title: Loss of cannabinoid CB(1) receptors in the basal ganglia in the late akinetic phase of rats with experimental Huntington's disease.
abstract: We have recently examined the status of the endocannabinoid transmission in the basal ganglia in Huntington's disease (HD) using a rat model generated by bilateral intrastriatal injections of 3-nitropropionic acid (3-NP). In these previous studies, we focused on the early phase of hyperactivity that occurs 1-2 weeks after the lesion, comparable to early grades of the human disease, while in the present study, we wanted to explore the late akinetic phase observed 3-4 weeks after the lesion (similar to advanced grades). First, we confirmed that 3-NP-lesioned rats exhibited a marked akinesia tested at 4 weeks post-lesion. We observed a marked reduction in ambulatory and exploratory activities and a trend towards a decrease in stereotypies, paralleled by a strong increase in the time spent in inactivity. There was also a profound reduction in GABA contents and glutamic acid decarboxylase activity, particularly in the caudate-putamen and the globus pallidus. Dopamine and DOPAC contents, as well as the activity of tyrosine hydroxylase, were also reduced, particularly in the caudate-putamen. mRNA levels for neuronal-specific enolase, proenkephalin and substance P were also dramatically reduced in the caudate-putamen, thus indicating a death of both the direct (striatonigral) and the indirect (striatopallidal) GABAergic projection pathways, which corresponded with a marked loss of CB(1) receptor-mRNA levels observed in both parts, lateral and medial, of the caudate-putamen. However, losses of CB(1) receptor binding were confined to the globus pallidus and the caudate-putamen, whereas there were no changes in the substantia nigra and the entopeduncular nucleus. Finally, we failed to reduce the marked akinesia found in these animals by administering SR141716A, a selective antagonist of CB(1) receptors, which had exhibited hyperlocomotor effects in previous studies with naive animals. In summary, behavioral and biochemical changes observed in rats intrastriatally lesioned with 3- NP were compatible with a profound degeneration of striatal efferent GABAergic neurons, similar to those occurring in advances stages of the human disease. As expected, a loss of CB(1) receptors was evident in the basal ganglia of these rats during the late akinetic stage of the disease. Further studies should demonstrate whether these receptors might be a target for a new therapy in HD, a disease with a poor pharmacological outcome.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lastres-Becker
authors.forename: María
authors.initials: M
authors.lastname: Gómez
authors.forename: Rosario
authors.initials: R
authors.lastname: De Miguel
authors.forename: José A.
authors.initials: JA
authors.lastname: Ramos
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz