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Behav Pharmacol. 2015 Feb;26(1-2):33-44. doi: 10.1097/FBP.0000000000000102.

Can 5-HT3 antagonists contribute toward the treatment of schizophrenia?

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aSchool of Psychology, Victoria University of Wellington, Wellington, New Zealand bRoche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.


In one of his earlier papers, Lex Cools stated that the 'concept of an impaired balance between the in series connected […] dopamine system, […] 5-HT system and […] noradrenaline system offers a single coherent and integrated theory of schizophrenia' (Cools, 1975). Since then, considerable attention has focused on the interaction between dopamine and 5-HT and it is now well accepted that most antipsychotics (especially the second-generation drugs) modulate both dopaminergic and serotonergic receptors. However, the vast majority of research has focused on the 5-HT1A, 5-HT2A and 5-HT2C receptors. In the present paper, we review the literature pertaining to the 5-HT3 receptor, the only ionotropic 5-HT receptor. We discuss both the interactions between 5-HT3 receptors and dopamine, and the animal and human literature investigating the role of 5-HT3 receptors in schizophrenia. The results show that the interactions between 5-HT3 receptors and dopamine are complex, but that 5-HT3 receptors do not have a strong influence on the positive symptoms of schizophrenia. However, when added to standard antipsychotic medication, several recent studies have found that 5-HT3 receptor antagonists can induce a statistically significantly improvement in negative and cognitive symptoms. The implications of these findings in relation to animal modelling and drug development are discussed.

[Indexed for MEDLINE]

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