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

The present study investigates the relationship between binding at the sigma site labelled by the prototypic sigma ligand (+)-[3H]-N-allylnormetazocine [+)-[3H]-SKF10,047) and binding at the phencyclidine (PCP) site labelled by [3H]-phencyclidine in rat whole brain membranes. (+)-[3H]-SKF10,047 bound with a KD of 251 +/- 66 nM. [3H]-PCP bound with a KD of 180 +/- 35 nM (KD +/- asymptotic s.e.). 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 sigma and PCP sites are different entities. The relationship between binding at the sigma site and dopamine receptors was investigated in rat whole brain membranes and in striatal membranes. (+/-)-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. 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 sigma sites and the binding to striatum being predominantly to dopamine receptors.