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.
BACKGROUND
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-HT(2A), 5-HT(2C), and 5-HT(6) receptor antagonists were used, given alone and in combination with the preferential DA D(2) receptor antagonist, haloperidol, to further clarify the action of the two drugs.


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-HT(2A) receptor antagonist, M100907; the 5-HT(2C) receptor antagonist, SB242084; and the 5-HT(6) 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-HT(6) receptor antagonist, SB-271046, significantly increased the extracellular levels of Glu.


CONCLUSIONS
Sertindole and risperidone markedly increased extracellular levels of DA in mPFC. The built-in 5-HT(2A)/5-HT(2C)/D(2) 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-HT(6) receptor compared to risperidone may differentiate sertindole from risperidone.
Mørk
Arne
A
Department of Neurophysiology, Discovery Pharmacology Research, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Copenhagen, Denmark. arm@lundbeck.com
Witten
Louise M
LM
Arnt
Jørn
J
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D004357:Drug Synergism; D005110:Extracellular Space / Q000378:metabolism*; D005464:Fluorobenzenes / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D005464:Fluorobenzenes; D007093:Imidazoles; D007211:Indoles; D010880:Piperidines; D058830:Serotonin 5-HT2 Receptor Antagonists; D018698:Glutamic Acid; C079049:volinanserin; C066304:sertindole; D006220:Haloperidol; D018967:Risperidone; D000109:Acetylcholine; D004298:Dopamine