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Psychopharmacology (2010) 209:3750 DOI 10.1007/s00213-009-1772-4
ORIGINAL INVESTIGATION
Antagonism at serotonin 5-HT2A 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
AbstractRationale Several second-generation antipsychotics are char-acterised by a significant antagonistic effect at serotonin 5-HT2A receptors (5-HT2AR), a feature that has been associated with lower incidence of extra-pyramidal symptoms and a putative amelioration of positive and negative symptoms experienced by schizophrenic patients. However, the neurofunctional substrate of 5-HT2A antagonism and its exact contribution to the complex pharmacological profile of these drugs remain to be elucidated.
Objectives Here, we used pharmacological magnetic resonance imaging to map the modulatory effects of the selective 5-HT2AR 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-HT2AR on frontal dopamine release, the role of post-synaptic dopamine D1 receptors on PCP-induced response was examined by using the potent antagonist SCH23390. Interestingly, SCH23390 did not affect PCPs 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-HT2AR in modulating glutamate-mediated cognitive performance in the prefrontal cortex and highlight the whole frontoseptohippocampal circuit as a key functional substrate of 5-HT2AR antagonism in normal and disease states.
Keywords fMRI . Phencyclidine . M100907 . phMRI . Schizophrenia . Cognition
Introduction
Schizophrenia is a disabling psychiatric disorder characterised 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 D2 receptors, second-generation antipsychotics (SGA; e.g. clozapine) are characterised by a multifaceted pharmacological
Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s00213-009-1772-4
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