5-HT<inf>2A</inf> receptors are involved in cognitive but not antidepressant effects of fluoxetine

Abstract

© 2015 Elsevier B.V. and ECNP. The prefrontal cortex (PFC) plays a crucial role in cognitive and affective functions. It contains a rich serotonergic (serotonin, 5-HT) innervation and a high density of 5-HT receptors. Endogenous 5-HT exerts robust actions on the activity of pyramidal neurons in medial PFC (mPFC) via excitatory 5-HT2A and inhibitory 5-HT1A receptors, suggesting the involvement of 5-HT neurotransmission in cortical functions. However, the underlying mechanisms must be elucidated. Here we examine the role of 5-HT2A receptors in the processing of emotional and cognitive signals evoked by increasing the 5-HT tone after acute blockade of the 5-HT transporter. Fluoxetine (5-20mg/kg i.p.) dose-dependently reduced the immobility time in the tail-suspension test in wild-type (WT) and 5-HT2A knockout (KO2A) mice, with non-significant differences between genotypes. Fluoxetine (10mg/kg i.p.) significantly impaired mice performance in the novel object recognition test 24h post-administration in WT, but not in KO2A mice. The comparable effect of fluoxetine on extracellular 5-HT in the mPFC of both genotypes suggests that presynaptic differences are not accountable. In contrast, single unit recordings of mPFC putative pyramidal neurons showed that fluoxetine (1.8-7.2mg/kg i.v.) significantly increased neuronal discharge in KO2A but not in WT mice. This effect is possibly mediated by an altered excitatory/inhibitory balance in the PFC in KO2A mice. Overall, the present results suggest that 5-HT2A receptors play a detrimental role in long-term memory deficits mediated by an excess 5-HT in PFC.Funding for this study was provided by Grants SAF 2012-35183, the Ministry of Economy and Competitiveness, co-financed by European Regional Development Fund (ERDF) and by the Grants PI12/00156, PI13/01390 and PI10/00290 (PN de I+D+I 2008-2011, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación cofinanced by the European Regional Development Fund. “Una manera de hacer Europa”), and Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. AC was supported by a postdoctoral contract from the ISCIII (CD05/00234)Peer Reviewe