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

Philip M. Beart, Rbss D. O'Shea, David T. Manallack

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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.

Original languageEnglish
Pages (from-to)779-788
Number of pages10
JournalJournal of Neurochemistry
Issue number3
Publication statusPublished - 1 Jan 1989
Externally publishedYes


  • Biological adaptation
  • Guanine nucleotide regulatory protein
  • Guanosi ne‐5′‐triphosphate
  • Phencyclidine
  • Receptor
  • Sigma

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