Effects of Behavioral Depression and Chronic Influence of Antidepressants on NMDA/Glutamate Receptor-Mediated Responses of Neurons of the Rat Gyrus Dentatus

Abstract

In studies on superfused slices obtained from the rat hippocampus, we extracellularly recorded field EPSP (fEPSPs), pharmacologically isolated components of these fEPSP, which were related to activation of synaptic NMDA-glutamate receptors, and neuronal responses of the dentate gyrus, which were mediated by activation of extrasynaptic NMDA-glutamate receptors. Recordings were performed in junctions formed by fibers of the medial perforant pathway and dendrites of granular cells of the gyrus dentatus. In the course of the development of behavioral depression in rats, which was caused by zoosocial isolation or chronic injection of dexamethasone, the amplitude of fEPSPs decreased, on average, by 19.8 and 26.0%, respectively, while the NMDA components of fEPSP increased by 28.6 and 33.4%; the rise in the amplitude of neuronal responses recorded in the gyrus dentatus, which were mediated by the activation of extrasynaptic NMDA receptors (by 75.4 and 92.3%), was clearly expressed. In intact rats, chronic (over 14 days) injections of tricyclic antidepressants, imipramine and amitriptyline, as well as of an atypical antidepressant, maprotiline, resulted in an increase in the fEPSP amplitude by 22.1 to 25.9%. At the same time, the amplitude of NMDA components of fEPSP dropped by 27.0 to 29.1%, while the amplitude of responses mediated by the activation of extrasynaptic NMDA-glutamate receptors decreased by 46.1 to 49.8%. Changes in the neuronal responses in the gyrus dentatus, which were mediated by the activation of NMDA-glutamate receptors, are related to an increase or decrease in the number of such receptors. It is supposed that an increase in the total number of NMDA-glutamate receptors under conditions of behavioral depression results in a deterioration of the energy supply of cerebral neurons, while an increase in the extrasynaptic pool of NMDA-glutamate receptors leads to suppression of biosynthesis of neurotrophins and to injury of neurons. As a general result, informational processes in the brain are subjected to significant negative influences. Chronic injections of antidepressants promote a permanent rise in the concentration of noradrenaline and serotonin in extracellular environments and the activation of monoamine receptors positively conjugated with adenylate cyclase; suppression of expression of informational RNAs, which encode subunits of NMDA-glutamate receptors, and a decrease in the number of these receptors. These events improve the functional state of neurons.

Effects of Chronic Introduction of Antidepressants on NMDA-Induced Damage to Neurons of the Rat Hippocampus and Cerebral Cortex

“…We believe that, similarly to blockers of neuronal NMDA receptors, antidepressants somehow decrease the functional activity of this receptor population. In studies carried out earlier in our laboratory, it was found that under conditions of chronic injections of tricyclic antidepressants (imipramine and maprotiline) into rats, the amplitudes of responses of neurons localized in the dentate gyrus and induced by activation of both synaptic and (especially) extrasynaptic NMDA receptors decreased [37]. Since chronic injections of antidepressants were accompanied by intensification of the expression of neurotrophins and growth factors, we believe that the latter decrease the number of neuronal NMDA receptors.…”

Early Anoxic Damage to the Hippocampus and Its Modifications Resulting From Chronic Influences of Antidepressants

“…To prevent initiation of seizure activity, the CA3 area was eliminated from each hippocampal slice. After this procedure, slices were transferred to an incubation chamber, where they were superfused with a solution of the following composition (mM): NaCl, 124; NaHCO 3 , 26; KCl, 3; KH 2 PO 4 , 1.25; CaCl 2 , 2; MgSO 4 , 1, and glucose, 10. The solution in the incubation chamber (volume 2 ml) was continuously aerated with carbogen; the flow rate through the chamber, temperature, and pH of the solution (saturated with carbogen) were 2 ml/min, 25°C, and 7.3, respectively.…”

“…This effect is determined by suppression of the production of mRNA of subunits of these receptors in a few structures of the brain and is reflected in a drop in the amplitude of NMDA EPSP components in neurons of the gyrus dentatus. Manifestations of analgesic activity of antidepressants in the case of neuropathic pains and moderation of the impairment of neurons in the hippocampus and striatum [10][11][12] are also considered to be related to the above-described complex of events.…”

Mechanisms of Neuroprotective Action of Imipramine against Dexamethasone Neurotoxicity

“…It was also found that chronic administration of antidepressant drug impairs the function of neuronal NMDA receptors. This is manifested by the inhibition of mRNA NMDA subunit receptors formation in the hippocampus and decreasing of the amplitude of NMDAcomponents of EPSP of dentate gyrus neurons [19,20]. Therefore chronic administration of imipramine may reduce glutamatergic component glucocorticoid neurotoxicity.…”