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 beta-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 CB(1) receptor antagonist, rimonabant (1mg/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 A beta peptides inhibit memory retention in mice through the involvement of endocannabinoids.
Micale
Vincenzo
V
Department of Experimental and Clinical Pharmacology, University of Catania Medical School, V.le A. Doria 6, 95125 Catania, Italy.
Cristino
Luigia
L
Tamburella
Alessandra
A
Petrosino
Stefania
S
Leggio
Gian Marco
GM
Di Marzo
Vincenzo
V
Drago
Filippo
F
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000813:Anilides / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D002934:Cinnamates / Q000008:administration & dosage / Q000627:therapeutic use; D003071:Cognition; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D000077285:Rimonabant; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
D016229:Amyloid beta-Peptides; D000813:Anilides; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050637:Receptors, Dopamine D3; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C544092:beta-amyloid peptide 1-42 (E22delta) click peptide; D000077285:Rimonabant