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Chronic phencyclidine increases NMDA receptor NR1 subunit mRNA in rat forebrain
C Wang1, V M Showalter, G R Hillman
1Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston 77555-1031, USA.
Journal of Neuroscience Research
|April 29, 1999
Summary
Chronic phencyclidine (PCP) exposure in rats increases locomotor activity sensitization. This behavioral change correlates with increased N-methyl-D-aspartate (NMDA) receptor NR1 subunit mRNA in specific brain regions, suggesting altered receptor function.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Chronic phencyclidine (PCP) administration can lead to behavioral sensitization, a phenomenon where repeated drug exposure results in amplified responses.
- The N-methyl-D-aspartate (NMDA) receptor is a key player in synaptic plasticity and is implicated in the effects of psychotomimetic drugs like PCP.
Purpose of the Study:
- To investigate the relationship between locomotor activity sensitization induced by chronic PCP and changes in NMDA receptor function and mRNA expression in the rat brain.
- To identify specific brain regions affected by chronic PCP treatment concerning NMDA receptor NR1 subunit mRNA levels and receptor function.
Main Methods:
- Rats received daily PCP injections for 5 days, followed by a withdrawal period.
- Locomotor activity was measured after a challenge dose of PCP to assess sensitization.
- In situ hybridization was used to quantify NR1 subunit mRNA levels in various brain regions.
- NMDA-stimulated dopamine release and the inhibitory effects of PCP and other antagonists were measured in brain slices.
Main Results:
- Chronic PCP administration induced significant locomotor activity sensitization.
- A marked increase in NR1 subunit mRNA was observed in the forebrain, specifically in the olfactory tubercle, piriform cortex, frontal cortex, and anterior striatum.
- NMDA-stimulated dopamine release was not altered, but the inhibition of this release by PCP and other NMDA receptor antagonists was significantly diminished.
Conclusions:
- Behavioral sensitization to PCP is associated with increased NR1 subunit mRNA in selective forebrain regions.
- The diminished inhibitory effect of NMDA receptor antagonists suggests altered NMDA receptor stoichiometry or composition in response to chronic PCP treatment.
- These findings indicate that changes in NMDA receptor function, rather than just expression, may underlie the behavioral plasticity observed with chronic PCP exposure.