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Abstract
Several second-generation antipsychotics are characterised by a significant antagonistic effect at serotonin 5-HT^sub 2A^ receptors (5-HT^sub 2A^R), 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-HT^sub 2A^ antagonism and its exact contribution to the complex pharmacological profile of these drugs remain to be elucidated.
Here, we used pharmacological magnetic resonance imaging to map the modulatory effects of the selective 5-HT^sub 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.
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^sub 2A^R on frontal dopamine release, the role of post-synaptic dopamine D^sub 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.
Our data expand recent evidence suggesting a key role of 5-HT^sub 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^sub 2A^R antagonism in normal and disease states.[PUBLICATION ABSTRACT]