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Decrement in operant performance produced by NMDA receptor antagonists in the rat: tolerance and cross-tolerance
O A Dravolina1, E E Zvartau, A Y Bespalov
1Laboratory of Behavioral Pharmacology, Department of Psychopharmacology, Institute of Pharmacology, Pavlov Medical University, Lev Tolstoy str., 6/8, St. Petersburg, Russia.
Abstract:
Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different pathological states. The development of tolerance and cross-tolerance between different NMDA receptor antagonists may be an important factor contributing to the clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and cross-tolerance to the ability of various site-selective NMDA receptor antagonists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water reinforcement). Acute administration of D-CPPen (SDZ EAA 494; 1-5.6 mg/kg), dizocilpine (MK-801; 0.03-0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (10-56 mg/kg), and eliprodil (1-30 mg/kg) differentially affected operant responding. Both increases and decreases in response rates and accuracy of responding were observed. Repeated preexposure to D-CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral disruption produced by an acute challenge with D-CPPen or ACEA-1021, but potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the present results, one can suggest that the repeated administration of a competitive NMDA receptor antagonist differentially affects the functional activity of various sites on NMDA receptor complex.
Insights
Repeated use of NMDA receptor antagonists like D-CPPen can alter their effects. Tolerance developed to D-CPPen, but cross-tolerance varied among different NMDA antagonists, impacting their clinical efficacy.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- NMDA receptor antagonists are investigated for various pathological states, often requiring repeated administration.
- Tolerance and cross-tolerance to these drugs are crucial for understanding their clinical efficacy.
Purpose of the Study:
- To characterize the development of tolerance and cross-tolerance to site-selective NMDA receptor antagonists.
- To assess the impact of repeated antagonist administration on operant responding.
Main Methods:
- Acute and repeated administration of D-CPPen, dizocilpine, memantine, ACEA-1021, and eliprodil in an operant responding task.
- Behavioral disruption and response rates were measured to assess antagonist effects.
Main Results:
- Different NMDA receptor antagonists produced varied effects on operant responding, including changes in response rates and accuracy.
- Repeated D-CPPen administration attenuated its own effects and those of ACEA-1021.
- However, repeated D-CPPen potentiated the disruptive effects of dizocilpine, memantine, and eliprodil.
Conclusions:
- Repeated administration of competitive NMDA receptor antagonists differentially impacts the functional activity at various sites on the NMDA receptor complex.
- These findings suggest complex interactions and varying tolerance patterns among NMDA antagonists, influencing their therapeutic potential.