Long-Term α_1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity

Abstract

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

The role of α1-adrenergic receptors in regulating metabolism: increased glucose tolerance, leptin secretion and lipid oxidation

“…Thus, we hypothesize that a 1 -ARs mediate glucose uptake into adipocytes, which causes the release of leptin that regulates peripheral whole body lipid metabolism through the hypothalamus. Interestingly, leptin is also both cardioprotective (53)(54)(55) and neuroprotective with increasing cognition and anti-aging effects (56), all similar phenotypes in our CAM a 1A -AR mice (1,18,28).…”

“…While both the a 1A -and a 1B -AR subtypes appear to regulate metabolism in a similar fashion, the a 1A -AR is clearly more efficacious and confirmed in the a 1A -AR KO mice. Stimulation of a 1A -ARs results in a favorable metabolic profile of increased glucose tolerance, cardiac glucose uptake, leptin release, and enhanced whole body lipid metabolism, resulting in a favorable lipid and glucose blood profile that may contribute to CAM a 1A -AR's increased longevity and cardioprotection (1,18,28,29). These results suggest that a 1 -ARs, and in particular the a 1A -AR, is a significant, but previously unrecognized, regulator of whole body and organ-specific metabolism.…”

An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity

“…Interestingly, long-term systemic 2-fold overexpression of the α1A actually is associated with prolonged lifespan, decreased cancer incidence,(45) and improved cognition. (46)…”

Transcranial Current Brain Stimulation (tCS): Models and Technologies

“…Various stimulation protocols (electrical, chemical, etc.) mimicking physiological conditions that are believed to occur during the formation of new memories were proposed [89], [99]- [102]. Long-term potentiation (LTP) is a persistent increase in synaptic strength and long-term depression (LTD) is the weakening of neuronal synaptic strength that may last from hours to months.…”