Abstract
The ability of CB 1 receptors to regulate the release of glutamate in the striatum, together with the finding that, in experimental models of Huntington disease (HD), both endocannabinoid levels and CB 1 receptor densities are reduced, has prompted the investigation on the neuroprotective role of the cannabinoids in HD. Quinolinic acid (QA) is an excitotoxin that, when injected in the rat striatum reproduces many features of HD and that acts by stimulating glutamate outflow. The aim of the present study was to test the ability of the cannabinoid receptor agonist WIN 55,212-2 to prevent the effects induced by QA in the rat striatum. In microdialysis experiments, probe perfusion with WIN 55,212-2 significantly and dose-dependently prevented the increase in extracellular glutamate induced by QA. In electrophysiological recordings in corticostriatal slices, the application of WIN 55,212-2 prevented QA-induced reduction of the field potential amplitude. Both effects of WIN 55,212-2 were prevented by the CB 1 receptor antagonist AM 251. In in vivo experiments, intrastriatal WIN 55,212-2 significantly attenuated the striatal damage induced by QA, although no significant effects were observed on a behavioural ground. These data demonstrate that the stimulation of CB 1 receptors might lead to neuroprotective effects against excitotoxic striatal toxicity.
Highlights
In the central nervous system, the physiological actions of cannabinoids are mediated mainly by type 1 cannabinoid (CB1) receptors (Pertwee, 1997; Freund et al, 2003)
In a separate series of experiments we found that, when WIN 55,212-2 was applied over 20 min, and washed out, the field potentials (FPs) amplitude decreased up to 67.19 Æ 7.56% of basal (N 1⁄4 4) 30 min after the washout
The main findings of the present study are as follows: i) WIN 55,212-2 prevented Quinolinic acid (QA)-induced glutamate outflow and FP reduction in a concentration-dependent way; ii) the effects of WIN 55,212-2 were fully prevented by AM251, indicating a selective involvement of CB1 receptors; and iii) the ability of WIN 55,212-2 to prevent QA-induced increase in extracellular glutamate is associated with a weak neuroprotective effect in QA-lesioned rats
Summary
In the central nervous system, the physiological actions of cannabinoids are mediated mainly by type 1 cannabinoid (CB1) receptors (Pertwee, 1997; Freund et al, 2003). The finding that in Huntington disease (HD, a devastating and still untreatable neurodegenerative disease) the loss of CB1 receptor binding in the basal ganglia is one of the earliest neurochemical alterations (Richfield and Herkenham, 1994; Glass et al, 2000), has prompted the investigation of the neuroprotective role of cannabinoids in HD. In models of striatal degeneration induced by mitochondrial toxins in rats, the idea that CB1 receptor agonists could be neuroprotective was not confirmed. The role of CB1 receptors in HD and in HD-like striatal degeneration is far from being elucidated, and the ability of CB1 receptor agonists to exert neuroprotective effects, if any, might depend on the mechanisms responsible for striatal toxicity in a given experimental model
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