Methamphetamine induces ectopic expression of tyrosine hydroxylase within the intrinsic cerebellar neurons.

Methamphetamine (MA) targets monoamine nerve terminals and produces motor sensitization. These effects are attributed to changes in the basal ganglia. Although the cerebellum is critical in movement control, and learning of repetitive motor pattern, only a few studies investigated the effects of MA in this area. In the present study we demonstrate that MA produces changes in the expression of the primary transcript of the gene tyrosine hydroxylase (TH) within the cerebellar cortex, as measured by semiquantitative RT-PCR using specific TH primer pairs. This was accompanied by increased TH protein as measured by immunoblotting. This effect was localized at the level of granules layer and Purkinje cells as shown by light microscopy. Immunoelectronmicroscopy demonstrated that at subcellular level TH was present both in the cytoplasm and within the nucleus, although MA produces a more marked effect in the nucleus. Increased TH expression was accompanied by augmented norepinephrine content as shown by HPLC-ED. A time course analysis carried out at various time intervals following different doses of MA demonstrated increased TH expression up to 3 days following MA; this persisted at least for 1 week. Analysis of serial slices from the cerebellar cortex demonstrated that increased TH immunostaining was most pronounced in the cortex of the posterior vermal lobules. Conversely, only slight, non-significant effects on TH expression were detected in the cerebellar emispheres. The present data indicate that the cerebellum is a target of MA suggesting its involvement in acute and chronic motor alterations induced by this drugs of abuse. In line with this, inherited cerebellar movement disorders are associated with increased TH immunoreactivity within intrinsic neurons of the cerebellar cortex.