Regional binding of [3H]-MK801 to NMDA receptors in young and aged rat brain membranes

Norepinephrine (NE) and dopamine (DA) are essential neuromodulators in the central nervous system. They regulate several crucial physiological processes, including arousal/attention, focus, neuroendocrine functions, and the sleep-wake cycle; they also play complex roles in regulating cognition and affect; therefore, dysfunctions in catecholaminergic neurotransmission are associated with various neurological consequences. Previously, we confirmed that in brain slices from aged Fischer 344 rats, there is an age-related decrease in glutamate-stimulated NE release in the cerebral cortex and hippocampus (Gonzales et al., 1991 & Dezfuli et al., 2019) and a regionally specific decline in glutamate-stimulated DA release, with a deficit in the striatum but not in the olfactory tubercle (Aljohani et al., 2021a). Importantly, our studies demonstrated that NMDA receptors mediate glutamate-stimulated NE and DA release. We also have shown that the alpha-2 adrenergic receptors agonist clonidine decreases this glutamate-stimulated NE release in a concentration-dependent manner; while in contrast, blockade of these receptors with phentolamine, an alpha-1 and alpha-2 adrenergic receptor blocker, or with idazoxan, a selective alpha-2 receptor blocker, markedly potentiates glutamate-stimulated NE release in cortical brain slices (Aljohani et al., 2021b). Since aging has heterogeneous effects on NMDA receptors in different brain areas, we have now begun to examine [3 H]-MK801 binding to NMDA receptors to compare changes in receptor density and responsiveness during aging in the cortex, hippocampus, striatum, and olfactory tubercle, as a possible mechanistic explanation for the changes in NE and DA release. The data from cortical membrane preparations suggest that young and old rats have similar NMDA receptor densities but may differ in their response to stimulation with glutamate/glycine. © FASEB.