Evidence for dual mechanisms involved in methamphetamine-induced increases in striatal preprotachykinin mRNA.

The mechanism(s) whereby the indirect dopamine agonist methamphetamine causes a 2-3-fold increase in rat striatal preprotachykinin (PPT) mRNA was investigated. It was determined that the increase in PPT mRNA levels following a single injection of 5 mg of methamphetamine/kg of body weight was initiated in the cell nucleus, ruling out cytoplasmic PPT mRNA stabilization as a primary mechanism for this increase. It was established with T1 nuclease/RNA protection protocols that methamphetamine injection increased mature PPT message approximately 3-fold over a 2-h period, and this increase was sustained for at least 4 h after drug treatment. Striatal content of the PPT gene primary transcript (containing transcribed introns) was decreased by 50% within 20 min and remained suppressed for at least 4 h post-methamphetamine. Nuclear transcription assays indicated a 2-3-fold increase in the rate of gene transcription that lasted 60-90 min after methamphetamine treatment; by 2 h the transcription rate had returned to control levels. Taken together, these changes and their time courses suggest the indirect dopamine agonist alters striatal PPT gene expression at two levels: 1) a transient increase in the rate of PPT gene transcription and 2) a more sustained increase in the rate at which PPT hnRNA is processed to mature PPT mRNA. It is unclear whether these two changes are linked or are independent modes of action by methamphetamine.