Effects of non-competitive NMDA-receptor antagonists on the physiological function of A10 dopamine neurons

413 (+)-[3H]-(3)-PPP has been introduced as a dopaminergic autoreceptor agonist, and later was used to study the nonopioid and non-PCP sites, which werte called sigma receptors. We have characterized this site on cultured C6 glioma cells, using various compounds including potassium channel blockers (class M antiarrhythmics agents). (+)-[3H]-(3)-PPP was found to bind to cultured C6 glioma cells homogenate in a reversible manner. Haloperidol llaM was used to determine the non-specific binding. Following IC50 values were found: haloperidol 11 nM; (+)-WPP 75 nM; (-)-PPP 141 nM; dextrometorphan 117 nM; phencyelidine 1100 nM; N-allylnormetazocine >10.000 nM. Binding of (+)-[3H]-(3)-PPP was inhibited with nanomolar concentration of various drugs which are known to interact with a voltage-dependent potassium channel. IC50 values of clofilium tosylate, RP58866 and amiodarone was 3 nM, 40 ruM and 41 nM respectively. Stereoselectivity was found for the two enantiomers RP61010A and RP61009A with IC50 values of 3.2 nM and 48 nM respectively. In conclusion, we present evidence for the occurrence of (+)-[3I-I]-(3)-PPP binding sites on cultured C6 glioma cells, which display many characteristics of sigma receptors. It is difficult to assess whether these sites correspond to a sigma receptor subtype such as described in PCI'2 cells, or whether the expression of the receptor, or the access of drugs to this site, are modified in glioma cells. Our results are compatible with a narrow association, and perhaps coidentity between IK or IK 1 channels and 3-PPP binding site. References Walker, J.M., Bowen, W.D., Walker, F.O., Matsumoto, R.R., De Costa, B. and Rice, K.C., 1990, Sigma receptors: biology and function, Pharmaeol. Rev. 42, 355-402. Hellewell, S.B. and Bowen, W.D., 1990, A sigma-like binding site in rat pheochromocytoma (PCI2) cells: decreased affinity for (+)benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain, Br. Res. 527, 244-253.

Effects of non-competitive NMDA-receptor antagonists on the physiological function of A10 dopamine neurons

Svensson, T.H. and Murase, S. Department of Pharmacology, Karolinska Institute, Stockholm, Sweden The present study was undertaken to analyze the effects of systemically administered phencyclidine (PCP) or MK-801 on the firing characteristics of mesolimbocortical dopamine (DA) cells in the ventral tegmental area (VTA) in the rat. Extracellular recording techniques, previously described in detail (Pawlowski et al, 1990) were employed in male chloral hydrate anesthetized rats. Single cell activity was analyzed from interspike time-interval histograms created by an Appleu computer permitting quantitative analysis of firing rate, burst fh-ing and regularity of firing (as assessed by the variation coefficient, see reference). VTA-DA cells generally responded to both PCP and MK-801 with a significantly increased f'u'ing rate as previously observed, whereas the variation coefficient was reduced. Burst firing was either significantly depressed or increased above base-line, depending on the anatomical localization within the VTA of the cells. Thus cells within the n. parabrachialis pigmentosus showed reduced burst firing whereas cells within the paranigral nucleus showed increased burst firing to MK-801. Results will be discussed in relation to the schizophrenomimetic properties of this class of drugs. References

Pawlowski, L., Mathd, J.M. and Svensson, T.H., Phenc~yclidine activates rat AI0 dopamine neurons but reduces burst activity and causes regularization of fh'ing. Acta Physiol. Seand. 139, 529-530.