Elsevier

Neuropharmacology

Volume 48, Issue 6, May 2005, Pages 822-829
Neuropharmacology

The role of the NMDA receptor in alcohol relapse: a pharmacological mapping study using the alcohol deprivation effect

https://doi.org/10.1016/j.neuropharm.2005.01.002Get rights and content

Abstract

Modulators of glutamate receptors especially of the N-methyl-d-aspartate receptors (NMDARs) have recently been suggested as putative pharmacotherapeutic agents in the treatment of alcohol relapse. However, at present it is not clear, which binding and modulatory sites of the NMDAR are involved in relapse behavior. We, therefore, performed a pharmacological mapping study in long-term alcohol drinking rats using the alcohol deprivation effect (ADE) as a model for relapse behavior. In a comprehensive fashion, we studied dose–response curves, employing the following selective pharmacological agents: the NMDAR competitive antagonist CGP37849, the glycine binding site antagonist L-701.324, the NR2B subunit selective antagonist ifenprodil, which acts at the polyamine binding site, the NMDAR channel blocker neramexane, and ethanol, which acts as a functional antagonist at the NMDAR. Our data show that the animals' alcohol consumption inversely correlates with the dose of ethanol administered intraperitoneally. This indicates that under the present experimental conditions alcohol intake during an ADE is an entirely pharmacologically driven behavior that is not under the control of other factors such as taste or novelty of alcohol re-exposure. The effects of the administration of the aforementioned compounds were comparable to those of ethanol, suggesting a similar pharmacological impact on relapse behavior. Repeated administration of both competitive and uncompetitive NMDAR antagonist dose-dependently suppressed alcohol consumption during ADE. In addition, ifenprodil and L-701.324 dose-dependently reduced the expression of an ADE as well. In summary, the results suggest that an inhibition of NMDAR function in general, rather than a particular interference with a specific binding site of this receptor, is sufficient for the reduction of relapse behavior.

Section snippets

Animals

Two-month-old male Wistar rats (from our own breeding colony at the CIMH, Mannheim, Germany) were used. All animals were housed individually in standard rat cages under a 12 h artificial light–dark cycle (lights on at 6:00 a.m.). Room temperature was kept constant (temperature: 22 ± 1 °C, humidity: 55 ± 5%). Standard laboratory rat food and water were provided ad libitum throughout the experimental period. Body weights were measured weekly. The experiments were approved by the Committee on Animal

Results

The pharmacological studies were performed at the end of the seventh alcohol deprivation phase. Following the re-introduction of alcohol solutions, all four vehicle treated groups (G1, G6, G9 and G12) showed a typical increase in alcohol consumption indicating the occurrence of an ADE. This increase was not different from that observed during the first six deprivation periods. The treatment with CGP 37849, neramexane and L-701.324 produced rather similar effects, i.e. the drug treatment caused

Discussion

In the present study, the repeated administration of the competitive NMDAR antagonist CGP37849, the NMDAR channel blocker neramexane, and the NR2B subunit selective antagonist ifenprodil, which acts at the polyamine binding site, as well as the glycine binding site antagonist L-701.324, produced a significant dose-dependent reduction of alcohol intake in long-term drinking rats during ADE. As well, IP administration of ethanol displayed a similar effect, as it completely abolished alcohol

Acknowledgements

This study was supported by a BMBF grant FKZ EB 01011300 – Individually adapted therapy of alcoholism (RS) and an EC grant QLG3-CT-2002-01048 – Identification and validation of molecular targets for pharmacological treatment of alcohol dependence (TARGALC group; RS).

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