We have recently reported that the administration of
AM404, an inhibitor of the
endocannabinoid re-uptake process, which also has affinity for the vanilloid VR1 receptors, is able to reduce
hyperkinesia, and causes recovery from neurochemical deficits, in a rat model of
Huntington's disease (HD) generated by bilateral intrastriatal
injections of
3-nitropropionic acid (3NP). In the present study, we wanted to explore the mechanism(s) by which
AM404 produces its antihyperkinetic effect in 3NP-lesioned rats by employing several experimental approaches. First, we tried to block the effects of
AM404 with selective antagonists for the CB1 or VR1 receptors, i.e.
SR141716A and
capsazepine, respectively. We found that the reduction caused by
AM404 of the increased ambulation exhibited by 3NP-lesioned rats in the open-field test was reversed when the animals had been pre-treated with
capsazepine but not with
SR141716A, thus suggesting a major role of VR1 receptors in the antihyperkinetic effects of
AM404. However, despite the lack of behavioral effects of the
CB1 receptor antagonist, the pretreatment with this compound abolished the recovery of neurochemical [
gamma-aminobutyric acid (
GABA) and
dopamine] deficits in the caudate- putamen caused by
AM404, as also did
capsazepine. In a second group of studies, we wanted to explore the potential antihyperkinetic effects of various compounds which, compared to
AM404, exhibit more selectivity for either the endovanilloid or the
endocannabinoid systems. First, we tested
VDM11 or
AM374, two selective inhibitors or the
endocannabinoid re-uptake or hydrolysis, respectively. Both compounds were mostly unable to reduce
hyperkinesia in 3NP-lesioned rats, although
VDM11 produced a certain motor depression, and
AM374 exhibited a trend to stimulate ambulation, in control rats. We also tested the effects of selective direct agonists for VR1 (
capsaicin) or CB1 (
CP55,940) receptors.
Capsaicin exhibited a strong antihyperkinetic activity and, moreover, was able to attenuate the reductions in
dopamine and
GABA transmission provoked by the 3NP lesion, whereas
CP55,940 had also antihyperkinetic activity but was unable to cause recovery of either
dopamine or
GABA deficits in the basal ganglia. In summary, our data indicate a major role for VR1 receptors, as compared to CB1 receptors, in the antihyperkinetic effects and the recovery of neurochemical deficits caused in 3NP-lesioned rats by compounds that activate both CB1 and VR1 receptors, either directly or via manipulation of the levels of endogenous agonists.