Neuropharmacology 40 (2001) 242–253 www.elsevier.com/locate/neuropharm Detailed distribution of Neurokinin 3 receptors in the rat, guinea pig and gerbil brain: a comparative autoradiographic study Xavier Langlois * , Cindy Wintmolders, Paula te Riele, Jose ´e E. Leysen, Mirek Jurzak Department of Biochemical Pharmacology, Janssen Research Foundation, B-2340 Beerse, Belgium Received 5 May 2000; received in revised form 25 July 2000; accepted 31 July 2000 Abstract The neurokinin 3 (NK3) receptor is predominantly expressed in the central nervous system (CNS). Species differences in neuroki- nin 3 (NK3) receptor pharmacology have led to the preferential use of guinea pigs and gerbils in the characterization of non-peptide NK3 antagonists. Little is known about the central localization of NK3 receptors in the CNS of these species. To study this, [ 3 H]senktide and [ 3 H]SR 142801 were used in autoradiography experiments to visualize the NK3 receptors in the guinea pig and gerbil brain and compared to with the distribution of [ 3 H]senktide binding sites in the rat brain. In the three species, the NK3 receptor was similarly distributed within the cerebral cortex, the zona incerta, the medial habenula, the amygdaloid complex, the superior colliculus and the interpeduncular nucleus. Outside of these structures, our study has revealed that each species displayed a specific distribution pattern of central NK3 receptors. The rat was the only species where NK3 receptors could be visualized in the striatum, the supraoptic nucleus and the paraventricular nucleus of the hypothalamus. The guinea pig differed mainly from the two other species by the absence of detectable binding sites in the substantia nigra pars compacta and the ventral tegmental area. A specific localization of NK3 receptors in the anterodorsal and anteroventral thalamic nuclei characterized the gerbil. This last species is also unique by in the higher level of NK3 receptors in the dorsal and median raphe nuclei. All these differences suggest that the NK3 receptor mediates different functions in different species.  2000 Elsevier Science Ltd. All rights reserved. Keywords: Neurokinin 3 receptor; Radioligand autoradiography; Rat; Guinea pig; Gerbil; [ 3 H]Senktide; [ 3 H]SR142801 1. Introduction The three mammalian tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), are a family of structurally related peptides found in the per- iphery and the central nervous system (CNS). As neuro- transmitters, these peptides exert their biological activity via the activation of three different neurokinin (NK) receptors that have been pharmacologically charac- terized and cloned (for a review, see Maggi, 1995). SP binds preferentially to the NK1 receptor, NKA to the NK2 receptor, and NKB to the NK3 receptor. However, each of the tachykinins is able, at higher concentrations, to activate all three receptors and therefore shows poor selectivity (Maggi and Schwartz, 1997). Development of selective compounds for one or the other NK receptor * Corresponding author. Tel: + 32-14-606016; fax: + 32-14-605380. E-mail address: xlangloi@janbe.jnj.com (X. Langlois). 0028-3908/01/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(00)00149-0 was one of the keys for a better understanding of the involvement of a particular NK receptor in a physiologi- cal process. This was first accomplished by the structural modification of endogenous tachykinins. Numerous pep- tide analogues have been synthesized, displaying selec- tive agonistic or antagonistic properties (Mussap et al., 1993), and used as radioligands for determining binding parameters and distribution of each of the NK receptors in native tissues. NK1 receptors are highly expressed in both the CNS and peripheral tissues, NK2 receptors are characterized by a predominant expression in the periph- ery and NK3 receptors are found primarily in the CNS. In the last ten years, a major improvement was the intro- duction of non-peptide antagonists, these compounds being highly selective, resistant to degradation by pep- tidases and therefore metabolically stable (Betancur et al., 1997). SR142801 is the first potent non-peptide antagonist selective for the NK3 receptor to be described (Emonds- Alt et al., 1995). This compound has been used in