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Dose-dependent alteration in zif/268 and preprodynorphin mRNA expression induced by amphetamine or methamphetamine in
1Department of Anatomy and Cell Biology, East Carolina University School of Medicine, Greenville, North Carolina, USA.
Abstract:
The dose-related effects of a single injection of D-amphetamine (AMPH) or methamphetamine (METH) on the mRNA expression of the immediate early gene zif/268 and the opioid peptide preprodynorphin, in rat forebrain, were investigated with quantitative in situ hybridization histochemistry 3 h after injection. Both drugs at equimolar doses (3.75, 7.5, 15 and 30 mumol/kg) up-regulated zif/268 mRNA expression in cerebral cortex in a dose-dependent fashion. In the "nose" area of the sensory cortex, all doses of METH, but not AMPH, induced a substantial, dose-dependent increase in zif/268 mRNA. Dose-dependent induction of zif/268 mRNA also occurred in caudoputamen after injection of AMPH at all doses. However, dose-dependent increases in zif/268 mRNA in caudoputamen in METH-treated rats and in nucleus accumbens in AMPH-treated and METH-treated rats were seen only after the three lower doses. Injection of 30 mumol/kg actually decreased zif/268 mRNA induction in these areas to or below that detected after 3.75 mumol/kg. Preprodynorphin mRNA expression in the striatum was dose-dependently increased by either drug at all doses. These results demonstrate a clear dose-related responsiveness of zif/268 and preprodynorphin gene expression in cortical and/or striatal neurons that is positively correlated with a dose-dependent motor-stimulating effect of AMPH and METH. METH is a more potent psychostimulant than AMPH in eliciting behavioral and genomic activity at equimolar doses, and METH elicits a qualitatively different pattern of genomic activity in some forebrain regions, especially in the higher dose range.
Insights
Methamphetamine (METH) and D-amphetamine (AMPH) increase gene expression in rat brains dose-dependently. METH shows greater potency and distinct genomic effects, especially at higher doses.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- D-amphetamine (AMPH) and methamphetamine (METH) are psychostimulants with known effects on the central nervous system.
- Immediate early genes like zif/268 and opioid peptides such as preprodynorphin are rapidly activated by neuronal stimulation.
Purpose of the Study:
- To investigate the dose-related effects of single injections of AMPH and METH on zif/268 and preprodynorphin mRNA expression in the rat forebrain.
- To compare the genomic activity patterns induced by equimolar doses of AMPH and METH.
Main Methods:
- Quantitative in situ hybridization histochemistry was used to measure mRNA levels in specific rat brain regions.
- Rats received single injections of AMPH or METH at equimolar doses (3.75, 7.5, 15, and 30 mumol/kg).
- Gene expression was analyzed 3 hours post-injection.
Main Results:
- Both AMPH and METH dose-dependently increased zif/268 mRNA in the cerebral cortex.
- METH, but not AMPH, induced a substantial dose-dependent increase in zif/268 mRNA in the sensory cortex.
- Dose-dependent increases in zif/268 mRNA were observed in the caudoputamen (AMPH, METH) and nucleus accumbens (AMPH, METH) at lower doses, with a decrease at the highest dose (30 mumol/kg) for METH in caudoputamen and both drugs in nucleus accumbens.
- Preprodynorphin mRNA in the striatum increased dose-dependently with both drugs.
- Methamphetamine demonstrated greater potency and a qualitatively different genomic response pattern compared to D-amphetamine, particularly at higher doses.
Conclusions:
- Gene expression of zif/268 and preprodynorphin in rat forebrain neurons exhibits clear dose-related responsiveness to AMPH and METH.
- These genomic changes correlate with the motor-stimulating effects of these psychostimulants.
- Methamphetamine is a more potent psychostimulant than D-amphetamine, eliciting distinct genomic activity patterns.