Correlating behavoir and molecular endpoints indentifies IFNγ-regulated genes in the dopaminergic system after modafinil administration in mouse

The mechanisms of aciotn of modafinil continue to be poorly characterised and its potential for abuse 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. We used microarrays to detail gene expression in the ventral tegmental area (VTA), nucleaus accumbens (NAC) and prefrontal cortex (PFC) of the vehicle and modafinil treated animals to profile whole genome expression in the selected brain regions. Individual mice underwent conditioned place preference testing in identical Contextual Place Prefernce test apparatus (Columbus Instruments, USA). One side was baclk with a smooth floor, and the other was white with a textured plastic floor, a neutal zone 4 cm in width separated the two compartments. During the pre-conditioning phase (days 1 and 2) the guillotine door was not present and the animals were able to roam the entire apparatus for thirty minutes to habituate to the conditioning boxes. Time spent in each compartment was recorded for the first fifteen minutes of testing during pre-conditioning to assess the natual preference of the animals. All animals displayed a preferance for the black compartment. Mice were randomly assigned into treatment groups. During the conditioning phase (days 3-10) the guillotine doors were closed. Mice received one injection per day, saline and treatment (modafinil or saline) on alternate days. On recieving saline injection, they were immediately confined to the initially preferred (black) compartment for thirty minutes. On drug conditioning days animals received an injection of modafinil 65 mg/kg or saline (control) and were immediately confined to the initially aversive (white) compartment for thirty minutes. On day eleven, the guillotine doors were again removed and the animals were allowed to explore the entire apparatus for thirty minutes. Time spent in each compartment for the first fifteen minutes of testing was recorded and used to calculate the post-conditioning preference of the animals.