title: Correlating behaviour and gene expression endpoints in the dopaminergic system after modafinil administration in mouse.
abstract: The mechanisms of action of modafinil continue to be poorly characterised and its potential for abuse in preclinical models remains controverted. The aim of this study was to further elucidate the mechanism of action of modafinil, through a potential behavioural and molecular association in the mouse. A conditioned place preference (CPP) paradigm was implemented to investigate the rewarding properties of modafinil. Whole genome expression and qRT-PCR analysis were performed on the ventral tegmental area (VTA), nucleus accumbens (NAC) and prefrontal cortex (PFC) of modafinil-treated and control animals. Modafinil administration (65 mg/kg) induced an increase in locomotor activity, an increase in the change of preference for the drug paired side after a conditioning period as well as changes to gene expression profiles in the VTA (120 genes), NAC (23 genes) and PFC (19 genes). A molecular signature consisting of twelve up-regulated genes was identified as common to the three brain regions. Multiple linear correlation analysis showed a strong correlation (R(2)>0.70) between the behavioural and molecular endpoints in the three brain regions. We show that modafinil had a concomitant effect on CPP, locomotor activity, and up-regulation of interferon-γ (IFN-γ) regulated genes (Gbp2, Gbp3, Gbp10, Cd274, Igtp), while correlating the latter set of genes with behaviour changes evaluated through the CPP. A potential association can be proposed based on the dysregulation of p47 family genes and Gbp family of IFN-γ induced GTPases. In conclusion, these findings suggest a link between the behavioural and molecular events in the context of modafinil administration.
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: De Ron
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Dremier
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Winlow
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Jenkins
authors.affiliation: CNS Research, UCB Biopharma SPRL, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Hanon
authors.affiliation: Non-Clinical Development, UCB Biopharma SPRL, Belgium. Electronic address: andre.dacosta@ucb.com.
authors.forename: A
authors.initials: A
authors.lastname: Nogueira da Costa
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D000077408:Modafinil; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D000077408:Modafinil; D004298:Dopamine
keywords: Behaviour; Conditioned place preference; Drug abuse; Modafinil; Molecular profiling