Antidepressant- and anxiogenic-like effects of acute 5-HT2C receptor activation in rats exposed to the forced swim test and elevated plus maze.

Abstract

This study investigated the behavioral effects in the forced swim test (FST) and the elevated plus-maze (EPM) of acute administration of WAY 161503 ([4aR]-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5[6H]-one), a selective 5-HT 2C receptor agonist with putative antidepressant-like properties. Fifteen minutes after intraperitoneal (i.p.) injections of either WAY 161503 (1, 3 and 10 mg/kg) or saline, naive male Wistar rats were exposed to the EPM for 5 min to assess classical and ethological anxiety-like measures. Immediately after EPM exposure, each animal was exposed to the FST, and the latency to the first episode of immobility was recorded (trial session). Twenty-four hours later, the rats were reexposed to a second EPM-FST exposure sequence (test session for FST) under the effect of the same pharmacological treatment. The two lowest WAY 161503 doses selectively reduced open-arm exploration and increased risk-assessment without affecting locomotor activity. This selective anxiogenic-like effect was observed in both the first and second EPM exposures. The highest WAY 161503 dose produced robust locomotor impairment. In the FST, the same WAY 161503 doses significantly increased the latency to the first immobility in the test session, a behavioral profile that suggests an antidepressant-like action. These results further support the involvement of 5-HT 2C receptors in the mediation of anxiety and suggest an intricate relationship between anxiogenic-and antidepressant-like actions.

Envolvimento de receptores 5-HT2C do hipocampo ventral em comportamentos de defesa de ratos no labirinto em cruz elevado

“…O padrão comportamental decorrente da ativação farmacológica dos receptores 5-HT 2C pelo WAY-161503 corrobora resultados recentes de nosso laboratório com esta mesma droga administrada perifericamente (Gomes et al, 2010), bem como está de acordo com os efeitos ansiogênicos vastamente documentados para outros agonistas 5-HT 2C não apenas no labirinto em cruz elevado, mas também em outros modelos animais, incluindo o campo aberto, a interação social em ratos, a transição claro-escuro, a resposta de congelamento condicionada (Griebelet al, 1994;Kennett et al, 2000;Kennett, Whitton, Shah, & Curzon, 1989;Kimura et al, 2009;Li, Jiang, & Wang, 2012;Setem et al, 1999).…”

“…O padrão de resultados com a administração periférica desses ligantes, ainda que variados e altamente dependentes de peculiaridades metodológicas que incluem desde o tipo de modelo de animal até a seletividade para os receptores 5-HT 2C e rota de administração, pode ser assim resumido: agonistas causam efeito ansiogênico e antagonistas bloqueiam ou atenuam esses efeitos. Antagonistas administrados isoladamente, na ausência do agonista, são desprovidos de atividade intrínseca ou causam efeitos ansiolíticos discretos ou, paradoxalmente, efeitos ansiogênicos (Alves, Pinheiro, Motta, Landeira-Fernandez, & Cruz, 2004;Durand, Mormèd, & Chaouloff, 2003;Filip & Bader 2009;Gomes et al, 2010;Jones, Duxon, & King, 2002;Mosher, Smith, & Greenshaw, 2006;Setem, Pinheiro, Motta, Morato, & Cruz, 1999).…”

5-HT2C agonists and antagonists block different components of behavioral responses to potential, distal, and proximal threat in zebrafish

“…For Experiment 1, animals were injected intraperitoneally either with MK-212 (1 mg/kg and 2 mg/kg, doses which increase anxiety-like behavior in the rat elevated plus-maze; (de Mello Cruz et al, 2005)) or with the vehicle solution (Cortland's salt solution); WAY-161503 (1 mg/kg, a dose which produces anxiogenic-like effects in the rat elevated plus-maze: Gomes et al, 2010) or with the vehicle solution (DMSO); or RS-102221 (2 mg/kg, a dose that reduces anxiety in the mouse light/dark test; (Kuznetsova et al, 2006) To verify the effects of phasic activation of 5-HT2C receptors on the zebrafish alarm reaction, animals were pre-treated with either receptor agonists and exposed to CAS in a sequential design, with a "washout" period in between tests ( Figure 1A). For the exposure stage, each animal was transferred individually to a container (2 L) where after 3 minutes of acclimatization, it was carefully exposed to 7 ml of alarm substance (CAS), extracted using a 10/51 standardized protocol (do Carmo Silva et al, 2018b).…”

“…For Experiment 1, animals were injected intraperitoneally either with MK-212 (1 mg/kg and 2 mg/kg, doses which increase anxiety-like behavior in the rat elevated plus-maze; (de Mello Cruz et al, 2005)) or with the vehicle solution (Cortland's salt solution); WAY-161503 (1 mg/kg, a dose which produces anxiogenic-like effects in the rat elevated plus-maze: Gomes et al, 2010) or with the vehicle solution (DMSO); or RS-102221 (2 mg/kg, a dose that reduces anxiety in the mouse light/dark test; (Kuznetsova et al, 2006)). For Experiment 2, animals were injected intraperitoneally with MK-212 (2 mg/kg) or vehicle (Cortland's salt solution).…”