Systemic neurotransmitter responses to clinically approved and experimental neuropsychiatric drugs

Abstract

Neuropsychiatric disorders are the third leading cause of global disease burden. Current pharmacological treatment for these disorders is inadequate, with often insufficient efficacy and undesirable side effects. One reason for this is that the links between molecular drug action and neurobehavioral drug effects are elusive. We use a big data approach from the neurotransmitter response patterns of 258 different neuropsychiatric drugs in rats to address this question. Data from experiments comprising 110,674 rats are presented in the Syphad database [www.syphad.org]. Chemoinformatics analyses of the neurotransmitter responses suggest a mismatch between the current classification of neuropsychiatric drugs and spatiotemporal neurostransmitter response patterns at the systems level. In contrast, predicted drug–target interactions reflect more appropriately brain region related neurotransmitter response. In conclusion the neurobiological mechanism of neuropsychiatric drugs are not well reflected by their current classification or their chemical similarity, but can be better captured by molecular drug–target interactions.

No basal or drug‐induced sex differences in striatal dopaminergic levels: a cluster and meta‐analysis of rat microdialysis studies

“…While most studies used Sprague–Dawley rats (62%), sufficient data could be obtained from other strains such as Long–Evans (22%), and Holtzmann (11%) in order to statistically evaluate the impact of strain on dopaminergic response to drugs of abuse. Nonetheless, only 4% of all entries relate to experiments on Wistar rats, which are often used to assess the effect of drugs on neurochemical concentrations in male rats (Noori, et al, ). Therefore, special care needs to be applied in interpreting the overall findings of the present meta‐analysis in light of previous investigations and our findings should be considered as relating mostly to Sprague–Dawley rats.…”

“…A previously reported (Noori, et al, 2012a; Brand, et al, ; Fliegel, et al, ; Hirth, et al, ; Fritze, et al, ; Noori, et al, ), we have established a robust pipeline for standardized data mining, database creation and integrative analysis of pre‐clinical neuropsychopharmacology experiments. This approach allows accurate extraction of maximum amount of data with a minimized chance for missing critical information and was therefore applied here to characterize basal dopamine concentrations as well as overlapping and distinct features of striatal dopaminergic response to systemically administered drugs of abuse in female rats.…”

“…A previously reported (Noori, et al, 2012a; Brand, et al, ; Fliegel, et al, ; Hirth, et al, ; Fritze, et al, ; Noori, et al, ), three categories (i.e. biological, experimental procedure and outcome) of study variables and parameters were extracted using a structured template.…”

“…For basal dopamine levels, data for male animals were obtained previously (Brand, et al, ). For drug‐induced relative dopamine changes, data were extracted from syphad (http://www.syphad.com) database (Noori, et al, ). Since absolute values are used, a statistical outlier identification algorithm (isoutlier(A,’method’) in MATLAB R2018a) was applied prior to conducting the F ‐test.…”

Everything you always wanted to know about sex and dopamine, but were afraid to ask

“…In a systematic meta‐ and cluster analysis, they analyze all currently available in vivo microdialysis studies for female rats on this issue and compare it with those from a previously analyzed male data set (Noori et al . ). While a direct comparison of different in vivo microdialysis studies is difficult because of the often quite different methodological approaches, Egenrieder and colleagues overcame this obstacle by a multistep cluster analysis.…”