NMDA‐induced glutamate and aspartate release from rat cortical pyramidal neurones: evidence for modulation by a 5‐HT_1A antagonist

Abstract

1 We have investigated an aspect of the regulation of cortical pyramidal neurone activity. Microdialysis was used to assess whether topical application of drugs (in 10 M1) to fill a burr hole over the frontal cortex, where part of the corticostriatal pathway originates, would change concentrations of the excitatory amino acids glutamate and aspartate in the striatum of the anaesthetized rat. 2 Topical application of N-methyl-D-aspartate (NMDA, 2 and 20 mM) dose-dependently increased glutamate and aspartate concentrations in the striatum. Coapplication of tetrodotoxin (10 ,uM) blocked the NMDA-evoked rise in these amino acids. A calcium-free medium, perfused through the probe also blocked the rise, indicating that it was due to an exocytotic mechanism in the striatum. 3 It was hypothesized that the rise observed was due to an increase in the activity of the corticostriatal pathway. As 5-hydroxytryptaminelA (5-HTIA) receptors are enriched on cell bodies of corticostriatal neurones, a selective 5-HTIA-antagonist (WAY 100135)

Dissociable Roles for the Dorsal and Median Raphé in the Facilitatory Effect of 5-HT1A Receptor Stimulation upon Cocaine-Induced Locomotion and Sensitization

“…While the source of elevated glutamate was not identified in the present study, serotonergic projections from the DRN innervate densely the cortical and allocortical regions supplying glutamate to the accumbens, including the prefrontal cortex, hippocampus, thalamus, and amygdala (eg Vertes, 1991). Indeed, in vivo microdialysis and electrophysiological studies indicate that activation of several different subtypes of 5-HT heteroreceptors in these glutamatergic nuclei can inhibit excitatory neurotransmission (eg Dijk et al, 1995;Cheng et al, 1998;Dawson et al, 2001;Golembiowska and Dziubina, 2002;Hajos et al, 2003), a finding consistent with the observed facilitation of cocaine-induced glutamate release upon DRN inactivation.…”

Vicious Cycle Involving Na+Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation

“…First, it is responsible for further glutamate release, because NMDA receptor blockade reduced the concentration of glutamate in the medium in the period preceding the usual onset of neuronal cell death by 75%. The relevance of this finding is likely to extend to the intact brain because, in rat striatum in vivo, NMDA receptor activation has been shown to evoke delayed glutamate release (Dijk et al, 1995) and ischemiainduced glutamate release is inhibited by NMDA antagonists (Ghribi et al, 1994). Second, NMDA receptor activity represents the dominant mechanism by which NO is generated in the pathological setting, even though several alternative pathways, in principle, could be operative, including non-NMDA receptor activation and nonspecific cellular depolarization (Garthwaite and Garthwaite, 1987;Southam et al, 1991).…”

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

“…At the same time, 5-HT is able to counteract a number of effects mediated by NMDA receptors: for example, NMDA-induced stimulation of 5-HT release from fibers originating in raphe nuclei is inhibited by 5-HT autoreceptors belonging to the 5-HT 1 family [51]. Activation of NMDA receptors in frontal cortex by microdialysis stimulates the release of glutamate in the striatum while reducing local glutamate release, and such effects are inhibited respectively by 5-HT 1A and 5-HT 2A receptors [26,41]. NMDA-mediated NO-synthase activation and cGMP formation in cultured cortical neurons is inhibited by 5-HT 2 receptor agonists [60]; the same effect was observed in cortical slices after application of the 5HT 1B-D agonists sumatriptan and zolmitriptan [172].…”