Sigma receptors phencyclidine

Javitt DC, Jotkowitz A, Sircar R, Zukin SR. 1987. Noncompetitive regulation of phencyclidine/sigma-receptors by the N-methyl-D-aspartate receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid. Neurosci Lett... 

Characterization of Phencyclidine and Sigma Receptor-Binding Sites in Brain... 

Further Evidence of Phencyclidine/Sigma Opioid Receptor Commonality... 

The mechanisms of action of phencyclidine and ketamine are complex (Gorelick Balster, 1995). The drugs are non-competitive antagonists at NMDA receptors, and also bind to associated phencyclidine/sigma opioid receptors. They also have agonist actions at dopamine receptors, complex interactions with both nicotinic and muscarinic acetylcholine receptors and poorly understood interactions with noradrenergic and serotonergic systems. These multiple actions may combine to produce delirium and psychotic reactions. 

Both phencyclidine and ketamine bind with high affinity to a number of receptors in the brain, but it is now accepted that the primary target is the sigma-PCP receptor site located in the ion channel of the NMDA excitatory amino acid receptor complex. The precise function of this receptor in the brain is still the subject of debate. It is now known that there are two distinct sigma receptor sites in the mammalian brain (ctj and a2) which are not associated with the NMDA receptor complex. Haloperidol and the atypical neuroleptic remoxipride bind with high affinity to such sites, and it has been postulated that some typical and atypical neuroleptics may owe some of their pharmacological effects to their action on such receptors. 

The precise mechanisms by which phencyclidine causes its clinical effects have not been fully delineated. Phencyclidine blocks the N-methyl-D-aspartate (NMDA) receptors and thereby calcium influx into cells. Phencyclidine inhibits the biogenic amine reuptake complex and thereby inhibits norepinephrine and dopamine reuptake. Phencyclidine also increases adrenergic activity by indirectly releasing norepinephrine from presynaptic neurons. Phencyclidine in high doses stimulates sigma receptors. 

D., Tam, S.W., Woods, J.H., Zukin, S.R., 1987. Classification and nomenclature of phencyclidine and sigma receptor binding sites. Trends Neurosci. 10, 444-446. 

Hustveit, O. Maurset, A. Oye, 1. Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol. Toxicol. 1995, 77, 355-359. 

Jedema HP, Moghaddam B (1994) Glutamatergic control of dopamine release during stress in the rat prefrontal cortex. J Neurochem 63(2) 785-788 Jin J, Yamamoto T, Watanabe S (1997) The involvement of sigma receptors in the choice reaction performance deficits induced by phencyclidine. EurJ Pharmacol 319(2-3) 147-152... 

Phencyclidine (angel dust) sigma "opiate" receptor Visualization by tritiurn-sensitive film. Proc Natl Acad Sci USA 78 5881-5885, 1981. 

Sircar R. Nichtenhauser, R. Ieni, J.R. and Zukin, S-R Characterization and autoradiographic visualization of 3H-(+)SKF-10,047 binding in rat and mouse brain Further evidence for sigma opioid/phencyclidine receptors commonality. Submitted for publication. 

Contreras, P.G. Quirion, R. and O Donohue, T.L. Comparison of the binding and regional distribution of sigma opioid and phencyclidine receptors. Soc Neuro Sci Abst. in press. 

Quirion, R. Hammer, R.P., Jr Herkenham, M. and Pert, C.B. Phencyclidine (angel dust)/sigma "opiate" receptor Visualization by tri ti um-sensi ti ve film. Proc Natl Acad Sci USA 78 5881-5885, 1981a. 

Mount, H., Boksa, P., Chadieu, I., and Quirion, R., Phencyclidine and related compounds evoked [3H] dopamine release from rat mesencephalon cell cultures by mechanisms independent of the phencyclidine receptor, sigma binding site, or dopamine uptake site, Can. J. Physiol. Pharmacol., 68,1200,1990. 

Largent BL, Gundlach AL, Snyder SH. 1986. Pharmacological and autoradiographic discrimination of sigma and phencyclidine receptor binding sites in brain with (+)-[3H]SKF 10,047, (+)-[3H]-3-[3-hydroxyphenyl]-N-(l-propyl)... 

It has been however found to be specific competitive antagonistic of Sigma sites in brain. It reverses psychotic conditions induced in humans by phencyclidine and/or a-opiod antagonistics probably by these compound to receptors in brain. Rincazole has indirect effect on dopamine neurons (DA) with relative selection for AlO dopamine cells (102). 

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