Regulation of σ‐Receptors: High‐ and Low‐Affinity Agonist States, GTP Shifts, and Up‐Regulation by Rimcazole and 1,3‐Di(2‐Tolyl)guanidine

The regulation of the central σr‐binding site was investigated using both in vitro and in vivo manipulations in conjunction with radioligand binding. The displacement of the binding of R(+)‐[³H]3‐[3‐hydroxyphenyl][N‐(l‐pro‐pyl)piperidine (R(+)‐{³H]3‐PPP} to cortical homogenates by a range of drugs was consistent with the site labelled being a σ‐receptor. (+)‐SKF 10,047, (‐)‐SKF 10,047, (±)‐cyclazo‐cine, phencyclidine, and dexoxadrol displaced R(+)‐[³H]3‐PPP with pseudo‐Hill coefficients of less than . Further analysis employing nonlinear curve fitting techniques demonstrated that displacement data for these compounds were described better by a model whereby R(+)‐[³H]3(‐PPP was displaced from two discrete sites; approximately 6[5% of the total sites were in the high‐affinity state. In the presence of 10 mM Mg²⁺ and 0.3 mM GTP, displacement curves for (+)‐SKF 10,047 and (±)‐cyclazocine were shifted to the right. These findings were due to the shift of some 15% of the high‐affinity binding sites to a low‐affinity state. Saturation experiments revealed that 0.3 mM GTP acted competitively to decrease the affinity of R(+)‐[³H]3‐PPP for the σ suites. The σ‐binding site was thus likely to be linked to a guanine nucleotide regulatory (G) protein. Thus σ drugs could be subdivided on the basis of their GTP sensitivity and psdudo‐Hill coefficients, and by analogy with other receptors R(+)‐3‐PPP. (+)‐SKF 10,047, and (±)‐cyclazocine, may be putative σ‐agonists. l,3‐Di(2‐tolyl)guanidine (DTG), rimcazole, and haloperidol displaced R(+)‐[³H]3‐PPP with pseudo‐Hill coefficients of approximately unity and thus may be σ‐antagonists. Subchronic treatment with rimcazole was characterized by slight sedation and a concomitant up‐regulation, with a decrease in the affinity, of σr‐binding sites. The schedule of rimcazole also increased dopamine turnover in the nucleus ac‐cumbens; both the concentration of 3,4‐dihydroxyphenyl‐acetic acid (DOPAC) and the DOPAC/dopamine ratio were elevated. DTG produced similar alterations to the binding parameters of the σ‐binding site; however, changes were not observed in general behavior or accumbal dopamine turnover. (T‐Receptors are likely to be linked to a G protein and are functionally involved in the CNS.