Early Paradoxical Increase of Dopamine: A Neurochemical Study of Olfactory Bulb in Asymptomatic and Symptomatic MPTP Treated Monkeys

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease with both motor and non-motor manifestations. Hyposmia is one of the early non-motor symptoms, which can precede motor symptoms by several years. The relationship between hyposmia and PD remains elusive. Olfactory bulb (OB) pathology shows an increased number of olfactory dopaminergic cells, protein aggregates and dysfunction of neurotransmitter systems. In this study we examined tissue levels of dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and their metabolites, of noradrenaline (NA) and of the amino acid neurotransmitters aspartate, glutamate, taurine and γ-aminobutyric acid in OBs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated Macaca fascicularis in different stages, including monkeys who were always asymptomatic, monkeys who recovered from mild parkinsonian signs, and monkeys with stable moderate or severe parkinsonism. DA was increased compared to controls, while neither NA and 5-HT nor the amino acid neurotransmitters were significantly changed. Furthermore, DA increased before stable motor deficits appear with +51% in asymptomatic and +96% in recovered monkeys. Unchanged DA metabolites suggest a special metabolic profile of the newly formed DA neurons. Significant correlation of homovanillic acid (HVA) with taurine single values within the four MPTP groups and of aspartate with taurine within the asymptomatic and recovered MPTP groups, but not within the controls suggest interactions in the OB between taurine and the DA system and taurine and the excitatory neurotransmitter triggered by MPTP. This first investigation of OB in various stages after MPTP administration suggests that the DA increase seems to be an early phenomenon, not requiring profound nigrostriatal neurodegeneration or PD symptoms.

Chronic MPTP administration regimen in monkeys: a model of dopaminergic and non-dopaminergic cell loss in Parkinson’s disease

“…This increased DA activity in the OB of PD patients may lead to a suppression of olfactory information due to the inhibitory effect of DA on the transmission between olfactory receptor cells and mitral cells within the olfactory glomeruli (Doty and Risser 1989; Duchamp-Viret et al 1997; Hsia et al 1999; Koster et al 1999; Mundinano et al 2011; Wilson and Sullivan 1995). Recent findings revealed that DA levels are also increased in the OB of chronically MPTP-treated monkeys irrespective of their state of parkinsonism, such that motor asymptomatic and moderate or severe parkinsonian animals display comparable increases in OB DA levels (Pifl et al 2017). These findings are consistent with the previous report of an increased number of intrinsic DA neurons in the OB of chronically MPTP-treated monkeys (Belzunegui et al 2007).…”

The End Is the Beginning: Parkinson’s Disease in the Light of Brain Imaging

“…Notably, mice transgenic for wild type α-synuclein display augmented striatal tonic dopamine release and increased locomotor activity before the onset of striatal denervation and L-DOPA-responsive motor phenotype (Lam et al, 2011 ), thus supporting that early striatal synaptic dysfunctions precede neurodegeneration. In addition, the early paradoxical increase of dopamine in the olfactory bulb in the absence of motor impairment that has been recently found to occur in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated monkeys (Pifl et al, 2017 ) hints that synaptic changes precede the onset of PD symptoms. Since cell-to-cell transmission of α-synuclein proceeds via trans-synaptic spreading through intact neuronal connections (Ulusoy et al, 2015 ), it is likely that in the initial phases of PD its deposition at terminals might be the predominant factor prompting even diffusion of pathology (Longhena et al, 2017 ).…”

Recent advances in the pathology of prodromal non-motor symptoms olfactory deficit and depression in Parkinson’s disease: clues to early diagnosis and effective treatment

“…Marked decreases in the numbers and activity of cholinergic neurons in the mitral cell layer and increases in dopaminergic neuron numbers and TH protein levels in the glomerular layer were reported in α-synuclein A53T transgenic mice compared to wild-type littermates (Zhang et al 2015a). A significant increase in dopamine levels is also shown in the OB of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced monkey PD model (Pifl et al 2017) without changes in other monoamine neurotransmitters. However, a decrease in norepinephrine level was detected in the OB in Parkin null mice (Von Coelln et al 2004).…”