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.