Elizabeth Luger

α1A- and α1B-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.

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

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.

Regulator of G Protein Signaling Protein Suppression of Gαo Protein-Mediated α2A Adrenergic Receptor Inhibition of Mouse Hippocampal CA3 Epileptiform Activity

Activation of G protein-coupled α2 adrenergic receptors (ARs) inhibits epileptiform activity in the hippocampal CA3 region. The specific mechanism underlying this action is unclear. This study investigated which subtype(s) of α2ARs and G proteins (Gαo or Gαi) are involved in this response using recordings of mouse hippocampal CA3 epileptiform bursts. Application of epinephrine (EPI) or norepinephrine (NE) reduced the frequency of bursts in a concentration-dependent manner: (-)EPI > (-)NE >>> (+)NE. To identify the α2AR subtype involved, equilibrium dissociation constants (pKb) were determined for the selective αAR antagonists atipamezole (8.79), rauwolscine (7.75), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB-4101; 6.87), and prazosin (5.71). Calculated pKb values correlated best with affinities determined previously for the mouse α2AAR subtype (r = 0.98, slope = 1.07). Furthermore, the inhibitory effects of EPI were lost in hippocampal slices from α2AAR-but not α2CAR-knockout mice. Pretreatment with pertussis toxin also reduced the EPI-mediated inhibition of epileptiform bursts. Finally, using knock-in mice with point mutations that disrupt regulator of G protein signaling (RGS) binding to Gα subunits to enhance signaling by that G protein, the EPI-mediated inhibition of bursts was significantly more potent in slices from RGS-insensitive GαoG184S heterozygous (Gαo+/GS) mice compared with either Gαi2G184S heterozygous (Gαi2+/GS) or control mice (EC50 = 2.5 versus 19 and 23 nM, respectively). Together, these findings indicate that the inhibitory effect of EPI on hippocampal CA3 epileptiform activity uses an α2AAR/Gαo protein-mediated pathway under strong inhibitory control by RGS proteins. This suggests a possible role for RGS inhibitors or selective α2AAR agonists as a novel antiepileptic drug therapy.

Positive expectancies mediate the link between race and alcohol use in a sample of Native American and Caucasian college students

BACKGROUND Though abundant research suggests that Native Americans report high rates of alcohol use and related consequences, little research has examined drinking patterns among Native American college students. It is possible that drinking rates for this group may differ from their non-college counterparts and also from those of Caucasian college students. The aim of this study was to examine whether alcohol use differs between Native American and Caucasian college students, and specifically whether alcohol expectancy effects mediate the relationship between race and drinking. METHOD Participants were 43 Native American and 87 Caucasian college students who reported on their positive and negative expectancy effects and past-6-month drinking. RESULTS Caucasians reported drinking significantly more alcohol and holding stronger positive expectancies. Bootstrapping mediational analysis with 95% confidence intervals indicated that positive but not negative expectancy effects mediated the relationship between race and past-6-month drinking. CONCLUSIONS This preliminary research is the first to examine expectancy effects as mediators of the relationship between Native American and Caucasian race and drinking. Further understanding of the differences in positive expectancy effects between groups may have important implications for prevention and treatment of alcohol use among Native American college students.