Association of GRK3 with stress resilience and stress susceptibility: Behavioral and pharmacological evidence



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On exposure to stress, persistent stimulation of alpha2A-adrenoceptors (α2A-AR) and corticotrophin-releasing factor 1 receptors (CRF1-R) increase the receptor signaling in locus coeruleus (LC) and amygdala (two critical brain regions involved in stress response. If this stimulation remains uncontrolled, it initiates the adverse consequences of stress. G protein-coupled receptor kinase-3 (GRK3) mediated desensitization of α2A-AR and CRF1-R, which terminates the enhanced signaling, is considered an adaptive response. It is not known if there are any biochemical alterations in this adaptive response in stress resilient individuals which make them resistant to the negative consequences of stress. The purpose of this research was to understand the stress-induced alterations of GRK3 levels and their relationship with α2A-AR/ CRF1-R levels in LC/ amygdala of stress susceptible and stress-resilient rats. The model utilized, exposure of rats to a single bout of 100 unpredictable inescapable tail shocks, resulted in two distinct behaviors: learned helpless (LH) behavior, (stress susceptible, escape deficits≥ controls) and non-helpless (NH) behavior (stress resilient, escape behavior ≈ controls). A single bout of stress produced readily reversible behavioral changes. Thus, the present study examined time-dependent correlates of GRK3, α2A-AR/CRF1-R levels from the appearance to the disappearance of LH behavior. In order to evaluate the differences between readily reversible and prolonged LH behavior, a new model of repeated bouts of tail shocks was created. This model showed prolonged behavioral changes. Finally, the efficacy of desipramine treatment in reversing repeated stress-induced behavioral and biochemical changes was assessed. LH behavior induced by a single stress was associated with reduced levels of GRK3 and relatively higher levels of α2A-AR /CRF1-R in LC. These changes appear as early as 1h-post stress and disappear when LH behavior is no longer present. Amygdala showed similar changes compared to LC, but the biochemical distinctions don’t appear at 1h post-stress. Instead, the global effects of single stress are seen. Repeated bout of stress (Day 1, 4, 7) generated a bimodal population distribution among stressed rats with prolonged NH and LH behavior (14 days). Levels of GRK3 and α2A-AR/ CRF1-R were affected similarly to single stress LH rats. In contrast to GRK3, GRK2 also was reduced which was unchanged during single stress. Amygdala showed similar changes after repeated stress compared to LC except that there was no change in GRK2 levels. Desipramine treatment (5mg/Kg bid/14 days) reversed the behavioral deficits of repeated stress LH rats. The levels of GRK3/2 were normalized in LC along with down-regulation of α2A-AR and CRF1-Rs. Amygdala also showed restoration of GRK3 levels with no receptor down-regulation. Collectively this data suggest that LH behavior (single and repeated stress), an index of stress susceptibility, is associated with reduced GRK3 levels accompanied by relative increase in α2A-AR and CRF1-R levels in LC. The strength of this association is indicated by the fact that cluster analysis of these proteins, collectively, can predict rat behavior post-stress, independent of behavioral testing.



GRK3, Learned helpless (LH), Stress, GPCR