Cannabinoid CB1 receptor agonists produce cerebellar dysfunction in mice

The purpose of these studies was to characterize the effects of agonists of the CB1 cannabinoid receptor on cerebellar function in mice. We used two m easures specific for cerebellar function: gait analysis and the bar cross t est. CB1 receptor agonists CP55940, Win 55212-2, Delta (9)-tetrahydrocannab inol, arachidonylethanolamide (AEA), and two AEA analogs with high affinity for the CB1 receptor (arachidonyl-2-chloroethylamide and arachidonylcyclop ropylamide) all produced increases in gait width, a measure of truncal atax ia. All of the CB1 agonists tested significantly increased the number of sl ips on the bar cross test, which is consistent with motor incoordination. P retreatment with the CB1 receptor antagonist SR141716 attenuated both the c hange 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 CB1 receptor. Pretreatment with the dopamin e receptor agonists apomorphine or bromocriptine did not attenuate the dimi nished performance on the bar cross or the gait abnormality induced by CP55 940. These data indicate that the assays used in this study are specific fo r cerebellar-mediated behavioral deficits, and that these deficits are not mediated by the basal ganglia or cannabinoid-induced alterations in nigrost riatal 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 dysfunc tion and a working model of the effects of CB1 receptor activation on cereb ellar circuitry is presented.