Abstract
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.
Highlights
It was established with T1 nuclease/RNA protection protocols that methamphetamine injection increased mature PPT message approximately3-fold over a 2-h period, and this increase was sustained for at leas4t h after drug treatment.Striatal content of the PPT gene primarytranscript(containingtranscribedintrons) decreased in postmortem basaglanglia obtained from patients with Parkinson’s disease, a disease characterized by motor deficits and theloss of dopaminergic neurons [6, 7]
Previous data from our laboratory have demonstrated that the methamphetamine-induced increase in striatal PPT mRNA is not due to anychange in the patternof processing of the PPT gene transcript [12]
If PPT mRNA stabilization were the primary mechanism resulting from methamphetamine treatment, one would expect little or no change in thelevels of PPT mRNA in the nucleus and a steadily increasing cytoplasmic content, similar in time course and magnitude to results from the whole tissue
Summary
It was established with T1 nuclease/RNA protection protocols that methamphetamine injection increased mature PPT message approximately3-fold over a 2-h period, and this increase was sustained for at leas4t h after drug treatment.Striatal content of the PPT gene primarytranscript(containingtranscribedintrons) decreased in postmortem basaglanglia obtained from patients with Parkinson’s disease, a disease characterized by motor deficits and theloss of dopaminergic neurons [6, 7]. Chronic administration of various dopamine agonists has been shown to increase striatonigral tachykinins and PPT mRNA [8,9,10,11]. A single dose of the indirect dopamine agonist methamphetamine leads to a rapid elevation of total striatal PPT mRNA [12]. Through the use of specific D-1 or D-2 agonists and antagonists, it has been shown that the increase in PPT mRNA is mediated by D-2 dopamine receptors, this response is dependent upon D-1 dopamine receptor activation. The D-2 agonist-inwas decreased by 50%within 20 minandremained duced increase is prevented by concurrent administration of suppressedforatleast 4 hpost-methamphetamine. Taken together, these changesand their time courses cell fractionationtechniques ruled out cytoplasmic PPT suggest the indirect dopamine agonist alters striatal mRNA stabilization as a primarymechanism for the elevation
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