Anxiogenic effects in the rat elevated plus-maze of 5-HT2C agonists into ventral but not dorsal hippocampus

Abstract

The effect of the non-selective 5-HT2C receptor agonist trifluoromethyl-phenylpiperazine (TFMPP, 0.75, 1.5 and 3.0 microg) and the preferential 5-HT2C agonist 6-chloro-2(1-piperazinyl)pyrazine (MK-212, 0.1, 0.3 and 1.0 microg) microinjected into the ventral or dorsal hippocampus was investigated in anxiety measures of rats exposed to the elevated plus-maze test. Ventral hippocampal (VH) microinjections of the 0.75 or 1.5 microg doses of TFMPP reduced open-arm exploration without affecting the number of closed-arm entries, indicating a selective anxiogenic profile. The highest dose (3.0 microg) reduced open- and closed-arm entries, suggesting interference in locomotor activity. The 0.1 microg dose of MK-212 also caused a selective anxiogenic effect when microinjected into the ventral hippocampus, without disturbing locomotor activity. Microinjections of the two higher doses of MK-212 (0.3 or 1.0 microg) into the ventral hippocampus led to a decrease of exploration in both arms of the maze. In contrast to the anxiogenic effect observed in the VH, neither TFMPP nor MK-212 significantly changed anxiety measures when microinjected into the dorsal hippocampus. These results suggest that activation of 5-HT2C postsynaptic receptors located in the ventral, but not in the dorsal, hippocampus play an important role in anxiety triggered by the elevated plus-maze test.

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

“…In line with these observations, it has also been demonstrated that 5-HT 2C receptor-binding sites are more densely expressed in the VH compared with DH (Holmes et al, 1995). Interestingly, the anxiolytic properties of agomelatine principally reflect acute blockade of 5-HT 2C receptors , and 5-HT 2C receptors located in the VH are specifically involved in the response to anxiety (Alves et al, 2004). Altogether, these data reinforce the hypothesis of a functional dissociation in neurogenesis between hippocampal subregions that may be related to how hippocampal circuit dynamics underlie affective disorders (Meltzer et al, 2005;Airan et al, 2007).…”

Hippocampal Cytogenesis Correlates to Escitalopram-Mediated Recovery in a Chronic Mild Stress Rat Model of Depression

“…Rat studies indicate that the ventral hippocampal formation is involved in anxiety (Alves et al, 2004) and that the ventral hippocampal formation and amygdala contribute distinctly to brain systems processing anxiety and/or fear . Since anxiety is present in the majority of patients with major depressive disorder (Fawcett and Kravitz, 1983;Fava et al, 2000), involvement of mainly the ventral, as opposed to the dorsal, hippocampal formation is likely to be important in the pathology of depression.…”

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

“…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).…”

“…Já o núcleo dorsal da rafe envia projeções serotoninérgicas para o córtex pré-frontal, septo lateral, estriado dorsal, córtex entorinal, matéria cinzenta periaquedutal, amígdala e o hipocampo ventral (Azmitia & Segal, 1978;McQuade & Sharp, 1997;Pompeiano, Palácios, & Mengod, 1994). As projeções para a amígdala (Davis, Rainnie, & Cassell, 1994;LeDoux, 2000;Rainnie, 1999) e hipocampo ventral (Alves et al, 2004) estão implicadas na modulação da ansiedade frente a situações de perigo em potencial, enquanto a que se projeta para a matéria cinzenta periaquedutal parecem modular reações de medo e pânico diante de situações reais de perigo proximal (Deakin & Graeff, 1991).…”

“…Com exceção da matéria cinzenta periaquedutal, onde a própria serotonina e agonistas serotoninérgicos exercem efeito "antipânico" (para revisões, ver Deakin & Graeff, 1991;Graeff, 2004), agonistas 5-HT 2C microinjetados diretamente na amígdala (Campbell & Merchant, 2003;Zangrossi & Graeff, 1994) ou no hipocampo ventral (Alves et al, 2004;Scarpelli, Alves, LandeiraFernandez, & Cruz, 2008) promovem efeitos ansiogênicos em diversos modelos animais de ansiedade.…”