Abstract
It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT) and noradrenaline (NA) reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioral despair. The tail suspension test (TST) and forced swimming test (FST) were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT) were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 min to brightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.
Highlights
Wolfram syndrome (WS, MIM222300), caused by mutations in the WFS1 gene, is an autosomal recessive disorder most frequently characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness
Considering the efficacy of antidepressant drugs in the treatment of depression, we studied the effects of paroxetine and imipramine (a 5-HT and NA reuptake inhibitor) in the tail suspension test (TST) and forced swimming test (FST) in Wfs1-deficient mice
TAIL SUSPENSION TEST Effects of imipramine and paroxetine There was no difference in the basal immobility levels between genotypes
Summary
Wolfram syndrome (WS, MIM222300), caused by mutations in the WFS1 gene, is an autosomal recessive disorder most frequently characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. It has been suggested that mutations in the WFS1 gene in humans play a marked role in the susceptibility to mood disorders (Swift et al, 1998; Koido et al, 2005; Swift and Swift, 2005). It has become evident that Wfs1-deficient mice exhibit more passive coping style in terms of increased avoidance behavior and higher plasma corticosterone concentration in stressful circumstances (Luuk et al, 2009). The prevalence of passive coping style (e.g., distancing, escape/avoidance behavior, high hypothalamus–pituitary–adrenal axis responsiveness) during stressful periods is associated with the development of stress-induced depression (Billings and Moos, 1984; Folkman and Lazarus, 1988; Patterson et al, 1993; Razzoli et al, 2007). The prevalence of passive coping strategies and altered DA-ergic system possibly suggest that Wfs1-deficient mice could be an animal model of depressive states. Because of the apparently important role of serotonin (5-HT) and noradrenaline (NA) in the treatment of depression (Nemeroff and Owens, 2009; Goddard et al, 2010), we sought to study these neurotransmitter systems in www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
