Pharmacological target sites for restoration of age-associated deficits in NMDA receptor-mediated norepinephrine release in brain

Aging affects virtually all organs of the body, but perhaps it has the most profound effects on the brain and its neurotransmitter systems, which influence a wide range of crucial functions, such as attention, focus, mood, neuroendocrine and autonomic functions, and sleep cycles. All of these essential functions, as well as fundamental cognitive processes such as memory, recall, and processing speed, utilize neuronal circuits that depend on neurotransmitter signaling between neurons. Glutamate (Glu), the main excitatory neurotransmitter in the CNS, is involved in most neuronal excitatory functions, including release of the neurotransmitter norepinephrine (NE). Previous studies from our lab demonstrated that the age-associated decline in Glu-stimulated NE release in rat cerebral cortex and hippocampus mediated by NMDA glutamate receptors, as well as deficits in dendritic spines, and cognitive functions are fully rescued by the CNS stimulant amphetamine. Here we further investigated Glu-stimulated NE release in the cerebral cortex to identify additional novel target sites for restoration of Glu-stimulated NE release. We found that blockade of alpha-2 adrenergic receptors fully restores Glu-stimulated NE release to the levels of young controls. In addition, we investigated the density and responsiveness of NMDA receptors as a potential underlying neuronal mechanism that could account for the observed age-associated decline in Glu-stimulated NE release. In the basal state of the receptor (no added glutamate and glycine) the density of NMDA receptors in the cortex from young and aged rats was similar. However, in contrast, in the presence of 10 μM added glutamate, which opens the receptor channel and increases the number of available [³H]-MK-801 binding sites within the channel, the density of [³H]-MK-801 binding sites was significantly less in the cortex from aged rats.