Alzheimer's disease (AD) is characterized by cognitive disorders and alterations of behavioral traits such as anhedonia and anxiety. Contribution of nonphysiological forms of amyloid and tau peptides to the onset of neurological dysfunctions remains unclear because most preclinical models only present one of those pathological AD‐related biomarkers. A more recently developed model, the TgF344‐AD rat has the advantage of overexpressing amyloid and naturally developing tauopathy, thus making it close to human familial forms of AD. We showed the presence of a learning dysfunction in a reference memory test, without spatial working memory impairment but with an increase in anxiety levels and a decrease in motivation to participate in the test. In the sucrose preference test, TgF344‐AD rats did not show signs of anhedonia but did not increase the volume of liquid consumed when the water was replaced by sucrose solution. These behavioral phenomena were observed at an age when tau accumulation are absent, and where amyloid deposits are predominant in the hippocampus and the entorhinal cortex. Within the hippocampus itself, amyloid accumulation is heterogenous between the subiculum, the dorsal hippocampus and the ventral hippocampus. Thus, our data demonstrated heterogeneity in the appearance of various behavioral and neurochemical markers in the TgF344‐AD rat. This multivariate analysis will therefore make it possible to define the stage of the pathology, to measure its evolution and the effects of future therapeutic treatments.

Alzheimer’s disease (AD) is characterized by amyloid (Aβ) protein aggregation and neurofibrillary tangles accumulation, accompanied by neuroinflammation. With all the therapeutic attempts targeting these biomarkers having been unsuccessful, the understanding of early mechanisms involved in the pathology is of paramount importance. Dopaminergic system involvement in AD has been suggested, particularly through the appearance of dopaminergic dysfunction-related neuropsychiatric symptoms and an overall worsening of cognitive and behavioral symptoms. In this study, we reported an early dopaminergic dysfunction in a mouse model presenting both amyloid and Tau pathology. 3xTg-AD mice showed an increase of postsynaptic D2/3R receptors density in the striatum and D2/3-autoreceptors in SN/VTA cell bodies. Functionally, a reduction of anxiety-like behavior, an increase in locomotor activity and D2R hyper-sensitivity to quinpirole stimulation have been observed. In addition, microglial cells in the striatum showed an early inflammatory response, suggesting its participation in dopaminergic alterations. These events are observed at an age when tau accumulation and Aβ deposits in the hippocampus are low. Thus, our results suggest that early dopaminergic dysfunction could have consequences in behavior and cognitive function, and may shed light on future therapeutic pathways of AD.

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.

Several studies suggested that 5-HT2A receptor (5-HT2AR) blockade may provide a more favorable efficacy and side-effect profile to antipsychotic treatment. We hypothesized that a combined haloperidol (a D2/3 receptor (D2/3R) antagonist) and MDL-100,907 (a 5-HT2AR antagonist) treatment would reverse the side effects and the neurochemical alterations induced by haloperidol alone and would potentialize its efficacy. We thus chronically treated male Mdr1a knock-out rats with several doses of haloperidol alone or in combination with a saturating dose of a MDL-100,907. Receptor occupancy at clinically relevant levels was validated with a dual-radiotracer in-vivo SPECT imaging of D2/3R and 5-HT2AR occupancy. Experimental tests of efficacy (dizocilpine-disrupted prepulse inhibition (PPI) of the startle reflex) and side effects (catalepsy, vacuous chewing movements) were performed. Finally, a second dual-radiotracer in-vivo SPECT scan assessed the neurochemical changes induced by the chronic treatments. Chronic haloperidol failed to reverse PPI disruption induced by dizocilpine, whilst administration of MDL-100,907 along with haloperidol was associated with a reversal of the effect of dizocilpine. Haloperidol at 0.5 mg/kg/day and at 1 mg/kg/day induced catalepsy that was significantly alleviated (by ~50%) by co-treatment with MDL-100,907 but only at 0.5 mg/kg/day dose of haloperidol. Chronic haloperidol treatment, event at doses as low as 0.1 mg/kg/day induced a significant upregulation of the D2/3R in the striatum (by over 40% in the nucleus accumbens and over 20% in the caudate-putamen nuclei), that was not reversed by MDL-100,907. Finally, an upregulation of 5-HT2AR after chronic haloperidol treatment at a moderate dose only (0.25 mg/kg/day) was demonstrated in frontal cortical regions and the ventral tegmental area. Overall, a partial contribution of a 5-HT2AR antagonism to the efficacy and side-effect profile of antipsychotic agents is suggested.