Effects of sigma receptor ligands on schedule-controlled behavior of rats: relation to sigma and PCP receptor binding affinity.
Eleven drugs were examined for their ability to inhibit sigma and phencyclidine (PCP) receptor binding, as labelled by (+)[3H]-R-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), [3H]ditolylguanidine (DTG), (+)[3H]N-allylnormetazocine (NANM) and [3H]1-(1-(2-thienyl)cyclohexyl)piperidine (TCP), in membrane preparations from whole rat brain. The same drugs were studied for their effects under a fixed-ratio (FR) schedule of food reinforcement in rats. The relative potency order of the drugs for decreasing FR responding was: haloperidol greater than (+)-3-PPP greater than (-)NANM greater than BMY 14802 greater than PCP greater than (+)NANM greater than DTG greater than rimcazole greater than JO 1783 greater than JO1784 greater than (-)butaclamol. The binding affinities of all 11 drugs for either the [3H]DTG, (+)[3H]-3-PPP, (+)[3H]NANM or [3H]TCP site did not correlate significantly with the potencies of the same drugs for decreasing FR behavior. Rimcazole, (+)-3-PPP and haloperidol, at behaviorally inactive doses, were studied for their effects as antagonists of the rate-decreasing effects of JO 1784, DTG and (+)NANM: rimcazole attenuated the effects of DTG and (+)NANM but not JO 1784; (+)-3-PPP attenuated the effects of (+)NANM but not JO 1784 and DTG; and haloperidol was devoid of antagonistic actions. Moreover, BMY 14802 did not attenuate the rate-decreasing effects of (+)-3-PPP. These results further indicate that it is difficult to distinguish between purported sigma agonist and antagonist drugs.
Wettstein
J G
JG
Institut de Recherche Jouveinal, Department of CNS Pharmacology, Fresnes, France.
Roman
F J
FJ
Rocher
M N
MN
Junien
J L
JL
D000818:Animals; D001921:Brain / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D010622:Phencyclidine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D011957:Receptors, Opioid / Q000187:drug effects*; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D012055:Reinforcement Schedule
D008024:Ligands; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D010622:Phencyclidine