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

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.

Depressed contractile function and adrenergic responsiveness of cardiac myocytes in an experimental model of Parkinson disease, the MPTP-treated mouse.

Radiotracer and biochemical studies have shown that patients with Parkinson disease lack functional sympathetic innervation to the heart. The same observation was made in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an experimental model of Parkinson disease. This study examined the mechanical properties, adrenergic receptor level and intracellular Ca2+ handling in cardiac myocytes isolated from C57/BL6 mice that received either MPTP (30 mg/kg, i.p., twice in 24 h) or vehicle. Mechanical properties were evaluated using an IonOptix MyoCam system. Myocytes were electrically stimulated at 0.5 Hz. The contractile properties analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), and maximal velocities of shortening and relengthen (+/-dL/dt). Intracellular Ca2+ handling was evaluated with fura 2. Myocytes from MPTP-treated mice exhibited a depressed PS (85% of normal), normal TPS, prolonged TR90 (147% of normal), and reduced +/-dL/dt (both 79% of normal). These results were correlated with a 67% reduction of beta-adrenergic receptor expression in myocardial membranes from MPTP-treated mice when compared to normal. Myocytes from MPTP-treated mice also exhibited a reduced peak of intracellular Ca2+ sequestration and sarcoplasmic reticulum (SR) Ca2+ load (55 and 38% of normal, respectively). The resting intracellular Ca2+ and Ca2+-transient decay were comparable to the values seen in myocytes from untreated mice. Myocytes from MPTP-treated and untreated mice were equally responsive over a range of stimulation frequencies (0.1, 0.5, 1, 3 and 5 z). Response to norepinephrine (1 microM) and isoproterenol (1 microM) was reduced in myocytes from MPTP-treated mice. These results demonstrate substantial cardiac dysfunctions in this model of experimental Parkinson disease, probably due to reduced adrenergic responsiveness and SR Ca2+ load.

alpha(1A)- and alpha(1B)-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse.

Tricyclic antidepressant (TCA) drugs are used for the treatment of chronic depression, obsessive-compulsive disorder (OCD), and anxiety-related disorders. Chronic use of TCA drugs increases the expression of alpha(1)-adrenergic receptors (alpha(1)-ARs). Yet, it is unclear whether increased alpha(1)-AR expression contributes to the antidepressant effects of these drugs or if this effect is unrelated to their therapeutic benefit. In this study, mice expressing constitutively active mutant alpha(1A)-ARs (CAM alpha(1A)-AR) or CAM alpha(1B)-ARs were used to examine the effects of alpha(1A)- and alpha(1B)-AR signaling on rodent behavioral models of depression, OCD, and anxiety. CAM alpha(1A)-AR mice, but not CAM alpha(1B)-AR mice, exhibited antidepressant-like behavior in the tail suspension test and forced swim test. This behavior was reversed by prazosin, a selective alpha(1)-AR inverse agonist, and mimicked by chronically treating wild type mice with cirazoline, an alpha(1A)-AR agonist. Marble burying behavior, commonly used to model OCD in rodents, was significantly decreased in CAM alpha(1A)-AR mice but not in CAM alpha(1B)-AR mice. In contrast, no significant differences in anxiety-related behavior were observed between wild type, CAM alpha(1A)-AR, and CAM alpha(1B)-AR animals in the elevated plus maze and light/dark box. This is the first study to demonstrate that alpha(1A)- and alpha(1B)-ARs differentially modulate antidepressant-like behavior in the mouse. These data suggest that alpha(1A)-ARs may be a useful therapeutic target for the treatment of depression.