Olfactory impairment in the rotenone model of Parkinson’s disease is associated with bulbar dopaminergic D2 activity after REM sleep deprivation

Abstract

Olfactory and rapid eye movement (REM) sleep deficits are commonly found in untreated subjects with a recent diagnosis of Parkinson’s disease (PD). Additionally, different studies report declines in olfactory performance during a short period of sleep deprivation. Mechanisms underlying these clinical manifestations are poorly understood, and impairment of dopamine (DA) neurotransmission in the olfactory bulb and the nigrostriatal pathway may have important roles in olfaction and REM sleep disturbances. Therefore, we hypothesized that modulation of the dopaminergic D2 receptors in the olfactory bulb could provide a more comprehensive understanding of the olfactory deficits in PD and REM sleep deprivation (REMSD). We decided to investigate the olfactory, neurochemical, and histological alterations generated through the administration of piribedil (a selective D2 agonist) or raclopride (a selective D2 antagonist) within the glomerular layer of the olfactory bulb, in rats subjected to intranigral rotenone and REMSD. Our findings provide evidence of the occurrence of a negative correlation (r = −0.52, P = 0.04) between the number of periglomerular TH-ir neurons and the bulbar levels of DA in the rotenone, but not sham, groups. A significant positive correlation (r = 0.34, P = 0.03) was observed between nigrostriatal DA levels and olfactory discrimination index (DI) for the sham groups, indicating that increased DA levels in the substantia nigra pars compacta (SNpc) are associated with enhanced olfactory discrimination performance. Also, increased levels in bulbar and striatal DA were induced by piribedil in the rotenone control and rotenone REMSD groups, consistent with reductions in the DI. The present evidence reinforce the idea that DA produced by periglomerular neurons, particularly the bulbar dopaminergic D2 receptors, is an essential participant in olfactory discrimination processes, as the SNpc, and the striatum.

Olfactory impairment is related to REM sleep deprivation in rotenone model of Parkinson's disease

“…Such mechanism is attributed to the inhibitory effect of DA 24 , 27 , mediated by D2 receptors activity 30 , causing the suppression of the olfactory information. A very similar deficit has been recently described after the intranigral administration of rotenone in rats, reinforcing such process 31 . In fact, the mechanisms linking these findings remain unclear.…”

“…Needles were guided to the region of interest for a bilateral infusion of 1 µL of rotenone (12 µg/µL), or of dimethylsulfoxide - DMSO (Sigma-Aldrich(r), United States) for the sham group. Using an electronic infusion pump (Insight Instruments, Ribeirão Preto, Brazil) at a rate of 0.33 µL/min( 31 , 35 , 37 , 38 ).…”

An update on the rotenone models of Parkinson's disease: Their ability to reproduce the features of clinical disease and model gene–environment interactions

“…Thus, further studies are required to 364 establish the functional significance of the increased numbers of 365 TH-positive cells in the olfactory bulb following rotenone exposure 366 and in clinical PD. Nevertheless, the study ofRodrigues et al (2014) …”

Animal Model for Prodromal Parkinson’s Disease

“…The intranasal administration of MPTP-reproduced transient olfactory disturbance in rats [50]. Olfactory disturbance was also observed in rats with rotenone administered to the SNc, and DA produced by periglomerular neurons and D2 receptors in the olfactory bulb was thought to be important for the olfactory discrimination ability according to DA agonist/antagonist administration experiments in this model [51].…”