Altered serotonergic system and mood behaviors in a cuprizone-induced model of demyelination

Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system and is globally estimated to affect 2 new people/100.000/year. MS patients show among other symptoms mood changes including anxiety and depression. Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neurotransmitter that has been related to mood changes. We address the hypothesis that 5-HT neurotransmission may be altered in chronic MS, and for this, we evaluate the 5-HT system together with anxiety and depressive behaviors in an animal model of cuprizone (CPZ)-treated C57BL/6 mice. Animals were fed 0.2% CPZ for 5 weeks, and controls were given a standard diet. Demyelination was assessed with Luxol fast blue (LFB) stain and immunohistochemistry (IHC) with the antigens myelin proteolipid protein (PLP). 5-HT and its transporter protein (SERT) were assessed by IHC with antigens 5-HT and SERT respectively. Anxiety and depressive behaviors were assessed using the dark/light box and the forced swim tests respectively. Our findings show obvious demyelination in CPZ-treated mice together with increased 5-HT immunostaining of neurons of the dorsal and median raphe nuclei and their cortical projections. The 5-HT increase was concomitant to a decreased density of SERT fibers. Time spent in the light compartment reflecting an anxiety state, together with immobility time reflecting a depressive state were both increased in CPZ-treated mice. Our results show that exposure to CPZ for 5 weeks increases 5-HT and its cortical projections together with reduced SERT, suggesting an increased production of 5-HT and its availability. Our findings support the possible involvement of the 5-HT system in behavioral changes, demyelination and probably inflammatory processes in MS.