Molecular Pharmacology, Vol 14, 983-995, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Characteristics of Central 5-HT Receptors and Their Adaptive Changes following Intracerebral 5,7-Dihydroxytryptamine Administration in the Rat

¹ Groupe NB—INSERM U 114, College de France, 75231 Paris Cedex 05, France

Lysed synaptosomal (P₂) fractions from adult rat brain were extensively washed and incubated in such a way that most bound 5-HT was eliminated. These membranes contained a high affinity (K_d = 1.6 nM) binding site for [³H]5-HT that exhibited the expected properties of a specific receptor of 5-HT. In particular, known agonists and antagonists of 5-HT in the central nervous system inhibited the binding of [³H]5-HT to synaptosomal membranes with IC₅₀ values ranging between 5 nM (metergoline) and 2.18 µM (MK-212). The slopes of logit-log competitive inhibition plots of [³H]5-HT binding by various drugs including an agonist (quipazine) and several antagonists (methiothepin, mianserine) were less than 1.0 suggesting possible negative cooperativity. This did not occur with 5-HT itself since the Hill coefficient of [³H]5-HT binding was not significantly different than one. Chemical lesioning of serotoninergic neurons by the intracerebral injection of 5,7-dihydroxytryptamine (5,7-HT) resulted in a significant increase in the number of high affinity binding sites for [³H]5-HT in the hippocampus (+39%) but not in the striatum 18 days after the injection. This change was first detected on the 8th day after 5,7-HT treatment (+25%) when 5-HT levels in the hippocampus were decreased by 80% as compared with normal adult values. Neither the affinity nor the Hill coefficient of [³H]5-HT binding, nor the characteristics of the binding sites for [³H]dihydroalprenolol (a beta-noradrenergic antagonist) and [³H]haloperidol (a DA antagonist) in the hippocampus and the striatum, respectively, were altered by 5,7-HT treatment. These findings are discussed in relation to the reported behavioral evidence for supersensitivity toward 5-HT agonists in 5,7-HT-treated animals.

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ACKNOWLEDGMENTS We thank the pharmaceutical companies for generous gifts of drugs.

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