5-HT2A receptors are involved in cognitive but not antidepressant effects of fluoxetine.
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-HT2Aknockout (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.
Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: acfnqi@iibb.csic.es.
Anna
A
Castañé
Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Laboratory of Experimental Psychology & Neuroscience, Institute of Cognitive Neurology, Favaloro University, Buenos Aires, Argentina; UDP-INECO Foundation Core on Neuroscience, Diego Portales University, Santiago, Chile.
Lucila
L
Kargieman
Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Pau
P
Celada
Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Analía
A
Bortolozzi
Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Francesc
F
Artigas
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects* / Q000502:physiology; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D018687:Antidepressive Agents, Second-Generation; D018697:Nootropic Agents; D044402:Receptor, Serotonin, 5-HT2A; D005473:Fluoxetine
5-HT(2A) receptors; Antidepressant drugs; Novel object recognition; Prefrontal cortex; Tail suspension test; Working memory