ORIGINAL INVESTIGATION Antagonism at serotonin 5-HT 2A receptors modulates functional activity of frontohippocampal circuit Alessandro Gozzi & Valerio Crestan & Giuliano Turrini & Marcel Clemens & Angelo Bifone Received: 31 July 2009 / Accepted: 20 December 2009 / Published online: 29 January 2010 # Springer-Verlag 2010 Abstract Rationale Several second-generation antipsychotics are char- acterised by a significant antagonistic effect at serotonin 5-HT 2A receptors (5-HT 2A R), a feature that has been associated with lower incidence of extra-pyramidal symp- toms and a putative amelioration of positive and negative symptoms experienced by schizophrenic patients. However, the neurofunctional substrate of 5-HT 2A antagonism and its exact contribution to the complex pharmacological profile of these drugs remain to be elucidated. Objectives Here, we used pharmacological magnetic reso- nance imaging to map the modulatory effects of the selective 5-HT 2A R antagonist Ml00907 on the spatiotemporal patterns of brain activity elicited by acute phencyclidine (PCP) challenge in the rat. PCP is a non-competitive NMDA receptor antagonist that induces dysregulation of corticolimbic glutamatergic neurotransmission and produces cognitive impairment and psychotic-like symptoms reminiscent of those observed in schizophrenia. Results Pre-administration of M100907 produced focal and region-dependent attenuation of PCP-induced response in frontoseptohippocampal areas. As early studies highlighted a permissive role of 5-HT 2A R on frontal dopamine release, the role of post-synaptic dopamine D 1 receptors on PCP-induced response was examined by using the potent antagonist SCH23390. Interestingly, SCH23390 did not affect PCP’ s response in any of the regions examined. This finding rules out a significant contribution of dopamine in the functional changes mapped and, indirectly, the inhibitory effect of M100907, in favour of a glutamatergic origin. Conclusions Our data expand recent evidence suggesting a key role of 5-HT 2A R in modulating glutamate-mediated cognitive performance in the prefrontal cortex and highlight the whole frontoseptohippocampal circuit as a key functional substrate of 5-HT 2A R antagonism in normal and disease states. Keywords fMRI . Phencyclidine . M100907 . phMRI . Schizophrenia . Cognition Introduction Schizophrenia is a disabling psychiatric disorder charac- terised by complex and severe symptoms, including psychosis, hallucinations, cognitive deficits and mood alterations. Whilst the first antipsychotic agents targeted selectively the dopamine system through dopamine D 2 receptors, second-generation antipsychotics (SGA; e.g. clozapine) are characterised by a multifaceted pharmacological Electronic supplementary material The online version of this article (doi:10.1007/s00213-009-1772-4) contains supplementary material, which is available to authorized users. A. Gozzi : M. Clemens : A. Bifone Biology, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy V. Crestan : G. Turrini Laboratory Animal Science, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy A. Gozzi (*) Neuroimaging, GSK Neurosciences CEDD, Fleming 4, 37100 Verona, Italy e-mail: alessandro.gozzi@gsk.com Present Address: M. Clemens Osservatorio Astronomico di Padova, Padova, Italy Psychopharmacology (2010) 209:37–50 DOI 10.1007/s00213-009-1772-4