Loss of cannabinoid receptor binding and messenger RNA levels and cannabinoid agonist-stimulated [35S]guanylyl-5'O-(thio)-triphosphate binding in the basal ganglia of aged rats.
Recent reports have demonstrated that cannabinoid receptor binding decreases in several neurodegenerative diseases related to extrapyramidal function. However, there is little evidence with regard to potential changes of these receptors during senescence. The present study was designed to determine the possible existence of ageing-induced changes in cannabinoid receptor binding and gene expression in extrapyramidal areas. To this end, we analysed cannabinoid receptor binding and basal and cannabinoid receptor agonist-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate binding, by using autoradiography, and cannabinoid receptor messenger RNA levels, by using in situ hybridization, in slide-mounted brain sections obtained from young (three-month-old) and aged (>two-year-old) rats. Results were as follows. Aged rats exhibited a marked decrease in cannabinoid receptor binding in most of the basal ganglia, excepting the globus pallidus which had similar binding levels in both young and aged rats. The highest decreases were in the entopeduncular nucleus (-49.6%) and substantia nigra pars reticulata (-45.2%), whereas more moderate decreases were found in the lateral caudate putamen (-29%) and only a decremental trend in the medial caudate putamen (-13.1%). These decreases in cannabinoid receptor binding were paralleled by less marked increases in WIN 55212-2-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate binding in these structures in aged rats (% of agonist stimulation: 189% in the substantia nigra; 29.4% in the lateral caudate putamen) as compared to young rats (296% and 53.2%, respectively). Contrarily, the percentage of agonist stimulation was similar in the globus pallidus, an area where cannabinoid receptor binding did not change during ageing, of aged (205.5%) and young (215.5%) rats. In addition, aged rats also exhibited significant reductions in the cannabinoid receptor messenger RNA levels in the medial (-14.3%) and, in particular, in the lateral (-29.4%) caudate putamen, the area where the cell bodies of cannabinoid receptor-containing neurons, projecting to the substantia nigra, entopeduncular nucleus and globus pallidus, are located. In summary, the synthesis and binding levels of cannabinoid receptors markedly dropped in different structures of the extrapyramidal system of aged rats. Since these receptors, located in the basal ganglia, seem to play a role in motor control, this loss of cannabinoid receptors might be related to the motor impairment which progressively appears during senescence.
Romero
J
J
Instituto Complutense de Drogodependencias, Department of Biochemistry, Faculty of Medicine, Complutense University, Madrid, Spain.
Berrendero
F
F
Garcia-Gil
L
L
de la Cruz
P
P
Ramos
J A
JA
Fernández-Ruiz
J J
JJ
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001479:Basal Ganglia / Q000378:metabolism*; D048588:Benzoxazines; D002186:Cannabinoids / Q000819:agonists* / Q000378:metabolism / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000031:analogs & derivatives* / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000096:biosynthesis / Q000378:metabolism*
D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C034883:guanosine 5'-O-(2-thiotriphosphate); D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone