ANTAGONISM OF A (-ALLYLNORMETAZOCINE STIMULUS BY (-)PPAP AND SEVERAL STRUCTURALLY RELATED ANALOGS()N)

Employing rats trained to discriminate 5 mg/kg of the benzomorphan opi oid (+)N-allylnormetazocine (+)NANM! from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influenc e of several potential sigma-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at s igma- and phencyclidine (PCP) receptors. Although the low-affinity sig ma-antagonist rimcazole was without stimulus-attenuating effect, three novel sigma-ligands-(-)PPAP, CNS 3018, and CNS 3093 (ID50 doses = 3.2 , 6.7, and 4.5 mg/kg, respectively)-antagonized the (+)NANM stimulus i n a dose-related fashion. The nonselective serotonergic agent 1-(3-tri fluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine1A (5-HT1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT1A agonist 8-hydroxy-2-(d i-n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM s timulus at pharmacologically relevant doses, it seems unlikely that th e (+)NANM stimulus involves a 5-HT1A mechanism. TFMPP and buspirone di splay modest affinity for sigma-receptors and this may account for the present findings with these agents. The present results neither estab lish a role for a involvement in the stimulus properties of (+)NANM no r eliminate a role for PCP receptors. They do, however, demonstrate th at sigma-ligands with little to no affinity for PCP receptors are capa ble of antagonizing the (+)NANM stimulus.