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Notes: 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.