Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity

• Published in: Molecular pharmacology 2011-10, Vol.80 (4), p.747-758
• Main Authors: Doze, Van A, Papay, Robert S, Goldenstein, Brianna L, Gupta, Manveen K, Collette, Katie M, Nelson, Brian W, Lyons, Mariaha J, Davis, Bethany A, Luger, Elizabeth J, Wood, Sarah G, Haselton, James R, Simpson, Paul C, Perez, Dianne M
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-1 Receptor Agonists - pharmacology; Affect - drug effects; Affect - physiology; Animals; Cognition - drug effects; Cognition - physiology; Female; Hippocampus - drug effects; Hippocampus - metabolism; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Longevity - drug effects; Longevity - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Transgenic; Neuronal Plasticity - drug effects; Neuronal Plasticity - physiology; Organ Culture Techniques; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Adrenergic, alpha-1 - physiology; Synapses - drug effects; Synapses - physiology
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.111.073734

The role of α(1)-adrenergic receptors (α(1)ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. α(1A)AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term α(1A)AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the α(1A)AR. CAM-α(1A)AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the α(1A)AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-α(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 α(1A)AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-α(1A)AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-α(1A)AR mice was 10% longer than that of WT mice. Our results suggest that long-term α(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.