Evidence against an involvement of the haloperidol-sensitive sigma recognition site in the discriminative stimulus properties of (+)-N-allylnormetazocine ((+)-SKF 10,047).
1. The involvement of the haloperidol-sensitive, sigma recognition site and the N-methyl-D-aspartic acid (NMDA) receptor in the mediation of the discriminative stimulus properties of (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047), has been investigated in the rat by use of a two-lever, operant drug discrimination paradigm. 2. Six compounds with nanamolar affinity for the sigma recognition site [+/-)-pentazocine, (+)-3-(hydroxyphenyl)-N-propylpiperidine [+)-3-PPP), ditolylguanidine (DTG), haloperidol, (-)-butaclamol and BMY 14802) were investigated for their ability to generalise or antagonise the (+)-NANM discriminative stimulus. Each drug was tested at doses found in an ex vivo radioligand binding assay to displace [3H]-DTG from the central sigma recognition site by more than 40%. 3. While (+/-)-pentazocine (in the presence of naloxone) generalised and (+)-3-PPP partially antagonised the (+)-NANM cue, the other putative sigma ligands were ineffective either as agonists or antagonists at doses clearly occupying the sigma site in vivo. 4. Dose-dependent generalisation to the (+)-NANM cue was seen with the selective non-competitive NMDA receptor antagonist, MK-801, a compound devoid of significant affinity for the sigma recognition site. 5. (+/-)-Pentazocine was found to antagonise seizures induced in the mouse by NMDLA, a model reflecting antagonism of central NMDA receptors, and a strong correlation was found between the rank order of potency of compounds to generalise to the (+)-NANM discriminative stimulus and their potencies as anticonvulsants. 6. In conclusion, no evidence was found to substantiate the contention that the discriminative stimulus properties of (+)-NANM are mediated by the haloperidol-sensitive sigma recognition site. On the other hand, the results are consistent with the interoceptive stimulus being mechanistically based in the NMDA receptor complex.
Singh
L
L
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
Wong
E H
EH
Kesingland
A C
AC
Tricklebank
M D
MD
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects*; D016291:Dizocilpine Maleate; D006146:Guanidines / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000502:physiology*; D017465:Receptors, Opioid, delta; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology
D003986:Dibenzocycloheptenes; D006146:Guanidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C012134:SK&F 10047; D010620:Phenazocine; D006220:Haloperidol; C050232:1,3-ditolylguanidine