Receptor interactions of dopamine and serotonin antagonists: binding in vitro and in vivo and receptor regulation.

The advent of receptor binding techniques has provided new ways of studying the mechanism of action of drugs. In vitro radioligand binding is now currently applied to investigate the specificity or multiple action of compounds. By using the same technique, the binding affinity of a drug can be measured for a variety of neurotransmitter, drug, peptide and ion channel receptor binding sites, providing the drug's receptor binding profile (LEYSEN et al. 1981; LEYSEN 1984). However, in vitro receptor binding is only the initial step in the investigation of drug-receptor interactions. Investigations in vivo are required to allow evaluation of how and where a drug acts. In fact, the study of drug-receptor interactions comprises three main stages: (a) in vitro radioligand receptor binding; (b) in vivo receptor binding, providing information on the accessibility of the drugs to the receptors localized in various central and peripheral tissues, on the drug potency for occupying various receptors, on the duration of receptor occupation and on the relationship between the degree of receptor occupation and pharmacological effects; and (c) the study of receptor regulation: the effect of chronic drug treatment on receptor alterations compared with alterations in functional responses in vivo. In this article, we will illustrate the three stages of investigation of receptor interactions and discuss the relevance and importance of the findings, using as examples three drugs known in psychopharmacological research: (a) the neuroleptic haloperidol, a prototype of a dopamine D2 antagonist: (b) Setoperone, a potential antipsychotic agent with very potent serotonin S2 and moderate D2 antagonistic activity (CEULEMANS et al. 1985; LEYSEN et al. 1986); and (c) ritanserin, a potent and long-acting S2 antagonist (LEYSEN et al. 1985), which has revealed therapeutic activity in dysthymia and negative symptoms of schizophrenia (REYNTJENS et al. 1986; GELDERS et al. 1986). Particular attention will be paid to the problem of receptor regulation. We challenge the general applicability of the receptor regulation theory, which states that persistent receptor stimulation causes desensitisation and receptor downregulation, whereas chronic deprivation of receptor stimulation leads to supersensitivity and receptor upregulation. Recent research has revealed that the theory does not hold for S2 receptor alterations, which were found to downregulate following chronic receptor blockade.