Alterations in dopamine system and in its connectivity with serotonin in a rat model of Alzheimer’s disease

Abstract

Dopamine (DA) pathways alterations are reported in Alzheimer’s disease (AD). However, it is difficult in humans to establish when these deficits appear and their impact in the course of Alzheimer’s disease. In the TgF344-AD rat model at the age of 6 months, we showed a reduction in in vivo release of striatal DA due to serotonin 5HT2A-receptor (5HT2AR) blockade, in the absence of alterations in 5HT2AR binding, suggesting a reduction in 5HT2AR-DA system connectivity. In addition, a functional hypersensitivity of postsynaptic DA D2-receptors (D2R) and D2-autoreceptors was also reported without any change in D2R density and in the absence of amyloid plaques or overexpression of the 18 kDa translocator protein (TSPO, an inflammatory marker) in areas of the DA system. Citalopram, a selective serotonin reuptake inhibitor, induced functional 5HT2AR-D2R connectivity changes but had no effect on D2-autoreceptor hypersensitivity. In older rats, DA cell bodies overexpressed TSPO and DA projection sites accumulated amyloid. Interestingly, the 5HT2AR density is decreased in the accumbens subdivisions and the substantia nigra pars compacta. This reduction in the striatum is related to the astrocytic expression of 5HT2AR. Our results indicate that both serotonin/dopamine connectivity and DA signaling pathways are dysregulated and potentially represent novel early diagnostic and therapeutic avenues.

Finding Drug Repurposing Candidates for Neurodegenerative Diseases using Zebrafish Behavioral Profiles

“…It is important to note that many of these compounds have multiple targets and can simultaneously affect a variety of pathways. For instance, there is evidence of interaction between the dopamine and the serotonin pathways, implying the possibility of cross-pathway alteration in AD pathology (Ceyzériat et al, 2021). This is specifically utilized in the prescription of atypical antipsychotics, distinctively known as serotonin-dopamine antagonists.…”

The Neurodegenerative Elderly Syndrome (NES) hypothesis: Alzheimer and Parkinson are two faces of the same disease

“…Several works support the involvement of DRN in compensation processes ( Ceyzériat et al, 2021 , Jiménez-Sánchez et al, 2020 , Merlo et al, 2019 ). DRN could modulate DA concentration through the 5-HT projections it sends to VTA and SNc ( Bara-Jimenez et al, 2005 , Di Matteo et al, 2008 , Kirouac et al, 2004 , Politis and Niccolini, 2015 ).…”

“…By contrast, the impairments of the DA meso-striatal system contribute to the development of extrapyramidal motor deficits, usually occurring in the later stages of AD ( Martorana and Koch, 2014 ). Impairments in serotonin (5-HT) production and transmission could also affect AD pathogenesis ( Ceyzériat et al, 2021 , Vakalopoulos, 2017 , Whiley et al, 2021 , Xie et al, 2019 ). Finally, the locus coeruleus (LC), the dorsal pontine nucleus that synthesizes noradrenaline (NA), which is involved in attention, memory, and various other aspects of cognition, could show impairments in the early stages of disease progression ( Bondareff et al, 1987 , Braak et al, 2011 , Mather and Harley, 2016 , Šimić et al, 2017 , Weinshenker, 2018 , Zarow et al, 2003 ).…”

Alterations of Monoaminergic Systems in Alzheimer's Disease: A Traditional Review

“…Bilişsel süreçlerde DA'nın yer alması nedeniyle bu değişikliklerin bellek bozukluklarının başlamasında rol oynaması da mümkündür. 25 AH'de DA'nın prekürsörü L-3,4-dihidroksifenilalanin (L-DOPA) ve onun metabolitinin (DOPAC) seviyeleri singulat girusda, amigdalada, striatumda ve rafe çekirdeğinde anlamlı derecede düşük bulunmuştur. 23 Alzheimer hastalarında, striatumdaki hem D1 hem D2 reseptörlerinin sayısında da anlamlı azalma görülmüştür.…”