Evidence for involvement of nitric oxide and GABAB receptors in MK-801- stimulated release of glutamate in rat prefrontal cortex

Abstract

Systemic administration of NMDA receptor antagonists elevates extracellular glutamate within prefrontal cortex. The cognitive and behavioral effects of NMDA receptor blockade have direct relevance to symptoms of schizophrenia, and recent studies demonstrate an important role for nitric oxide and GABAB receptors in mediating the effects of NMDA receptor blockade on these behaviors. We sought to extend those observations by directly measuring the effects of nitric oxide and GABAB receptor mechanisms on MK-801-induced glutamate release in the prefrontal cortex. Systemic MK-801 injection (0.3 mg/kg) to male Sprague-Dawley rats significantly increased extracellular glutamate levels in prefrontal cortex, as determined by microdialysis. This effect was blocked by pretreatment with the nitric oxide synthase inhibitor L-NAME (60 mg/kg). Reverse dialysis of the nitric oxide donor SNAP (0.5 – 5 mM) directly into prefrontal cortex mimicked the effect of systemic MK-801, dose-dependently elevating cortical extracellular glutamate. The effect of MK-801 was also blocked by systemic treatment with the GABAB receptor agonist baclofen (5 mg/kg). In combination, these data suggest increased nitric oxide formation is necessary for NMDA antagonist-induced elevations of extracellular glutamate in the prefrontal cortex. Additionally, the data suggest GABAB receptor activation can modulate the NMDA antagonist-induced increase in cortical glutamate release.

Ketamine effects on anxiety and fear-related behaviors: current literature evidence and new findings

“…Under these circumstances, it is possible that the activation of AMPA receptors mediated by increased ketamine induced-glutamate neurotransmission would increase anxiety, an effect that would counteract the possible anxiolytic-like effect of ketamine mediated by blocking the NMDA receptors. On the other hand, MK-801 increased extracellular glutamate levels in the prefrontal cortex only at high doses (0.3-0.6 mg/kg) (Roenker et al, 2012;Zuo et al, 2006). Consequently, a very low dose of MK-801 like the one used in our study (0.05 mg/kg) probably did not increase glutamate levels, which resulted in an anxiolytic-like effect mediated by the exclusive NMDA receptors blockade.…”

Positive Allosteric Modulation of GABAB Receptors Ameliorates Sensorimotor Gating in Rodent Models

“…It has been reported that MK‐801 and PCP stimulate cortical glutamate release in PFC and hippocampus . In this scenario, rac‐BHFF could counteract the disinhibition of neuronal activity produced by exaggerated NMDAR stimulation in these areas or, alternatively, modulate distinct forebrain pathways under the control of non‐NMDA glutamatergic receptors, such as AMPA and kainate .…”

Synthesis, radiolabeling and evaluation of novel amine guanidine derivatives as potential positron emission tomography tracers for the ion channel of the N-methyl-d-aspartate receptor

“…One explanation could be that there is release of glutamate from the brain after MK-801 administration [44,45]. Since the uptake of 'use-dependent' antagonists is thought to be related to the amount of glutamate in the brain [46], it could be that injection of MK-801 increased the release of glutamate, opening more NMDAR ion channels, and resulting in higher uptake of [ 11 C]21, [ 11 C]23 and [ 18 F]26 than at baseline.…”