Molecular Pharmacology, Vol 15, 506-514, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Anomalous Properties of [³H]Spiperone Binding Sites in Various Areas of the Rat Limbic System

¹ Department of Pharmacology and Therapeutics, Medical Sciences Building, University of Leicester, University Road, Leicester. LE1 7RH.

[³H]Spiperone, a neuroleptic/dopamine receptor ligand, binds with high affinity (K_d 0.15 nM) to a single specific site on rat corpus striatum membranes. The "specific" binding represents about 80% of the total binding and is displaced by dopamime, apomorphine, and stereospecifically by neuroleptics such as butaclamol and flupenthixol. However, in contrast to the striatum, only 30-40% of the binding of [³H]spiperone to limbic forebrain membranes is displaced stereospecifically by butaclamol or flupenthixol, whereas dopamine and certain spiperone analogues compete with high affinity for about 70% of the labeled sites. These additional sites are saturable, reversible, and of high affinity. Kinetic analysis of association and dissociation rates yields a K_d value (1.5 nM) in agreement with equilibrium saturation data for these sites. They also possess a precise distribution, with high amounts being found in the hippocampus, septum, and nucleus accumbens, but they are completely absent in areas such as the corpus striatum, olfactory tubercles and hypothalamus. Moreover, these [³H]spiperone binding sites show strict structure-affinity relationships in that only spirodecanone butyrophenone derivatives and dopamine are capable of displacing this binding with relatively high affinities.

The results emphasize the complex nature of neuroleptic/dopamine "receptor" binding sites in brain and the need for precise definition of such "specific" binding sites.

Note:
ACKNOWLEDGMENTS The authors would like to thank Dr. P. Laduron and Janssen Pharmaceutica for the samples of butyrophenone derivatives; the Wellcome Trust for financial support and Miss Jenny Bell for preparing the manuscript.

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