Targeting Alpha-2 Adrenergic Receptors for Restoration of Age-Associated Decline in Norepinephrine Release, Long-Term Potentiation and Cognitive Performance

Abstract ID 100341 Poster Board 133 Maintaining optimal levels of catecholamine neurotransmission in the brain is important for regulating arousal/attention, mental focusing, cognition, and affect. Previously, we demonstrated that age-related decreases in NMDA-mediated glutamate (Glu)-stimulated [³H]-norepinephrine (NE) release in the cerebral cortex and hippocampus can be rescued by blocking the alpha-2 receptors in aged Fischer-344 rats. Specifically, blockade of these receptors with phentolamine, an alpha-1 and alpha-2 adrenergic receptor blocker, or idazoxan, a selective alpha-2 receptor adrenergic blocker, markedly increases Glu-stimulated NE release in cortical and hippocampal brain slices. Mirtazapine, an antidepressant drug thought to act by blocking presynaptic alpha-2 adrenergic receptors, thus potentiated Glu-stimulated NE release in the cerebral cortex and hippocampus in aged rats. To determine whether the Glu-stimulated NE release pathway plays a role in cognitive decline during aging, we investigated the effect of mirtazapine on memory performance and the induction & maintenance of long-term potentiation (LTP). In aged rats chronically treated with mirtazapine for 2 weeks (10 mg/kg via drinking water) there were significant improvements in memory performance as measured by Novel Object Recognition and Y-maze tasks which assess recognition and spatial memory, respectively. Hippocampal slices from treated animals were also tested for the induction and maintenance of LTP in synapses between Schaffer collaterals and CA1 pyramidal neurons. Preliminary results indicate that treatment with mirtazapine produced larger evoked responses in the local field potentials in the CA1 region, suggesting that blockade of alpha-2 receptors significantly strengthened the synaptic efficacy. Taken together, our results suggest that blockade of alpha-2 adrenergic receptors is a promising target for restoring age-related declines in cognition and memory. Further comparisons of young and aged rats in hippocampus slices LTP induction and maintainers are ongoing and will be reported.