Effects of L-Dopa on Circadian Rhythms of 6-Ohda Striatal Lesioned Rats: A Radiotelemetric Study

Abstract

Temporal variation in the motor function of Parkinson's disease (PD) patients suggests the potential importance of a chronobiological and chronopharmacological approach in its clinical management. We previously documented the effects of striatal injection of 6-OHDA (as an animal model of PD) on the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (A). The present work assessed the possible influence of L-Dopa on these same rhythms in the 6-OHDA animal model of PD. The study began after a four-week recovery period following surgical implantation of telemetric devices to monitor the study variables and/or anaesthesia. The study was divided into an initial one-week control period (W1) for baseline measurement of T, HR, and A rhythms. Thereafter, stereotaxic 6-OHDA lesioning was done. and a second monitoring for two weeks followed (W2, W3). Rats were then randomly divided into two groups: eight control rats received, via a mini-osmotic pump implanted subcutaneously, the excipient saline; the other eight rats received L-Dopa (100 mg/kg SC/day). After a seven-day period (W4), the pumps were removed and the T, HR, and A rhythms were monitored for two weeks (W5 and W6). To control for 6-OHDA striatal dopamine-induced depletion, 12 other rats were injected by identical methods (eight rats with 6-OHDA and four controls with saline) and sacrificed at W1, W3, and W5 for dopamine striatal content determination. To verify the delivery of levodopa from the osmotic pumps, plasma levels of levodopa and its main metabolites 3-OMD, DOPAC, and HVA were determined on separate group of rats receiving the drug under the same experimental conditions (osmotic pumps delivering continuously 10 microl/h for seven days, 100 mg/kg/subcutaneously). Our results agree with previously reported rhythmic changes induced by 6-OHDA--loss of circadian rhythmicity or changes in the main parameters of the registered rhythms. When circadian rhythmicity was abolished, L-Dopa treatment improved or accelerated recovery of the circadian rhythms, the effect being more pronounced for the HR rhythm. When circadian rhythms were not abolished but perturbed, L-Dopa treatment did not improve the 6-OHDA-induced changes in the T and A mesor (24 h mean level), while a significant effect was observed for HR. It appears that constant-rate L-Dopa infusion is unable to totally balance dopamine depletion; taking into account the circadian pattern of many structures implicated in drug effect, a sinusoidal delivery of L-Dopa must be evaluated in future experiments.

Non-dipping nocturnal blood pressure and psychosis parameters in Parkinson disease

“…[21,46] We did not find a statistically significant correlation between LED and psychosis scores or non-dipping.…”

Global Depletion of Dopamine Using Intracerebroventricular 6-Hydroxydopamine Injection Disrupts Normal Circadian Wheel-Running Patterns and PERIOD2 Expression in the Rat Forebrain

“…injection of 6-OHDA disrupts the free-running activity pattern of rats is noteworthy in view of evidence that pathologies of the DA system, such as PD, are associated with abnormal rhythms of activity, sleep, and cortisol secretion (Bruguerolle and Simon 2002;Gunn et al 2010). Animal models of PD also exhibit deficits in several physiological rhythms following the destruction of DA fibers, including body temperature and heart rate (Ben and Bruguerolle 2000;Boulamery et al 2010). Our finding that 6-OHDA-lesioned rats showed a disorganized wheel-running pattern when housed in constant darkness would seem consistent with the circadian deficits reported in other contexts of DA depletion.…”

“…The importance of dopamine (DA) in the regulation of circadian rhythms is suggested by clinical evidence of altered behavioral and physiological rhythms in patients with Parkinson's disease (PD) (Bruguerolle and Simon 2002;Cai et al 2010), and by experimental findings in rodents showing that depletion of striatal DA, the primary neuropathology of PD, disrupts circadian rhythmicity (Ben and Bruguerolle 2000;Boulamery et al 2010). How depletion of striatal DA affects circadian rhythms is poorly understood.…”

A historical justification for and retrospective analysis of the systematic application of light therapy in Parkinson’s disease

“…That there are features of NSD function that are strongly • suggestive of a major involvement of circadian biology (Fertl et al , 1991 ;Boulamery et al , 2010 ;Gravotta et al , 2011 ) That nigral cells are, in fact, melanocytes being derived • from the same portion of the neural crest as pineal and retinal cells and that they engage in similar physiological processes involving DA, melatonin and melanin (Willis , 2008a ) That current approaches to understanding and treating PD • actually violate the basic biological principles governing how these cells operate (Willis, 2008a).…”