J. psychiat. Res., Vol. 21, No. 4, pp. 531-537, 1987. 0022-3956/87 $3.00+ .00 Printed in Great Britain. © 1987 Pergamon Journals Ltd. PHYLOGENETIC RECEPTOR RESEARCH: IMPLICATIONS IN STUDYING PSYCHIATRIC AND NEUROLOGICAL DISEASE JOHANNES HEBEBRAND and WALTRAUT FRIEDL Institut ftir Humangenetik der Universitiit Bonn, Wilhelmstr. 31, 53 Bonn 1, F.R.G. (Received 12 October 1986; revised 12 November 1986; in final form 16 December 1986) Summary--Phylogenetic studies will help to evaluate the structure and function of receptors. We were able to show that the regional heterogeneityof the central benzodiazepinereceptor previously described in mammals also applies to avians. In addition, a systematicspecies comparison of the subunit patterns revealeda certain phylogeneticrelationship suggestingevolutionby geneduplication and subsequent divergence. In analogy to isozymesystems, these results possibly indicate that the GABA/benzodiazepine receptor is an isoreceptor complex. The implications for neuropsychiatric genetics are discussed. RECEPTOR research has been greatly stimulated by the hope of finding a cause for certain human disease states. The list of neurological and psychiatric disorders that are possibly due to alterations in receptor systems has grown quite impressively: such diverse disease entities as epilepsy, schizophrenia, uni- and bipolar depression, anxiety states and neuromuscular disorders have all been hypothesized to be caused by abnormal receptor functioning. While this may merely reflect our ignorance of the basic neuro- pathophysiological mechanisms involved, other non-neuropsychiatric diseases have been shown to be due to receptor defects, among them the most common monogenic disease in Caucasians caused by a defect of the LDL receptor (GOLDSTErN and BROWN, 1983). Research strategies concerning diseases in which a specific receptor is presumed to be involved might profit from a thorough knowledge of the evolution of this receptor. By comparison of the receptor in different species the structure of a receptor can be evaluated, possibly also leading to a better understanding of its function. For pharmacological research purposes it is important to know whether the receptor in the animal model has a structure and function comparable to the human receptor. Possibly, biological phenomena can be correlated with the evolution of a receptor. Our research work has concentrated on one of the most interesting neuroreceptor systems, the 7-aminobutyric acid/benzodiazepine receptor chloride ionophore complex (GABA/BZR). There are several reasons for the high degree of interest in this receptor complex: (1) it is estimated that 30°7o of all central neurons are GABAergic (FAHN and COTE, 1968); (2) a wide range of drugs have been proven or are presumed to exert their effects via this receptor complex (reviewed in OLSEN et al., 1984; TALLMANand GALLAGER, 1985); (3) many diverse neuropsychological functions such as anxiety, seizure susceptibility, muscle tension, sleep, learning and memory are affected by these drugs. (TALLMAN et aL, 1980; VENAULT et al., 1986); (4) practically opposite effects have been attained by various ligands of this receptor complex, a finding quite different from the usual classification 531