Chronic l-DOPA treatment increases striatal cannabinoid CB1 receptor mRNA expression in 6-hydroxydopamine-lesioned rats

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

“…The above changes in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated marmosets and 6-hydroxydopamine-lesioned rats were reversible by chronic Ldopa treatment, which indicates that the similar changes observed in PD patients were unlikely to have been induced by the replacement therapy (LastresBecker et al, 2001a;Maccarrone et al, 2003). There is broad agreement that the endocannabinoid system becomes overactive in the basal ganglia in PD (reviewed in Brotchie, 2003), although some studies report a reduction (Silverdale et al, 2001) or no change in CB 1 receptor expression (Herkenham et al, 1991a) or a dependence on L-DOPA cotreatment of the increased CB 1 receptor expression in the basal ganglia of animals with experimental PD (Zeng et al, 1999).…”

“…Third, endogenous, plant-derived, and synthetic cannabinoids have potent, mostly inhibitory, effects on motor activity (Crawley et al, 1993;Fride and Mechoulam, 1993;Wickens and Pertwee, 1993;Smith et al, 1994;Romero et al, 1995aRomero et al, ,b, 2002breviewed in Sañ udo-Peñ a et al, 1999b). Fourth, CB 1 receptor and endocannabinoid levels are altered in the basal ganglia both in experimental models (Zeng et al, 1999;Page et al, 2000;Romero et al, 2000;Lastres-Becker et al, 2001aGonzalez et al, 2006) and human forms of movement disorders (Glass et al, 1993Lastres-Becker et al, 2001a;reviewed in Romero et al, 2002b). Fifth, the endocannabinoid system interacts with several neurotransmitter pathways at various levels of the basal ganglia circuitry (Glass et al, 1997a;Miller et al, 1998;Giuffrida et al, 1999;Rodriguez De Fonseca et al, 2001;Brotchie, 2003;van der Stelt and Di Marzo, 2003;de Lago et al, 2004a).…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…In the rat, striatal levels of CB 1 receptor mRNA were unchanged following 6-OHDA lesion but increased following chronic L-DOPA therapy when the animals were killed 3 hours after last L-DOPA dose (Zeng et al, 1999). As no behavioral correlate was provided, it is difficult to link the increase in CB 1 receptor mRNA to the dyskinetic phenotype (Zeng et al, 1999).…”

“…As no behavioral correlate was provided, it is difficult to link the increase in CB 1 receptor mRNA to the dyskinetic phenotype (Zeng et al, 1999). In the MPTP-lesioned marmoset (time of death with respect to last dose of L-DOPA not mentioned), striatal CB 1 binding levels were not different to those in control animals but were lower than those encountered in MPTP-lesioned, L-DOPA-naive animals (LastresBecker et al, 2001).…”

Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases

“…CB 1 receptor mRNA levels in cell bodies of striatal efferent neurons were markedly increased in rats unilaterally injected with 6-hydroxydopamine (6-OHDA) to deplete dopamine, but this did not result in changes in CB 1 receptor binding capacity and activation of intracellular signal transduction mechanisms (Mailleux and Vanderhaeghen, 1993;Romero et al, 2000). Zeng et al (1999) also observed increased striatal CB 1 mRNA in 6-OHDA-lesioned rats, but only after chronic L-DOPA treatment. By contrast, CB 1 receptor transcription was increased in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) marmoset model of PD, and the mRNA levels returned to control values upon chronic L-DOPA treatment (Lastres-Becker et al, 2001a).…”