Changes in endocannabinoid transmission in the basal ganglia in a rat model of Huntington's disease.
Recent studies have demonstrated a loss of cannabinoid CB1 receptors in the basal ganglia in Huntington's disease (HD), but there are no data on endocannabinoid levels in this disease. In the present study, we have addressed this question by using rats with bilateral intrastriatal injections of 3-nitropropionic acid (3-NP), a toxin that, through the selective damage of striatal GABAergic efferent neurons, produces a useful model of HD. Twelve days after the lesion, 3-NP-lesioned rats exhibited motor disturbances, characterized by an ambulatory hyperactivity accompanied by a loss of guided activities. Analysis of GABA contents in the basal ganglia showed a trend towards a reduction compatible with motor hyperactivity. In addition, CB1 receptor binding and, to a greater extent, CB1 receptor activation of GTP-binding proteins, were also reduced in the basal ganglia. These changes were paralleled by a decrease of the contents of the two endocannabinoids, anandamide and 2-arachidonoylglycerol, in the striatum, and by an increase, particularly of anandamide, in the ventral mesencephalon where the substantia nigra is located. Both CB1 receptors and endocannabinoid levels were not altered in the cerebral cortex, an area not affected by the lesion. In summary, behavioral and biochemical changes observed in rats intrastriatally lesioned with 3-NP were similar to those occurring in the brain of HD patients. As expected, a loss of CB1 receptor function was evident in the basal ganglia of these rats and this was accompanied by different changes in endocannabinoid levels.
Lastres-Becker
I
I
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
Fezza
F
F
Cebeira
M
M
Bisogno
T
T
Ramos
J A
JA
Milone
A
A
Fernández-Ruiz
J
J
Di Marzo
V
V
D000818:Animals; D001479:Basal Ganglia / Q000503:physiopathology*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism*; D003292:Convulsants / Q000008:administration & dosage; D004195:Disease Models, Animal; D063388:Endocannabinoids; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009574:Nitro Compounds; D011422:Propionates / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D003292:Convulsants; D063388:Endocannabinoids; D009574:Nitro Compounds; D011422:Propionates; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D005680:gamma-Aminobutyric Acid; C015392:3-nitropropionic acid