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Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved

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Abstract

Rationale

Second-generation antipsychotics have some beneficial effect on cognition. Recent studies, furthermore, indicate differential effects of second-generation antipsychotics on impairment in executive cognitive function.

Objective

We evaluated the effect of the second-generation antipsychotic drug, sertindole, on extracellular levels of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in the rat medial prefrontal cortex (mPFC). Risperidone was studied for comparison. Moreover, selective serotonin 5-HT2A, 5-HT2C, and 5-HT6 receptor antagonists were used, given alone and in combination with the preferential DA D2 receptor antagonist, haloperidol, to further clarify the action of the two drugs.

Materials and methods

Rats were treated acutely with vehicle or drugs, and extracellular levels of neurotransmitters were assessed by microdialysis in freely moving animals.

Results

Sertindole and risperidone significantly increased extracellular levels of DA. Haloperidol; the 5-HT2A receptor antagonist, M100907; the 5-HT2C receptor antagonist, SB242084; and the 5-HT6 receptor antagonist, GSK-742457, induced minor increases in levels of DA, but the three latter compounds raised the DA levels notably in combination with haloperidol. Sertindole and risperidone significantly increased the extracellular levels of ACh but only sertindole raised the extracellular levels of Glu. The selective 5-HT6 receptor antagonist, SB-271046, significantly increased the extracellular levels of Glu.

Conclusion

Sertindole and risperidone markedly increased extracellular levels of DA in mPFC. The built-in 5-HT2A/5-HT2C/D2 receptor antagonism of the two drugs might be involved in this action. Both drugs increased the extracellular levels of ACh but only sertindole enhanced Glu levels. The high affinity of sertindole for the 5-HT6 receptor compared to risperidone may differentiate sertindole from risperidone.

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Acknowledgements

The authors would like to thank Anette Frederiksen, Jeanett Raun Lott, and Nina Guldhammer for the skilful technical assistance.

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  1. Department of Neurophysiology, Discovery Pharmacology Research, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Copenhagen, Denmark

    Arne Mørk & Louise M. Witten

  2. Lundbeck Research DK, H. Lundbeck A/S, Valby, Copenhagen, Denmark

    Jørn Arnt

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  1. Arne Mørk
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Correspondence to Arne Mørk.

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Mørk, A., Witten, L.M. & Arnt, J. Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved. Psychopharmacology 206, 39–49 (2009). https://doi.org/10.1007/s00213-009-1578-4

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