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.
Department of Experimental and Clinical Pharmacology, University of Catania Medical School, V.le A. Doria 6, 95125 Catania, Italy.
Vincenzo
V
Micale
Luigia
L
Cristino
Alessandra
A
Tamburella
Stefania
S
Petrosino
Gian Marco
GM
Leggio
Vincenzo
V
Di Marzo
Filippo
F
Drago
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