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The 5-HT2A receptor antagonist M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism

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Abstract

In the present series of studies, we have investigated the effects of antagonists selective for the 5-HT2A, 5-HT2B and 5-HT2C receptors on motor and 'impulsive'-type behaviours elicited by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine. The selective 5-HT2A receptor antagonist M100,907 (0.5 mg/kg) attenuated the hyperlocomotion and stereotypy produced by dizocilpine (0.1–0.3 mg/kg). The selective 5-HT2B receptor antagonist SB215,505 (3 mg/kg) and the selective 5-HT2C receptor antagonist SB242,084 (0.5 mg/kg) had no effect against either measure, except that SB242,084 produced a small potentiation of the hyperactivity response. Dizocilpine (0.03 mg/kg) increased premature responding in rats performing the 5-choice serial reaction time task (5-CSRTT), and increased response frequency consequently reducing the mean inter-response time (IRT) and efficiency of responding in a DRL24 task. M100,907 (0.5 mg/kg) attenuated each of these effects, as well as the increased premature responding produced by the NMDA NR2B selective antagonist Ro 63–1908 (1 mg/kg) in the 5-CSRTT. In contrast SB242,084 (0.5 mg/kg) did not attenuate the dizocilpine-induced premature responding or increased responding in the DRL24 task. Rather, SB242,084 (0.05–0.5 mg/kg) produced qualitatively similar effects to dizocilpine, increasing premature responding and reducing IRT. The results suggest that 5-HT2A receptor antagonists may normalise certain 'impulsive' behaviours produced by NMDA receptor hypofunction. The 5-HT2C receptor antagonist SB242,084 failed to exert equivalent effects, rather a trend toward exacerbation of the behavioural changes produced by dizocilpine was apparent.

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Acknowledgements

We thank Phillippe Guerry and Stephan Roever for the synthesis of M100,907 and SB242,084 respectively. We also thank Drs. Mark Duxon and Derek Middlemiss (GlaxoSmithKline) for the generous donation of SB215,505.

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Correspondence to Guy A. Higgins.

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Higgins, G.A., Enderlin, M., Haman, M. et al. The 5-HT2A receptor antagonist M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism. Psychopharmacology 170, 309–319 (2003). https://doi.org/10.1007/s00213-003-1549-0

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