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A robust increase in expression of arc gene, an effector immediate early gene, in the rat brain after acute and
1Department of Neuropsychiatry, Okayama University Medical School, Japan. m-kodama@ja2.so-net.or.jp
Abstract:
The effect of acute and chronic administration of methamphetamine (METH) on the levels of activity-regulated cytoskeleton-associated protein (arc), an effector-immediate early gene, mRNA has been investigated in rat brain using in situ hybridization. Levels of arc mRNAs in the brain regions examined increased significantly from 0.5-1 h after an acute METH (4 mg/kg) administration compared with basal levels. The increase in arc mRNA continued by 3 h, and then subsided to basal levels by 6 h. The degree of increase in arc mRNA and the peak time after METH administration varied according to brain area. Arc mRNA in cerebral cortices showed robust increase 1 h after METH administration. In the striatum and hippocampus, it showed earlier and later increase, respectively, and its degree of both was less than in the cortices. Microscopic examination revealed that the METH-induced arc mRNAs in the parietal cortex were enriched in layers IV and VI, and those in the striatum existed mainly in the medium-sized neuron. Pretreatment with either 0.5 mg/kg SCH23390 or 0.25 mg/kg MK-801 almost completely blocked the enhanced striatal arc mRNA levels induced by acute METH administration, whereas such pretreatments only partially reduced the effect of METH in the cerebral cortical regions. In the chronic treatment experiment, the arc mRNA levels of the group that received chronic treatment with METH followed by a METH challenge showed an increase like seen after acute METH administration. Since previous studies proposed that arc is one of cytoskeleton-associated proteins and is selectively localized in neural dendrites, the results of the present study suggested that arc may play an important role in the synaptic plasticity underlying METH-induced adaptational changes including behavioral sensitization.
Insights
Methamphetamine (METH) significantly increases activity-regulated cytoskeleton-associated protein (arc) mRNA in rat brains, particularly in the cortex and striatum. This suggests arc plays a key role in synaptic plasticity and METH-induced behavioral changes.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Methamphetamine (METH) is a potent psychostimulant with significant neurobiological effects.
- Activity-regulated cytoskeleton-associated protein (arc) is an immediate early gene involved in synaptic plasticity.
Purpose of the Study:
- To investigate the effects of acute and chronic METH administration on arc mRNA levels in specific rat brain regions.
- To explore the role of arc in METH-induced neuroadaptations and behavioral sensitization.
Main Methods:
- In situ hybridization was used to quantify arc mRNA levels in rat brain.
- Rats were administered acute or chronic METH (4 mg/kg).
- Pharmacological pretreatments with SCH23390 or MK-801 were employed.
Main Results:
- Acute METH administration significantly increased arc mRNA levels in the cerebral cortex, striatum, and hippocampus, with regional variations in timing and magnitude.
- METH-induced arc mRNA increases were concentrated in specific cortical layers and neuronal populations within the striatum.
- Pretreatment with SCH23390 or MK-801 partially or fully blocked METH-induced arc mRNA increases in the striatum and cortex.
- Chronic METH treatment followed by a challenge dose also elevated arc mRNA levels.
Conclusions:
- Arc mRNA levels are dynamically regulated by METH in a dose- and time-dependent manner across different brain regions.
- The findings suggest that arc is involved in the synaptic plasticity associated with METH-induced behavioral sensitization.
- Targeting arc may offer therapeutic potential for mitigating METH addiction and its neurological consequences.