Research Reportα1A- and α1B-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse
Introduction
Epinephrine and norepinephrine are important modulators of animal behavior. These catecholamines mediate the “fight or flight” response to an imminent threat, participate in the regulation of mood, regulate feeding behavior, and modulate cognitive function, (see reviews by Elhwuegi, 2004, Wellman and Davies, 1991, Lapiz and Morilak, 2006). Abnormalities in adrenergic signaling in the brain are associated with a variety of behavioral pathologies including clinical depression, motor dysfunction, loss of memory, anxiety, and post-traumatic stress disorder (Murchison et al., 2004, Rommelfanger et al., 2007, Dierks et al., 2007). Drugs that inhibit the reuptake or metabolism of norepinephrine and other catecholamines in the central nervous system are widely used in the treatment of depression, obsessive–compulsive disorder (OCD), and narcolepsy.
Depression is characterized by subjective feelings of hopelessness, loss of interest in pleasurable activities, sleep disturbances, and fatigue. Evidence from both clinical studies and animal models indicates that adrenergic signaling modulates mood and depression-related behavior. For example, early research showed that the antidepressant efficacy of tricyclic antidepressants (TCA) such as imipramine correlated with inhibition of norepinephrine reuptake (Glowinski and Axelrod, 1964). In addition, selective inhibitors of the norepinephrine transporter such as desipramine and reboxetine exhibit robust antidepressant activity with similar efficacy as that reported for serotonin-selective reuptake inhibitors (SSRIs) when given to patients with major depressive disorder (Bowden et al., 1993, Roth et al., 1990, Nelson, 1999). More recent meta-analysis studies suggest that antidepressants with mixed serotonin-noradrenergic reuptake inhibitor (SNRI) activity may offer therapeutic advantages to treatment with SSRIs alone (Machado et al., 2006, Papakostas et al., 2007, reviewed by Shelton 2004). However, the roles of individual adrenergic receptor (AR) subtypes in modulating depression-related behavior are not well characterized.
The effects of epinephrine and norepinephrine are mediated by adrenergic receptors (ARs). Nine different AR subtypes (α1A-, α1B-, α1D-, α2A-, α2B-, α2C, β1-, β2-, β3-AR) have been cloned and characterized (see review by Strosberg, 1993), and they differ in their amino acid sequences, ligand binding properties, tissue distribution, and coupling to signal transduction pathways. Stone and Quartermain (1999) reported that α1-AR blockade in the central nervous system induces depression-related behavior in mouse models of depression. In addition, previous studies have reported that administration of TCA drugs increases the density of α1-ARs in the forebrain, hippocampus, and cerebral cortex of mice and rats (Deupree et al., 2007, Rehavi et al., 1980) and that α1-ARs in dorsal lateral geniculate neurons, the facial nucleus, and other brain regions become supersensitized following chronic administration of TCA drugs (Menkes and Aghajanian, 1981, Menkes et al., 1983). In contrast, α2-ARs and β-ARs are downregulated by chronic use of TCA drugs (Deupree et al., 2007, Subhash et al., 2003). However, it has been unclear whether these changes in AR expression and sensitivity actually contribute to the antidepressant effect of these drugs or are only ancillary effects that are not involved in the antidepressant action of TCA drugs. The goal of this study was to investigate the effects of α1A- and α1B-AR signaling on antidepressant-like behavior of the mouse.
The currently available α1-AR ligands are not sufficiently selective for individual α1-AR subtypes in vivo to conclusively determine which subtypes modulate behavior. Therefore, we used transgenic mice that express either constitutively active mutant (CAM) α1A- or CAM α1B-ARs (Rorabaugh et al., 2005a) in addition to the endogenous α1A- and α1B-ARs. These mice selectively express CAM α1A- or CAM α1B-ARs only in tissues that normally express the respective wild type receptors (Rorabaugh et al., 2005b, Zuscik et al., 2000). Brains of CAM α1A-AR and CAM α1B-AR mice exhibit a 3-fold and 4.5-fold increase, respectively, in basal inositol-1,4,5-triphosphate production relative to wild type mouse brains, confirming their constitutive activity in vivo (Rorabaugh et al., 2005a, Zuscik et al., 2000). These mice provide a unique tool to investigate the chronic effects of signaling through the α1A- and α1B-AR receptors without the need for subtype-selective drugs.
It has been recently reported that neurogenesis is enhanced in CAM α1A-AR mice (relative to wild type mice) and that this effect can be mimicked by chronically treating wild type mice with cirazoline, an α1A-AR agonist (Gupta et al., in press). In contrast, CAM α1B-AR signaling induces neurodegeneration (Zuscik et al., 2000). Since several different types of chronic antidepressant therapies are known to induce neurogenesis (Malberg et al., 2000), we investigated the effects of α1A- and α1B-AR signaling on depression-related behavior. Our data provide evidence that α1A-AR signaling, but not α1B-AR signaling, produces antidepressant-like behavior in the mouse.
Section snippets
α1A-AR signaling, but not α1B-AR signaling causes antidepressant-like behavior
The tail suspension test (TST) is a well established model for the characterization of antidepressant-like behavior (Cryan et al., 2005). We used the TST to determine whether chronically elevated α1A- or α1B-AR signaling promotes antidepressant-like behavior. CAM α1A-AR mice were immobile for significantly less time (44 ± 13 s) than wild type mice (128 ± 16 s), suggesting that α1A-AR signaling promotes antidepressant-like behavior (Fig. 1A). In contrast, immobility was slightly increased in CAM α1B
Discussion
The involvement of norepinephrine in the modulation of antidepressant behavior is well established, and drugs that increase synaptic norepinephrine concentrations by inhibiting norepinephrine reuptake from the synaptic cleft have become important in the treatment of clinical depression. Previous work has demonstrated that α1-ARs are involved in the antidepressant effects of norepinephrine (Stone and Quartermain, 1999), but the ability of individual α1-AR subtypes to mediate this antidepressant
Transgenic mice
B6/CBA mice expressing a constitutively active mutant (CAM) α1A-AR, B6/CBA mice expressing a CAM α1B-AR, and wild type B6/CBA mice were generously donated by Dr. Dianne M. Perez (Cleveland Clinic Foundation, Cleveland, OH). These transgenic mice express constitutively active forms of the α1A- or α1B-ARs in addition to the endogenous wild type α1-ARs. Generation and genotyping of these mice has been previously described (Rorabaugh et al., 2005a, Zuscik et al., 2000). Briefly, tissue-specific
Acknowledgments
The authors thank Dr. Dianne Perez (Cleveland Clinic Foundation) for generously donating CAM α1A-AR and CAM α1B-AR mice for this study. This work was supported by the Bower, Bennet, and Bennet Endowed Research Chair Award to Boyd Rorabaugh, an American Association of Colleges of Pharmacy New Investigator Program Award to Jeff Talbot, and a National Science Foundation CAREER award 0347259 to Van Doze. Additional student support was provided by the Ronald E. McNair Achievement Program and the
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