Abstract
The role of α1-adrenergic receptors (α1ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. α1AAR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term α1AAR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the α1AAR. CAM-α1AAR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the α1AAR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-α1AAR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the α1AAR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-α1AAR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-α1AAR mice was 10% longer than that of WT mice. Our results suggest that long-term α1AAR 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.
Footnotes
This work was supported in part by the National Institutes of Health National Center for Research Resources [Grants P20-RR016741, P20-RR017699]; and the National Heart, Lung and Blood Institute [Grants R01-HL61438 (to D.M.P.) and R01-HL098279 (to P.C.S.)]; the National Science Foundation (NSF) North Dakota EPSCoR IIP Seed Award [Grant EPS-0814442] (to V.A.D.), an NSF Faculty Early Career Development Award [Grant 0347259] (to V.A.D.), an NSF Research Experience for Undergraduates Site [Grants 0639227, 0851869] (to V.A.D.), NSF Graduate Research Fellowship Program Awards (to B.L.G. and K.M.C.); respectively.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.073734.
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ABBREVIATIONS:
- NE
- norepinephrine
- AR
- adrenergic receptor
- AD
- Alzheimer's disease
- KO
- knockout
- CA
- cornu ammonis
- DG
- dentate gyrus
- fEPSP
- field excitatory postsynaptic potential
- PPF
- paired-pulse facilitation
- TBS
- θ-burst stimulation
- CAM
- constitutively active mutant
- LTP
- long-term potentiation
- LTD
- long-term depression
- SSRI
- selective serotonin-reuptake inhibitor
- ERK
- extracellular signal-regulated kinase
- OCD
- obsessive-compulsive disorder
- WT
- wild type.
- Received May 24, 2011.
- Accepted July 26, 2011.
- U.S. Government work not protected by U.S. copyright
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