EFFECTS OF SR141716 (RIMONABANT), A SELECTIVE CANNABINOID CB1 RECEPTOR ANTAGONIST, IN A RAT MODEL OF PARKINSON?S DISEASE

SCORTICATI, C; GONZALEZ, S; GARCÍA-ARENCIBIA, M; RAMOS, JA; FERNANDEZ-RUIZ, J

Busto Arsizio, Varese, Italy

Congreso; Second European Workshop on Cannabinoid Research; 2005

The International Cannabinoid Research Society

Recent evidence suggests that the blockade of cannabinoid CB1 receptors might be beneficial to alleviate motor inhibition typical of Parkinson?s disease (PD). To explore this hypothesis, we developed an animal model of PD, rats subjected to intracerebroventricular injection of 6-hydroxydopamine, which, compared with the classic model of unilateral injection of this toxin in the medial forebrain bundle, allows that nigral dopaminergic neurons were symmetrically affected, whereas the degeneration of other dopaminergic pathways out of the basal ganglia does not significantly interfere with the hypokinetic profile of these rats. Dose-response studies with 6-hydroxydopamine revealed that application of a dose of 200 mg per animal caused hypokinetic signs (decreased ambulatory activity, increased inactivity, and reduced motor coordination) originated by the occurrence of degeneration of nigrostriatal dopaminergic neurons (marked dopamine depletion in the caudate-putamen, and decreased mRNA levels for tyrosine hydroxylase and superoxide dismutase-1 and ?2 in the substantia nigra), disturbances comparable to those occurring in PD. Higher doses significantly elevated the mortality whereas lower doses failed in general to reproduce motor inhibition. Like other animal models of PD, these rats exhibited an increase in the density of CB1 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 SR141716, a selective antagonist of CB1 receptors,  in a range of doses between 0.1 up to 0.5 mg/kg attenuated the marked hypokinesia shown by these animals with no effects in control rats, although higher doses (0.5 - 1.0 mg/kg) tended to inhibit movement in both 6-hydroxydopamine-lesioned and control rats. We also found that the antihypokinetic effects of low doses of SR141716 did not influence the dopamine deficits of these animals, whereas the trend towards motor inhibition caused by high doses of this antagonist seems to be mediated through a reduction in dopamine activity in the caudate-putamen. In summary, SR141716 may have potential antihypokinetic activity in PD although it must be used at low doses, since high doses might enhance motor disability. Changes in nigrostriatal dopaminergic transmission do not appear to be involved in the antihypokinetic effect of rimonabant, so the elucidation of the neurochemical substrate involved in this effect remains a major challenge for the future. (Supported by MCYT (SAF2003-08269) and ?Red CIEN? (C03/06)