3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Huntington-Disease

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,

Topics: 3,4-Dihydroxyphenylacetic Acid; Amino Acids, Neutral; Animals; Arachidonic Acids; Basal Ganglia; Cannabinoid Receptor Modulators; Capsaicin; Corpus Striatum; Cyclohexanols; Disease Models, Animal; Dopamine; Endocannabinoids; gamma-Aminobutyric Acid; Huntington Disease; Hyperkinesis; Male; Motor Activity; Nitro Compounds; Palmitates; Piperidines; Propionates; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Previous autoradiographic studies in rats using [3H]CP55,940 have demonstrated the cannabinoid receptor to be located on the axon terminals of striatal efferent neurons projecting to the globus pallidus and substantia nigra. Because these neurons are selectively lost in Huntington's disease, a loss of [3H]CP55,940 binding is predicted in the substantia nigra of the Huntington's disease brain. We have used autoradiography to compare the binding of [3H]CP55,940 in the substantia nigra of Huntington's disease and neurologically normal brains. The results have demonstrated that cannabinoid receptors in the normal human substantia nigra are discreetly localized within the substantia nigra pars reticulata. In contrast, the Huntington's disease brains show a massive loss (97.5%) of cannabinoid receptor binding in the substantia nigra pars reticulata. These results show that in the substantia nigra of the human brain cannabinoid receptors are located on striatonigral terminals which degenerate in Huntington's disease.

Topics: Aged; Aged, 80 and over; Autoradiography; Cannabinoids; Cyclohexanols; Humans; Huntington Disease; In Vitro Techniques; Male; Middle Aged; Presynaptic Terminals; Receptors, Cannabinoid; Receptors, Drug; Substantia Nigra