Effects of two selective 5-HT 2C receptor-acting compounds into the ventral hippocampus of rats exposed to the elevated plus-maze Graziela Scarpelli 1 , Sergio Henrique Alves 2 , J. Landeira-Fernandez 3, 4 and Antonio Pedro de Mello Cruz 2 1 Instituo de Ensino Superior de Brasília, Brazil 2 Universidade de Brasília, Brazil 3 Pontifícia Universidade Católica, Rio de Janeiro, Brazil 4 Universidade Estácio de Sá, Rio de Janeiro, Brazil Abstract This study investigated the effects of two selective serotonin 2C (5-hydroxytryptamine, 5-HT 2C ) receptor-acting compounds into the ventral hippocampus (VH) of rats exposed to the elevated plus-maze (EPM). In the frst experiment, rats were exposed to the EPM 10 min following VH infusions of either vehicle or the selective 5-HT 2C -receptor agonist RO-60-0175 (0.3, 1.0, 3.0 and 10.0µg). In addition to conventional parameters of open arm exploration (i.e. percentages of open arm entries and of time spent in these arms), risk assessment- related behaviors were recorded as anxiety-like measures in EPM scoring. RO-60-0175 selectively decreased open arm exploration at the dose of 1.0 µg, while inducing locomotor-suppressant effects at the two highest doses. In the second experiment, VH infusions of the selective 5-HT 2C antagonist RS 102221 (0.75, 1.25 and 2.5 µg) did not affect open arm exploration, while reducing risk assessment in the closed ones. This behavioral profle of risk assessment is suggestive of an anxiolytic-like action. These results further corroborate our previous fndings showing that VH 5-HT 2C receptor activation elicits anxiogenic-like and locomotor-suppressant effects, and suggest that the selective blockade of this receptor is accompanied by an anxiolytic-like action as detected by ethologically derived measures in the EPM. Keywords: anxiety, 5-HT 2C receptors, RO-60-0175, RS 102221, ventral hippocampus, elevated plus-maze, risk assessment. Introduction Serotonin 2C (5-hydroxytryptamine, 5-HT 2C ) receptor activation, either by nonselective 5-HT 2C agonists such as m-chlorophenylpiperazine (m-CPP) and trifluoromethyl- phenylpiperazine (TFMPP) or the preferential 5-HT 2C agonist 6-chloro-2[1-piperazinyl]pyrazine (MK-212), has long been associated with anxiogenic-like profiles in a variety of animal models of anxiety, including the elevated plus-maze (EPM; Benjamin, Lal, & Meyerson, 1990; Kshama, Hrishikeshavan, Shanbhogue, & Munonyedi, 1990; Rodgers et al., 1992; Gibson et al., 1994; Griebel, Moreau, Jenck, Mutel, Martin, & Misslin, 1994; Fone, Shalders, Fox, Arthur, & Marsden, 1996; Wallis and Lal, 1998; Setem, Pinheiro, Motta, Morato, & Cruz, 1999; Jones, Duxon, & King, 2002; Bull, Huston, & Fone , 2003; Durand, Mormèd, & Chaouloff, 2003). In fact, newly selective 5-HT 2C agonists (e.g. RO- 60-0175) have been found to increase anxiety-related behaviors (Griebel et al., 1997; Kennett, et al., 1997, Kennett, Lightowler, S., Trail, Bright, & Bromidge, 2000; Martin, Ballard, & Higgins, 2002; Millan, Brocco, Gobert, & Dekeyne , 2005), although null and even anxiolytic-like effects have also been reported (Nic Dhonnchadha, Bourin, & Hascoet, 2003; Rippol, Hascoet, & Bourin, 2006). Despite growing insights into the neural mechanisms through which 5-HT systems might infuence defensive behavior, the circuits responsible for the above fndings as well as the exact role of the 5-HT 2C receptor in specifc types of anxiety remain unclear. For example, 5-HT 2C agonists increase anxiety-related behaviors in the basolateral nucleus of the amygdala (Campbell & Merchant, 2003) but decrease panic-related behaviors in the dorsal periaqueductal gray (Jenck, Bos, Wichmann, Stadler, Martin, & Moreau, 1998; Graeff, 2002; Jacob et al., 2002; Zanoveli, Nogueira, & Zangrossi, 2003). Therefore, different brain structures that receive direct 5-HT projections from the dorsal raphe nucleus might have a distinct contribution to anxiety mediation. Besides the amygdala and the periaqueductal gray, the ventral portion of the hippocampus (VH) is another important postsynaptic 5-HT site whose cell bodies are located in the dorsal raphe nucleus (Azmitia & Segal, 1978; Vertes, 1991). It appears that 5-HT receptors present Graziela Scarpelli, Curso de Psicologia, Instituo de Ensino Superior de Brasília, DF, Brasil. Sergio Henrique Alves and Antonio Pedro de Mello Cruz, Departamento de Processos Psicológicos Básicos, Instituto de Psicologia, Universidade de Brasília, Brasilia, DF, Brasil. J. Landeira-Fernandez, Departamento de Psicologia, Pontifícia Universidade Católica do Rio de Janeiro, Brasil and Curso de Psicologia, Universidade Estácio de Sá, Campus Akxe, Rio de Janeiro, Brasil. Correspondences regarding this articles should be directed to Antonio Pedro Mello Cruz, Ph.D. University of Brasília, Institute of Psychology, Asa Norte, Brasilia DF, 70910-900, Brazil. Tel/fax: +55 61 3307 2625 ext. 502. E-mail: apmcruz@unb.br Psychology & Neuroscience, 2008, 1, 1, 87 - 96 DOI:10.3922/j.psns.2008.1.014 PSYCHOLOGY NEUROSCIENCE & Received 2 February 2008; received in revised form 2 June 2008; accepted 2 June 2008; Available online 10 June 2008.