Potential involvement of cannabinoid receptors in 3-nitropropionic acid toxicity in vivo.
Several neurotransmitter systems are involved in the pathogenesis of Huntington's disease. Here, we examined the involvement of cannabinoid CB(1) receptors in striatal degeneration in the rat model of this disease generated by administration of 3-nitropropionic acid (3NP). Several days before onset of striatal degeneration, G-protein activation by cannabinoid agonists was significantly decreased whereas density and mRNA levels of CB(1) receptors remained essentially normal. This change was transient, CB(1) receptors recovering full functionality after few days. Later, at onset of striatal degeneration, profound alterations of CB(1) receptors were detected, including marked reductions of their density, mRNA levels and coupling to G proteins. In these rats, the administration of the cannabinoid agonist Delta(9)-tetrahydrocannabinol was neuroprotective, which indicates that the early loss of CB(1) receptor signaling could be instrumental in 3NP toxicity. In conclusion, the present study supports the hypothesis that cannabinoid receptors, possibly the CB(1) receptor subtype, may be involved in HD pathogenesis and could be an interesting therapeutic target to slow disease progression.
Lastres-Becker
Isabel
I
Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
Bizat
Nicolas
N
Boyer
Frédéric
F
Hantraye
Philippe
P
Fernández-Ruiz
Javier
J
Brouillet
Emmanuel
E
D000818:Animals; D001345:Autoradiography / Q000379:methods; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D013759:Dronabinol / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004347:Drug Interactions; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D011619:Psychotropic Drugs / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020955:Striatonigral Degeneration / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D013385:Succinate Dehydrogenase; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D003292:Convulsants; D009574:Nitro Compounds; D011422:Propionates; D011619:Psychotropic Drugs; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D005680:gamma-Aminobutyric Acid; D013759:Dronabinol; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid; D004298:Dopamine