Effects of pharmacological manipulations of cannabinoid receptors on severity of dystonia in a genetic model of paroxysmal dyskinesia.
Previous studies have shown beneficial effects of the cannabinoid CB(1)/CB(2) receptor agonist (R)-4,5-dihydro-2-methyl-4-(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo [3,2,1-ij]quinolin-6-one mesylate (WIN 55,212-2) in dt(sz) mutant hamsters, a model of idiopathic paroxysmal dystonia (dyskinesia). To examine the pathophysiological significance of the cannabinergic system in the dystonic syndrome, the effect of the cannabinoid CB(1) receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716A) on severity of dystonia was investigated in dt(sz) mutants which exhibit episodes of dystonic and choreoathetotic disturbances in response to mild stress. SR 141716A (5 and 10 mg/kg i.p.) failed to exert any effects on the severity of dystonia. While the antidystonic efficacy of WIN 55,212-2 (5 mg/kg i.p.) was confirmed, cannabidiol (which has low affinity to cannabinoid receptors) tended to delay the progression of dystonia only at a high dose (150 mg/kg i.p.). The antidystonic and cataleptic effects of WIN 55,212-2 (5 mg/kg i.p.) were completely antagonized by pretreatment with SR 141716A at doses of 2.5 mg/kg (catalepsy) and 10 mg/kg (antidystonic efficacy). These data indicate that the antidystonic efficacy of WIN 55,212-2 is selectively mediated via CB(1) receptors. The lack of prodystonic effects of SR 141716A together with only moderate antidystonic effects of WIN 55,212-2 suggests that reduced activation of cannabinoid CB(1) receptors by endocannabinoids is not critically involved in the dystonic syndrome. In view of previous pathophysiological findings in mutant hamsters, the antidystonic efficacy of WIN 55,212-2 can be explained by modulation of different neurotransmitter systems within the basal ganglia.
Richter
Angelika
A
Institute of Pharmacology and Toxicology, School of Veterinary Medicine, FU Berlin, Koserstrasse 20, 14195 Berlin, Germany. angelika.richter@tiho-hannover.de
Löscher
Wolfgang
W
D000818:Animals; D048588:Benzoxazines; D002185:Cannabidiol / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002819:Chorea / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D006224:Cricetinae; D004195:Disease Models, Animal; D004421:Dystonia / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D008297:Male; D008647:Mesocricetus; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077285:Rimonabant
D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D002185:Cannabidiol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant