Increased vulnerability to 6-hydroxydopamine lesion and reduced development of dyskinesias in mice lacking CB1 cannabinoid receptors.
Motor impairment, dopamine (DA) neuronal activity and proenkephalin (PENK) gene expression in the caudate-putamen (CPu) were measured in 6-OHDA-lesioned and treated (L-DOPA+benserazide) CB1 KO and WT mice. A lesion induced by 6-OHDA produced more severe motor deterioration in CB1 KO mice accompanied by more loss of DA neurons and increased PENK gene expression in the CPu. Oxidative/nitrosative and neuroinflammatory parameters were estimated in the CPu and cingulate cortex (Cg). CB1 KO mice exhibited higher MDA levels and iNOS protein expression in the CPu and Cg compared to WT mice. Treatment with L-DOPA+benserazide (12 weeks) resulted in less severe dyskinesias in CB1 KO than in WT mice. The results revealed that the lack of cannabinoid CB1 receptors increased the severity of motor impairment and DA lesion, and reduced L-DOPA-induced dyskinesias. These results suggest that activation of CB1 receptors offers neuroprotection against dopaminergic lesion and the development of L-DOPA-induced dyskinesias.
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Apartado de correos 18, 03550 San Juan de Alicante, Spain.
Sandra
S
Pérez-Rial
María S
MS
García-Gutiérrez
José A
JA
Molina
Beatriz G
BG
Pérez-Nievas
Catherine
C
Ledent
Carlos
C
Leiva
Juan C
JC
Leza
Jorge
J
Manzanares
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001545:Benserazide / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D007980:Levodopa / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index
D015259:Dopamine Agents; D043884:Receptor, Cannabinoid, CB1; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; D000661:Amphetamine