Cannabinoid CB(1) receptor agonists produce cerebellar dysfunction in mice.
The purpose of these studies was to characterize the effects of agonists of the CB(1) cannabinoid receptor on cerebellar function in mice. We used two measures specific for cerebellar function: gait analysis and the bar cross test. CB(1) receptor agonists CP55940, Win 55212-2, Delta(9)-tetrahydrocannabinol, arachidonylethanolamide (AEA), and two AEA analogs with high affinity for the CB(1) receptor (arachidonyl-2-chloroethylamide and arachidonylcyclopropylamide) all produced increases in gait width, a measure of truncal ataxia. All of the CB(1) agonists tested significantly increased the number of slips on the bar cross test, which is consistent with motor incoordination. Pretreatment with the CB(1) receptor antagonist SR141716 attenuated both the change in gait width and number of slips induced by CP55940 and AEA. Neither cannabidiol nor Win 55212-3 affected these measures, further evidence that this effect is mediated by the CB(1) receptor. Pretreatment with the dopamine receptor agonists apomorphine or bromocriptine did not attenuate the diminished performance on the bar cross or the gait abnormality induced by CP55940. These data indicate that the assays used in this study are specific for cerebellar-mediated behavioral deficits, and that these deficits are not mediated by the basal ganglia or cannabinoid-induced alterations in nigrostriatal dopaminergic transmission. Other well known effects of cannabinoids in mice, such as hyperreflexia exemplified by jumping or "popcorn" behavior and postural hypotonia are discussed in relationship to cerebellar dysfunction and a working model of the effects of CB(1) receptor activation on cerebellar circuitry is presented.
Patel
S
S
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Hillard
C J
CJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D002526:Cerebellar Diseases / Q000139:chemically induced*; D003511:Cyclohexanols / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D005684:Gait / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*; D000077285:Rimonabant
D048588:Benzoxazines; D002121:Calcium Channel Blockers; D002186:Cannabinoids; D003511:Cyclohexanols; D018491:Dopamine Agonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant