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

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 5HT(2A)-receptor blockade, in the absence of alterations in 5HT(2A)-receptor binding, suggesting a reduction in 5HT(2A)-receptor-dopamine system connectivity. In addition, a functional hypersensitivity of postsynaptic dopamine 132-receptors and D-2-autoreceptors was also reported without any change in Da-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 SHT2A-receptor D-2-receptor connectivity changes but had no effect on D-2-autoreceptor hypersensitivity. In older rats, dopamine cell bodies overexpressed translocator protein and dopamine projection sites accumulated amyloid. Interestingly, the 5HT(2A)-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 5HT(2A)-receptor. Our results indicate that both serotonin/dopamine connectivity and dopamine signalling pathways are dysregulated and potentially represent novel early diagnostic and therapeutic avenues.

Automated summary

The study found alterations in dopamine pathways in Alzheimer's disease, particularly in a rat model where 5-HT2A receptor blockade led to reduced dopamine release in the striatum. Additionally, functional hypersensitivity of dopamine receptors in rats was reported, independent of amyloid plaques or inflammatory marker expression. Furthermore, changes in receptor connectivity induced by a selective serotonin reuptake inhibitor may offer potential therapeutic avenues for Alzheimer's disease.