Efeitos da 6-OHDA sobre o ritmo de atividade repouso e expressão circadiana de histamina no sistema nervoso central de ratos

Abstract

Parkinson's Disease (PD) is a neurodegenerative disease mainly characterized by a progressively dopaminergic depletion on the central nervous system (CNS). Furthermore, PD patients exhibit non-motor symptoms like sexual dysfunction, cognitive impairment, olfactory damage, depression, anxiety, sleep disturbance, circadian disruptions, and other signs. These non-motors symptoms result from the neurochemical changes in other neurotransmission circuitries like noradrenergic, cholinergic, serotoninergic, and/or histaminergic systems. Human post mortem studies showed alterations in histaminergic receptors and neural projections distribution throughout the CNS of PD patients. Moreover, studies based on neurotoxin infusion reinforced this relationship between the histaminergic system and the physiopathology process of PD. In mammals, the histaminergic system controls alertness and wakefulness status, acting as an essential component of the sleep-wake regulatory system. Here, we used an intracerebroventricular infusion of 6-hydroxydopamine as a pharmacological tool to induce rest-activity rhythm fragmentation and investigated what types of rhythmic parameters were affected and how the wake-promoter histaminergic system contributes to this phenomenon. Our protocol induced a progressive rest-activity rhythm impairment, without changing histidine decarboxylase or bmal1 protein expression in tuberomammillary or suprachiasmatic nucleus. Parametric and non-parametric rhythm analyses were conducted to describe the impairment of rest-activity rhythm as a progressive circadian dysfunction with increased fragmentation/variability on animal activity throughout the day, as well as reduced stability of this activity pattern between consecutive days within both entrained and constant conditions (i.e. light-dark and constant darkness schedules, respectively). We conclude that dopamine exerts an important role in rest-activity rhythm regulation, in both synchronized and constant photoperiods, without affecting the histaminergic tonus.