Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity

The role of alpha(1)-adrenergic receptors (alpha(1)ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. alpha(1A)AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term alpha(1A)AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the alpha(1A)AR. CAM-alpha(1A)AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the alpha(1A)AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-alpha(1A)AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the alpha(1A)AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-alpha(1A)AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-alpha(1A)AR mice was 10% longer than that of WT mice. Our results suggest that long-term alpha(1A)AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.