Abstract
Dopamine pathways alterations are reported in Alzheimer’s disease. 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-Alzheimer’s disease rat model at the age of 6 months, we showed a reduction in in vivo release of striatal dopamine due to serotonin 5HT2A-receptor blockade, in the absence of alterations in 5HT2A-receptor binding, suggesting a reduction in 5HT2A-receptor-dopamine system connectivity. In addition, a functional hypersensitivity of postsynaptic dopamine D2-receptors and D2-autoreceptors was also reported without any change in D2-receptor density and in the absence of amyloid plaques or overexpression of the 18 kDa translocator protein (an inflammatory marker) in areas of the dopamine system. Citalopram, a selective serotonin reuptake inhibitor, induced functional 5HT2A-receptor−D2-receptor connectivity changes but had no effect on D2-autoreceptor hypersensitivity. In older rats, dopamine cell bodies overexpressed translocator protein and dopamine projection sites accumulated amyloid. Interestingly, the 5HT2A-receptor 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 5HT2A-receptor. Our results indicate that both serotonin/dopamine connectivity and dopamine signalling pathways are dysregulated and potentially represent novel early diagnostic and therapeutic avenues.
Highlights
In addition to the major pathological hallmarks of Alzheimer’s disease, including the presence of Ab deposits, neurofibrillary tangles, neuroinflammation and brain atrophy, some reports seem to indicate that earlier events could to some extent be indicators of the progression towards the development of pathology
In the TgF344-Alzheimer’s disease rat model at the age of 6 months, we showed a reduction in in vivo release of striatal dopamine due to serotonin 5HT2A-receptor blockade, in the absence of alterations in 5HT2A-receptor binding, suggesting a reduction in 5HT2A-receptor-dopamine system connectivity
We tested the effect of chronic citalopram treatment, a selective serotonin reuptake inhibitor (SSRI), on D2R and 5HT 2A-receptor (5HT2AR) function. We examined these results with regard to neurochemical alterations in 18 kDa translocator protein (TSPO), amyloid deposits, D2R and 5HT2AR densities observed at a pre-symptomatic stage and at a more advanced stage, using the well described [125I]CLINDE,27,28 [125I]DRM106,29–31 [125I]Epidepride32,33 and [125I]R9115034,35 radioligands, respectively
Summary
In addition to the major pathological hallmarks of Alzheimer’s disease, including the presence of Ab deposits, neurofibrillary tangles, neuroinflammation and brain atrophy, some reports seem to indicate that earlier events could to some extent be indicators of the progression towards the development of pathology. Among them have been described the presence of neuropsychiatric symptoms which may appear before clinical manifestations of dementia and are linked to the loss of capacity of patients to perform instrumental activities of daily living.. The possibility of dopaminergic dysfunction has been suggested as an actor in these behavioural disorders.. The possibility of dopaminergic dysfunction has been suggested as an actor in these behavioural disorders.1 In this sense, post-mortem studies have shown a reduction in dopamine (DA) synthesis, an alteration of the neurons producing DA and DA release in the striatum and hippocampus, but the impact on DA D2-receptor (D2R) density is not clear.. More than half of the patients develop behavioural disorders related to the DA system.. It is even possible that these alterations play a role in the onset of memory disorders, due to the involvement of DA in cognitive processes. Among them have been described the presence of neuropsychiatric symptoms which may appear before clinical manifestations of dementia and are linked to the loss of capacity of patients to perform instrumental activities of daily living. The possibility of dopaminergic dysfunction has been suggested as an actor in these behavioural disorders. In this sense, post-mortem studies have shown a reduction in dopamine (DA) synthesis, an alteration of the neurons producing DA and DA release in the striatum and hippocampus, but the impact on DA D2-receptor (D2R) density is not clear. More than half of the patients develop behavioural disorders related to the DA system. It is even possible that these alterations play a role in the onset of memory disorders, due to the involvement of DA in cognitive processes.
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