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Eur Neuropsychopharmacol. 2018 Sep;28(9):1035-1046. doi: 10.1016/j.euroneuro.2018.05.016. Epub 2018 Jul 10.

The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity.

Author information

1
Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
2
Eli Lilly and Company, Indianapolis, IN 46285, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA; Department of Radiological and Imaging Sciences, Indiana University School of Medicine, Indiana University - Purdue University Indianapolis, Indianapolis, IN 46202, USA.
3
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
4
Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
5
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
6
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address: alexander.sartorius@zi-mannheim.de.

Abstract

One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors and decreased affinity to D3 receptors associated with increased prefrontal-striatal FC (p = 0.0004, r² = 0.46; p = 0.004, r² = 0.33; p = 0.002, r² = 0.37; p = 0.02, r² = 0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D2 receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics.

KEYWORDS:

Antipsychotic agents; Dopamine antagonists; Magnetic resonance imaging; Psychotic disorders; Schizophrenia; Serotonin antagonists

PMID:
30006253
DOI:
10.1016/j.euroneuro.2018.05.016
[Indexed for MEDLINE]

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