496 J. Fernández-Ruiz and S. González
2.3.1
Changes in the Endocannabinoid Transmission
Compared with HD, much less data exist on the status of CB 1 receptors in the
postmortem basal ganglia of humans affected by PD. Only recently we have found
that CB 1 receptor binding and the activation of G proteins by cannabinoid agonists
were significantly increased in the basal ganglia as a consequence of the selective
degeneration of nigrostriatal dopaminergic neurons (Lastres-Becker et al. 2001a).
These increases were not related to the chronic dopaminergic replacement therapy
withl-dopa that these patients were undergoing, since they were also seen in
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a pri-
mate PD model, and disappeared after chronicl-dopa administration in these
animals (Lastres-Becker et al. 2001a). It has also been found that endocannabinoid
levels increase in a rat model of PD and that this increase can be reversed by
l-dopa (Gubellini et al. 2002; Macarrone et al. 2003). This suggests the existence
of an imbalance between dopamine and endocannabinoids in the basal ganglia in
PD (see Fernández-Ruiz et al. 2002 for a review).
As in HD, a change in CB 1 receptor density might also be an early event in the
pathogenesis of PD. This is supported by data obtained from individuals affected
by incidental Lewy body disease, an early and presymptomatic phase of PD. These
individuals, who did not receive any therapy as they presented Lewy bodies and
a low degree of nigral pathology without any neurological symptoms, exhibited
a trend towards an increase in CB 1 receptors in some basal ganglia structures
(Lastres-Becker et al. 2001a). Moreover, preliminary experiments with a genetic
model of PD, the parkin-2 knockout mouse (Itier et al. 2003), have yielded data
showinganincreaseinCB 1 receptorbindinginthesubstantianigraoftheknockout
mice that occurs in the absence of neuronal death (González S, Lastres-Becker I,
Ramos JA, Fernández-Ruiz J, unpublished results).
Overactivity of endocannabinoid transmission (as measured by increases in
CB 1 receptor or endocannabinoid levels) has also been observed in the basal
ganglia in different rat models of PD (Mailleux and Vanderhaeghen 1993; Romero
et al. 2000; Di Marzo et al. 2000a; Gubellini et al. 2002), although the data are
not consistent, with some authors reporting no changes (Herkenham et al. 1991b),
reductions in CB 1 receptor levels (Silverdale et al 2001), or a dependency on chronic
l-dopa co-treatment (Zeng et al. 1999). Despite these conflicts, we consider that
most of the data indicate that endocannabinoid transmission becomes overactive
in the basal ganglia in PD, a conclusion that is compatible with the hypokinesia
that characterizes this disease. This would also support the suggestion that CB 1
receptor antagonists, rather than agonists, might be useful for alleviating motor
deterioration in PD, or for reducing the development of dyskinesia caused by
prolonged replacement therapy withl-dopa (Brotchie 2000).