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Changes in NMDAR2 subunit mRNA levels during pentobarbital tolerance/withdrawal in the rat brain: an in situ
1Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Abstract:
Little is known about the functional modulation of NMDA receptor subunits at the molecular level. Therefore, a series of experiments were conducted to elucidate more fully the role of NMDA receptor subtypes in pentobarbital tolerance and withdrawal. We investigated the influence of centrally administered pentobarbital on the regulation of mRNA levels of the family of NMDA receptor 2 (NR2) subtypes (NR2A, NR2B, and NR2C) by in situ hybridization histochemistry in rat brain. Animals were rendered tolerant by continuous intracerebroventricular (i.c.v.) infusion with pentobarbital (300 microg/10 microl/hr for 6 days) through pre-implanted cannulae connected to osmotic mini-pumps, and dependent, by abrupt withdrawal from pentobarbital. The NR2A subunit mRNA was increased in cortical areas in pentobarbital tolerant and withdrawal rats. In contrast, the NR2B mRNA was decreased in parietal cortex and hippocampus in both tolerance and withdrawal rats. The level of NR2C mRNA was increased in withdrawal rats, while there was no change in tolerant rats. These results indicate that continuous i.c.v. infusion with pentobarbital alters NR2 subunit mRNA expression in the rat brain, suggesting that NR2 subunits may play an important role in the development of tolerance to and withdrawal from pentobarbital.
Insights
Pentobarbital alters NMDA receptor subunit mRNA levels, impacting tolerance and withdrawal. Specifically, NR2A and NR2C mRNA increased, while NR2B mRNA decreased in rat brains.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The molecular mechanisms underlying NMDA receptor subunit modulation during drug tolerance and withdrawal remain largely unexplored.
- NMDA receptors are crucial for synaptic plasticity and neuronal excitability.
Purpose of the Study:
- To investigate the role of NMDA receptor 2 (NR2) subunits (NR2A, NR2B, NR2C) in pentobarbital tolerance and withdrawal.
- To elucidate the impact of pentobarbital on NR2 subunit mRNA expression in the rat brain.
Main Methods:
- Animals were rendered tolerant to pentobarbital via continuous intracerebroventricular (i.c.v.) infusion.
- Pentobarbital dependence was induced, followed by abrupt withdrawal.
- In situ hybridization histochemistry was used to quantify NR2A, NR2B, and NR2C mRNA levels in specific brain regions.
Main Results:
- Pentobarbital tolerance and withdrawal significantly altered NR2 subunit mRNA expression.
- NR2A mRNA levels increased in cortical areas in both tolerant and withdrawal states.
- NR2B mRNA levels decreased in the parietal cortex and hippocampus, while NR2C mRNA levels increased during withdrawal.
Conclusions:
- Continuous pentobarbital administration modulates NR2 subunit mRNA expression in the rat brain.
- These findings suggest that NR2 subunits play a significant role in the development of pentobarbital tolerance and withdrawal symptoms.