Tolerance to the tremorogenic effects of harmaline: evidence for altered olivo-cerebellar function.

Administration of the beta-carboline alkaloid, harmaline, causes the neurons of the inferior olive to fire synchronously and to act as a pacemaker for the generation of tremor. Rats treated daily with harmaline showed a progressive loss of drug-induced tremor. This tolerance was long-lasting and specific. No cross-tolerance was noted to the drug oxotremorine. Prevention or attenuation of tremor by pretreatment with diazepam or morphine preserved the tremorogenic capacity of harmaline when administered alone. These results suggest a relatively permanent change in the olivo-cerebello-bulbar pathway that underlies the generation of tremor induced by harmaline. Treatment with harmaline also increased cyclic 3',5'-guanosine monophosphate (cGMP) in the cerebellum, presumably through activation of the climbing fiber pathway from the inferior olive to the cerebellar cortex. These increases were attenuated after repeated treatment. These results suggest that the site of tolerance to the tremogenic effects of harmaline lies within the olivo-cerebellar system.