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.