Antidepressant-like effect of Ro5-4864, a peripheral-type benzodiazepine receptor ligand, in forced swimming test Elaine Cristina Gavioli a , Filipe Silveira Duarte a , Elizangela Bressan a , Pascual Ferrara b , Roseli Coimbra Farges a , Thereza Christina Monteiro De Lima a, * a Department of Pharmacology, Center of Biological Science (CCB), Universidade Federal de Santa Catarina, Rua Ferreira Lima, 82- Centro, 88015-420 Floriano ´polis SC, Brazil b Sanofi Synthe ´labo Recherche, Labe `ge, France Received 25 February 2003; received in revised form 22 April 2003; accepted 29 April 2003 Abstract This study examined the effects of peripheral-type benzodiazepine receptors in the forced swimming test. PK 11195 (1-(2-chloro-phenyl)- N-methyl-N-(1-methylpropyl)-1-isoquinoline carboxamide) and Ro5-4864 (7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-ben- zodiazepine-2-one) were i.p. injected in mice, according to an acute (1 or 24 h) and a repeated (14 days) schedule. Pretreatment with the agonist, Ro5-4864, significantly reduced immobility time 1 h after treatment but not 24 h after it, whereas the antagonist, PK11195, did not interfere with the test parameters. Nevertheless, PK11195 pretreatment inhibited the Ro5-4864 antidepressant-like effect. Animals repeatedly treated with Ro5-4864 had a similar profile of action with no sign of motor impairment or locomotor activation as evaluated in the rota-rod and open-field tests, respectively. Aminoglutethimide pretreatment, which blocks the early step of steroid synthesis, inhibited the antidepressant- like effect of Ro5-4864. The present findings suggest an antidepressant-like profile for the benzodiazepine, Ro5-4864, that seems to involve steroid synthesis as underlying mechanism. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Benzodiazepine receptor, peripheral-type; PK11195; Ro5-4864; Depression; Steroid; (Mouse); Forced swimming test 1. Introduction The benzodiazepines are among the most prescribed drugs because of their anxiolytic, anticonvulsant and seda- tive actions. On the basis of the selectivity for their ligands and subcellular localisation, benzodiazepine-binding sites can be divided into central and peripheral types. Central- type benzodiazepine receptors occur only in neurons in the central nervous system whereas peripheral-type benzodiaze- pine receptors are detected mainly in the outer mitochondrial membranes in various tissues including the central nervous system (Anholt et al., 1986; Veenman and Gavish, 2000; Casellas et al., 2002). The therapeutic activities (anxiolytic, hypnosedative, anticonvulsant and muscle relaxant effects) of benzodiazepines are attributed to an action on central-type benzodiazepine receptor sites. In fact, diazepam binds with nearly similar affinity to both receptors, but other ligands, such as the benzodiazepine, Ro5-4864, and the isoquinoline, PK11195, show selectivity. These last compounds have high affinity for the peripheral-type benzodiazepine receptors but do not bind to the central-type benzodiazepine receptors site (Le Fur et al., 1983; Schoemaker et al., 1983). High levels of peripheral-type benzodiazepine receptors have been found in several peripheral tissues such as steroidogenic organs and blood cells (Papadopoulos et al., 1990). Peripheral-type benzodiazepine receptor ligands stimulate steroid synthesis in adrenal (Mukhin et al., 1989), placental (Barnea et al., 1989), testicular, ovarian tissues (Amsterdam and Suh, 1991) and glial cells (Papadopoulos et al., 1990) by translocation of cholesterol from outer to inner mitochondrial membranes, the rate-limiting step in steroidogenesis (Kru ¨eger, 1991). In the brain, peripheral-type benzodiazepine receptors are predominantly localised on glial cells (Costa and Guidotti, 1991). Neurosteroids, so-called because they are produced in the nervous system, are synthesised particu- 0014-2999/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0014-2999(03)01789-8 * Corresponding author. Tel.: +55-48-331-9491; fax: +55-48-222- 4164. E-mail address: thereza@farmaco.ufsc.br (T.C.M. De Lima). www.elsevier.com/locate/ejphar European Journal of Pharmacology 471 (2003) 21 – 26