Effects of rimonabant, a selective cannabinoid CB1 receptor antagonist, in a rat model of Parkinson's disease.
Recent evidence suggest that the blockade of cannabinoid CB1 receptors might be beneficial to alleviate motor inhibition typical of Parkinson's disease (PD). In the present study, we have explored the motor effects of rimonabant, a selective antagonist of CB1 receptors, in a rat model of PD generated by an intracerebroventricular injection of 6-hydroxydopamine. Compared with rats subjected to unilateral injection of this toxin in the medial forebrain bundle, this model allows nigral dopaminergic neurons be symmetrically affected. Dose-response studies with 6-hydroxydopamine revealed that the application of 200 microg per animal caused hypokinetic signs (decreased ambulatory activity, increased inactivity, and reduced motor coordination), which paralleled several signs of degeneration of nigrostriatal dopaminergic neurons (dopamine depletion in the caudate-putamen, and decreased mRNA levels for tyrosine hydroxylase and superoxide dismutase-1 and -2 in the substantia nigra). In these conditions, the degree of hypokinesia and dopaminergic degeneration may be considered moderate, comparable to the disturbances occurring in early and middle stages of PD in humans, a period that might be appropriate to test the effects of rimonabant. There is also degeneration of other dopaminergic pathways out of the basal ganglia, but this does not appear to interfere significantly with the hypokinetic profile of these rats. Higher doses of 6-hydroxydopamine elevated significantly animal mortality and lower doses failed in general to reproduce motor inhibition. Like other animal models of PD, these rats exhibited an increase in the density of CB(1) receptors in the substantia nigra, which is indicative of the expected overactivity of the cannabinoid transmission in this disease and supports the potential of CB1 receptor blockade to attenuate hypokinesia associated with nigral cell death. Thus, the injection of 0.1 mg/kg of rimonabant partially attenuated the hypokinesia shown by these animals with no effects in control rats, whereas higher doses (0.5-1.0 mg/kg) were not effective. We also found that the antihypokinetic effects of low doses of rimonabant did not influence the dopamine deficits of these animals, as well as it did not modify GABA or glutamate transmission in the caudate-putamen. In summary, rimonabant may have potential antihypokinetic activity in moderate parkinsonism at low doses, but this effect is not related to changes in dopaminergic, GABAergic, or glutamatergic transmission in the striatum. Therefore, the elucidation of the neurochemical substrate involved in this effect remains a major challenge for the future.
González
Sara
S
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040-Madrid, Spain.
Scorticati
Camila
C
García-Arencibia
Moisés
M
de Miguel
Rosario
R
Ramos
José A
JA
Fernández-Ruiz
Javier
J
D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D017403:In Situ Hybridization / Q000379:methods; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology; D010880:Piperidines / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077285:Rimonabant; D045442:Rotarod Performance Test / Q000379:methods; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D018663:Adrenergic Agents; D004298:Dopamine; D018698:Glutamic Acid; D016627:Oxidopamine; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014446:Tyrosine 3-Monooxygenase; D005680:gamma-Aminobutyric Acid; D000099156:Superoxide Dismutase 2; C000606290:SOD1 protein, human; C000606292:Sod1 protein, rat