A comparison of the binding of σ opioids and phencyclidine, and the interaction with antipsychotic drugs in rat brain membranes

Abstract

1 The present study investigates the relationship between binding at the s̀ site labelled by the prototypic s̀ ligand (+)-[³H]-N-allylnormetazocine ((+)-[³H]-SKF10,047) and binding at the phencyclidine (PCP) site labelled by [³H]-phencyclidine in rat whole brain membranes. 2 (+)-[³H]-SKF10,047 bound with a K_D of 251 ± 66 nM. [³H]-PCP bound with a K_D of 180 ± 35 nM (K_D ± asymptotic s.e.). 3 The potencies of a range of compounds to displace these ligands were only poorly correlated (r = 0.3). Furthermore selective displacement of (+)-[³H]-SKF10,047 but not of [³H]-PCP was demonstrated using the non-selective dopamine ligand haloperidol and the dopamine₂-selective ligand 3-(3-hydroxyphenyl)N-n-propylpiperidine (3PPP). These results indicate that the s̀ and PCP sites are different entities. 4 The relationship between binding at the s̀ site and dopamine receptors was investigated in rat whole brain membranes and in striatal membranes. 5 (±)-SKF10,047 displaced [³H]-haloperidol bound to whole brain membranes with a greater potency than it displaced [³H]-haloperidol bound to striatal membranes. The opposite was true for the dopamine antagonist, clozapine, which showed greater potency in striatal membranes. 6 Comparison of [³H]-haloperidol binding in whole brain and striatum gave only a poor correlation (r = 0.6). Hence, different binding sites would appear to exist in these brain regions, the binding of [³H]-haloperidol to whole brain being predominantly to s̀ sites and the binding to striatum being predominantly to dopamine receptors.