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.