RIMONABANT, A SELECTIVE CANNABINOID CB1 RECEPTOR ANTAGONIST, REDUCES HYPOKINESIA IN A RAT MODEL OF PARKINSON?S DISEASE

GARCIA-ARENCIBIA, M; SCORTICATI, C; GONZALEZ, S; DE MIGUEL, R; RAMOS, JA; FERNANDEZ-RUIZ, J

Huelga, España

Congreso; Implications of Comorbidity for Etiology and Treatment of Neuropsychiatric Disorders; 2005

Fundación Cerebro y Mente

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 used rats subjected to intracerebroventricular injection of 6-hydroxydopamine, a suitable rat model of PD where exploring the motor effects of SR141716 (rimonabant), a selective antagonist of CB1 receptors. This rat model of PD, compared with unilateral injections of this toxin in the medial forebrain bundle, allows nigral dopaminergic neurons be symmetrically affected, whereas the degeneration of other dopaminergic pathways out of the basal ganglia does not interfere significantly with the hypokinetic profile of these rats. Dose-response studies with 6-hydroxydopamine revealed that the application of 200 mg per animal caused hypokinetic signs (decreased ambulatory activity, increased inactivity, and reduced motor coordination) originated by 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 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 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 0.1 mg/kg of SR141716 attenuated the marked 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 SR141716 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, SR141716 may have potential antihypokinetic activity in PD 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.