Competitive and glycine/NMDA receptor antagonists attenuate withdrawal-induced behaviours and increased hippocampal acetylcholine efflux in morphine-dependent rats.
The present study has examined the glycine/N-methyl-D-aspartate (NMDA) receptor antagonist, R-(+)-3-amino-1-hydroxypyrrolid-2-one (R-(+)-HA-966) and the competitive NMDA receptor antagonist, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755) on the behavioural syndrome and increased hipppocampal acetylcholine efflux induced during morphine-withdrawal in the rat. Subcutaneous naltrexone (1 mg/kg) injection, 48 hr after implantation of a 75 mg morphine pellet, induced a robust withdrawal syndrome consisting of wet dog shakes, ejaculations, mouth movement, ptosis, irritability to touch and diarrhoea. Pretreatment with the alpha2-adrenoceptor agonist, clonidine (0.1-0.4 mg/kg), R-(+)-HA-966 (10-60 mg/kg) or CGS 19755 (5 or 10 mg/kg) significantly reduced the incidence of withdrawal behaviours. In addition, all three compounds significantly attenuated the increase in hippocampal acetylcholine efflux induced following naltrexone (1 mg/kg, s.c.) injection in morphine-dependent rats. These results provide further evidence demonstrating that NMDA receptor antagonists attenuate both the behavioural and neurochemical effects observed during morphine withdrawal in the rat.
Bristow
L J
LJ
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Center, Harlow, Essex, UK.
Hogg
J E
JE
Hutson
P H
PH
D000109:Acetylcholine / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D009021:Morphine Dependence / Q000378:metabolism*; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000523:psychology
D000316:Adrenergic alpha-Agonists; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D010875:Pipecolic Acids; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C053672:selfotel; D009271:Naltrexone; C001369:1-hydroxy-3-amino-2-pyrrolidone; D003000:Clonidine; D000109:Acetylcholine