Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat.
It has been repeatedly reported that NMDA receptors may contribute to ethanol-induced discriminative stimulus effects and withdrawal syndrome. However, the role of NMDA receptors in the reinforcing properties of ethanol remains unclear. The aim of the present study was to evaluate effects of the novel low-affinity, uncompetitive NMDA receptor antagonist, 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride (MRZ 2/579), on ethanol self-administration and ethanol withdrawal-associated seizures in rats. Both an operant (lever pressing for ethanol) and non-operant two-bottle choice setups were employed to initiate ethanol self-administration. In another procedure, forced treatment with high doses (9--15 g/kg/day) was used to induce physical dependence on ethanol. MRZ 2/579 delivered chronically by osmotic minipumps (9.6 mg/day, s.c.) did not alter either operant or non-operant ethanol drinking behaviour in a maintenance phase of ethanol self-administration. In contrast, repeated daily injections of the drug (5 mg/kg, i.p.) led to a progressive decrease in operant responding for ethanol. MRZ 2/579 (0.5--7.5 mg/kg, i.p.) and another low-affinity NMDA receptor antagonist, memantine (1--10 mg/kg, i.p.) dose-dependently suppressed ethanol withdrawal seizures with efficacies comparable with that of a standard benzodiazepine derivative, diazepam. The results of the present study indicate that: (i) intermittent administration of MRZ 2/579 may lead to a gradual decrease of operant responding for ethanol; and (ii) the group of low-affinity uncompetitive NMDA receptor antagonists may be an interesting alternative to benzodiazepines in the treatment of alcohol withdrawal.
Bienkowski
P
P
Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, Al. Sobieskiego 1/9, PL-02957 Warsaw, Poland. pbienko@yahoo.com
Krzascik
P
P
Koros
E
E
Kostowski
W
W
Scinska
A
A
Danysz
W
W
D000428:Alcohol Drinking / Q000009:adverse effects / Q000188:drug therapy*; D020270:Alcohol Withdrawal Seizures / Q000188:drug therapy*; D000818:Animals; D003216:Conditioning, Operant / Q000502:physiology; D003517:Cyclopentanes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D003975:Diazepam / Q000627:therapeutic use; D020195:Epilepsy, Reflex / Q000188:drug therapy; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008559:Memantine / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012646:Self Administration; D012890:Sleep / Q000502:physiology
D003517:Cyclopentanes; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; C114144:neramexane; D003975:Diazepam; D008559:Memantine