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Title: Regulation of sigma-receptors: high- and low-affinity agonist states, GTP shifts, and up-regulation by rimcazole and 1,3-Di(2-tolyl)guanidine.
Austin Authors: Beart, P M;O'Shea, R D;Manallack, D T
Affiliation: University of Melbourne, Clinical Pharmacology and Therapeutics Unit, Austin Hospital, Heidelberg, Victoria.
Issue Date: 1-Sep-1989
Publication information: Journal of Neurochemistry; 53(3): 779-88
Abstract: The regulation of the central sigma-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-(1-propyl)piperidine [R(+)-[3H]3-PPP] to cortical homogenates by a range of drugs was consistent with the site labelled being a sigma-receptor. (+)-SKF 10,047, (-)-SKF 10,047, (+/-)-cyclazocine, phencyclidine, and dexoxadrol displaced R(+)-[3H]3-PPP with pseudo-Hill coefficients of less than 1. 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 65% 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 sigma sites. The sigma-binding site was thus likely to be linked to a guanine nucleotide regulatory (G) protein. Thus sigma drugs could be subdivided on the basis of their GTP sensitivity and pseudo-Hill coefficients, and by analogy with other receptors R(+)-3-PPP, (+)-SKF 10,047, and (+/-)-cyclazocine, may be putative sigma-agonists. 1,3-Di(2-tolyl)guanidine (DTG), rimcazole, and haloperidol displaced R(+)-[3H]3-PPP with pseudo-Hill coefficients of approximately unity and thus may be sigma-antagonists. Subchronic treatment with rimcazole was characterized by slight sedation and a concomitant up-regulation, with a decrease in the affinity, of sigma-binding sites. The schedule of rimcazole also increased dopamine turnover in the nucleus accumbens; both the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were elevated. DTG produced similar alterations to the binding parameters of the sigma-binding site; however, changes were not observed in general behavior or accumbal dopamine turnover. sigma-Receptors are likely to be linked to a G protein and are functionally involved in the CNS.
Gov't Doc #: 2569504
Journal: Journal of neurochemistry
Type: Journal Article
Subjects: 3,4-Dihydroxyphenylacetic Acid.metabolism
Binding, Competitive
Dopamine Agents
GTP-Binding Proteins.metabolism
Guanosine Triphosphate.pharmacology
Phenazocine.analogs & derivatives.pharmacology
Rats, Inbred Strains
Receptors, Opioid.drug effects.metabolism
Receptors, sigma
Appears in Collections:Journal articles

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