Rationale: While the N-methyl-d-aspartate (NMDA) glutamate receptor has been strongly implicated in chronic opiate dependence, relatively few studies have examined the effects of NMDA receptor antagonists on withdrawal from acute opiate exposure. Objectives: The current study examined the effects of memantine, a well-tolerated NMDA receptor antagonist, on acute opiate dependence as assessed by elevations in rodent startle responding (i.e., "withdrawal-potentiated startle") and increased pain sensitivity (i.e., hyperalgesia). Results: Administration of memantine either attenuated (5 mg/kg) or blocked (10 mg/kg) the expression of withdrawal-potentiated startle during naloxone (2.5 mg/kg)-precipitated withdrawal from a single dose of morphine sulfate (10 mg/kg). Pre-treatment with the NMDA receptor antagonist also inhibited the exacerbation of withdrawal-potentiated startle across repeated acute opiate exposures. Memantine blocked the expression of acute dependence, but was less effective in inhibiting its escalation, when hyperalgesia was used as a measure of withdrawal. These doses of memantine did not affect startle responding or nociception in otherwise drug-free animals. Data from additional control groups indicated that the effects of memantine on the expression of withdrawal were not influenced by nonspecific interactions between the NMDA antagonist and either morphine or naloxone. Conclusions: These findings suggest that the NMDA receptor may play a key role in the earliest stages of opiate dependence and provide further evidence that memantine may be useful for the treatment of opiate withdrawal.
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Acknowledgements The authors wish to thank Nathan Gallus and Senem Under for their assistance in data collection. This work was supported by the University of Minnesota, the National Institute of Drug Abuse T32 DA07097 (A.C.H.) and T32 DA07234 (P.E.R.), and the NARSAD Young Investigator Award (J.C.G.).