Enhanced cognitive performance of dopamine D3 receptor “knock-out” mice in the step-through passive-avoidance test: Assessing the role of the endocannabinoid/endovanilloid systems

Increasing evidence suggests a pivotal role of the D3 receptor (D3R) in cognitive processes and the involvement of endocannabinoid/endovanilloid signaling in the pathophysiology of neurodegenerative disorders such as Alzheimer's disease. This study was undertaken to investigate both the basal and β-amyloid peptide 1-42 (BAP 1-42)-impaired cognitive performance of D3R(−/−) mice, and the role therein of endocannabinoids/endovanilloids. D3R(−/−) mice were either untreated or injected i.c.v. with 400 pMol BAP 1-42 or vehicle to be tested 14 days later in a step-through passive-avoidance paradigm. The CB1 receptor antagonist, rimonabant (1 mg/kg), or the transient receptor potential vanilloid-type 1 channel (TRPV1) antagonist SB366791, were injected intraperitoneally for 11 or 7 days. The retention test was performed 1, 7 and 14 days after the learning trial. Wild-type (WT) mice were subjected to the same procedures. D3R(−/−) mice exhibited a better basal cognitive performance as compared to WT mice (p < 0.001), which was reversed by TRPV1 antagonism. BAP 1-42 induced a pronounced worsening of the passive-avoidance response in all tests and in both genotypes (p < 0.001). Rimonabant treatment never affected the cognitive performance of healthy mice, but fully counteracted BAP 1-42-induced amnesic effects in both D3R(−/−) and WT mice only when administered for 11 days, whereas, when administered for 7 days, only transiently affected WT mice and caused more prolonged cognitive ameliorations in D3R(−/−) mice. These results support the involvement of D3R and TRPV1 in cognitive processes and the concept that Aβ peptides inhibit memory retention in mice through the involvement of endocannabinoids.