Comparing sertindole to other new generation antipsychotics on preferential dopamine output in limbic versus striatal projection regions: mechanism of action.
The effects of acute administration of sertindole on DA output were examined in the shell part of the nucleus accumbens (NACS) and the striatum (STR), areas which are associated with limbic functions and motor control, respectively, by using in vivo differential normal pulse voltammetry in rats. The effect of sertindole was compared to those obtained with the reference antipsychotic drugs clozapine and haloperidol, new generation antipsychotics represented by risperidone, olanzapine, ziprasidone, quetiapine, and aripiprazole, as well as, with those of preferential D2/3, D4, 5-HT1A, 5-HT2A, 5-HT2C, alpha1, and alpha2 receptor ligands. In similarity with the new generation antipsychotics, sertindole preferentially increase DA output in the NACS as compared to the STR whereas the opposite was true for haloperidol. The regional specific effect of the partial D2 receptor agonist aripiprazole was mainly driven by a decrease in striatal rather that by an increase in accumbal DA output. The selective 5-HT2A and D4 receptor antagonists MDL100,151 and Lu 38-012, respectively, both preferentially increased DA output in the NACS. Thus, the present results are in line with the hypothesis that 5-HT2A receptor antagonism is of importance for the observed limbic selectivity of new generation antipsychotics and, in turn, to their favorable clinical profile especially as regards extrapyramidal side effects (EPS) liability. For some compounds, blockade of D4 receptors may also play a role in this regard.
Hertel
Peter
P
Department of Psychopharmacology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark. phertel@jacdk.jnj.com
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004525:Efferent Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008032:Limbic System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D007093:Imidazoles; D007211:Indoles; D044402:Receptor, Serotonin, 5-HT2A; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents; D012701:Serotonin; C066304:sertindole; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine