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  • Another important finding in this

    2018-11-07

    Another important finding in this study is that REMSD was able to induce remarkable anxiolytic-like effects similar to 8-M-PDOT. This outcome becomes evident due to the ceiling effect induced by REMSD (Fig. 2E). However, these results cannot be interpreted as a merely consequence of an alteration in locomotion inflicted by REMSD, since REMSD itself did not appear to produce motor changes. Nonetheless, locomotor adjustments occurred only in the presence of a dopaminergic lesion induced by rotenone. In fact, striatal MT2 blockade produced an increased locomotion not replicated in the context of REMSD. Also, MT2 activation appeared to generate a prevalent locomotor increase compared to MT2 blockade. This result could also be interpreted as a possible anxiogenic effect or even a mania-like effect [50], probably caused by REMSD. Indeed, REMSD is known to cause hyperactivity as a result of dopaminergic supersensitivity [51], and is also considered as a model of mania [50]. Many studies describe anxiolytic-like effects as consequence of insufficient sleep [15–17]. Meanwhile, anxiogenic-like effects are also reported in animal studies [18–20]. One possible explanation for this discrepancy is due to the variations in the REMSD protocols and different behavioral tests employed to access anxiety [52]. The intranigral infusion of rotenone did not induce an anxiogenic-like effect, suggesting that this neurotoxin, or perhaps our protocol (or both), presented limitations in mimicking anxiety-like alterations such as observed in PD. Rotenone is a classical inhibitor of the mitochondrial complex I of the diltiazem hcl transport chain, hence, inducing apoptosis mechanisms of dopaminergic neurons very similarly to PD [2]. That is, lipid peroxidation, changes in the mitochondrial membrane potential, caspase-3 activation and DNA fragmentation [53]. In fact, 40–80% of striatal dopamine depletion can be observed after intranigral administration of rotenone [46,54,55], while serotoninergic neurons is not affected by this neurotoxin [54]. The use of rotenone as a PD model is gaining growing attention particularly in light of non-motor disturbances like REM sleep behavior disorder [56]. Further, this neurotoxin mimics olfactory dysfunction [24] and depression [25,26] which are pathophysiological conditions with a strong dopaminergic influence. Meanwhile, the findings presented in the literature regarding anxiety behaviors induced by animal models of PD have been inconsistent. While some studies suggest the neurotoxin induction of anxiogenic-like behaviors [6,57,58], others reported absence of these effects [13,59]. Therefore, the present study takes place with this investigation and becomes the first report, to our knowledge, to show the effects of intranigral rotenone in the context of anxiety-like behaviors in rats. Another important point to be examined is the possible sedative effect that could be induced by the MT2 activation. In this regard we did not detect such effect, according to our protocol, as can be seen by the locomotion profile of the 8-M-PDOT treated animals. Interestingly, there is a strong relationship between anxiety disorders and glutamate receptors [60,61]. In particular, abnormalities in the glutamatergic transmission underlie anxiety [62]. Preclinical data indicate that antagonists of the N-methyl-D-aspartate (NMDA) and group I mGlu receptors reduce anxiety [61,63]. However, the involvement of glutamate in the neurobiology of anxiety in PD is not yet clear. Another neuropsychiatric condition relevant for PD is depression. It has been demonstrated that melatonin operates as a mediator of the antidepressant-like effects induced by NMDA receptors [64]. Although, more studies about the glutamatergic role of melatonin are needed and this constitutes a very interesting field for futures studies.
    Conclusions
    Conflict of interests
    Acknowledgments This paper was supported by CAPES and the Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq-Brasil Grants Casadinho/Procad # 552226/2011-4 and Universal # 473861/2012-7 to MMSL. MMSL is recipient of CNPq fellowship.