiolytic effects of mGlu receptor ligands and other neurotransmitters involved in anxiety, particularly GABA and serotonin, will also be discussed, and the neuronal networks involved will be described in order to discuss the mechanism of the proposed anxiolytic effects.09/2010: pages 157-173;