Striatal dopamine D2, adenosine A2A and cannabinoid CB1 receptors balance as a target against non-cognitive symptoms in a mouse model of Alzheimer's disease

Behavioral and psychological symptoms of dementia are almost ubiquitous in Alzheimer's disease (AD) but current therapies are not fully effective and safe. In this study, we aim to evaluate the role played by the interplay among striatal D2, adenosine A2A (A2AR) and cannabinoid CB1 (CB1R) receptors in some of these non-cognitive impairments in a well-established animal model of AD, the double transgenic APP/PS1 mice. Our results reveal that the alterations existing in the ratios between these three receptors significantly correlate with the sensorimotor gating and the social interaction impairments occurring in APP/PS1 mice at 12 months of age. Moreover, the pharmacological stimulation of A2AR and CB1R blunted the sensorimotor gating deficiencies in APP/PS1 mice. To note, we observed some age-dependent differences among male and female mice. In conclusion, the present study provides evidence for the contribution of an altered interplay between dopaminergic, adenosinergic and endocannabinoid systems in the sensorimotor gating deficits and social withdrawal occurring in AD and points to A2AR and CB1R as a potential target to reverse these non-cognitive symptoms in AD patients.