Modafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical 
stimulant and is a putative cognition enhancer for schizophrenia, but the 
precise mechanisms of action remain unclear. Receptor knockout (KO) mice offer 
an opportunity to identify receptors that contribute to a drug-induced effect. 
Here we examined the effects of modafinil on exploration in C57BL/6J mice, in 
dopamine drd1, drd2, drd3, and drd4 wild-type (WT), heterozygous (HT), and KO 
mice, and in 129/SJ mice pretreated with the drd1 antagonist SCH23390 using a 
cross-species test paradigm based on the behavioral pattern monitor. Modafinil 
increased activity, specific exploration (rearing), and the smoothness of 
locomotor paths (reduced spatial d) in C57BL/6J and 129/SJ mice (increased 
holepoking was also observed in these mice). These behavioral profiles are 
similar to that produced by the dopamine transporter inhibitor GBR12909. 
Modafinil was ineffective at increasing activity in male drd1 KOs, rearing in 
female drd1 KOs, or reducing spatial d in all drd1 KOs, but produced similar 
effects in drd1 WT and HT mice as in C57BL/6J mice. Neither dopamine drd2 nor 
drd3 mutants attenuated modafinil-induced effects. Drd4 mutants exhibited a 
genotype dose-dependent attenuation of modafinil-induced increases in specific 
exploration. Furthermore, the drd1 KO effects were largely supported by the 
SCH23390 study. Thus, the dopamine drd1 receptor appears to exert a primary role 
in modafinil-induced effects on spontaneous exploration, whereas the dopamine 
drd4 receptor appears to be important for specific exploration. The 
modafinil-induced alterations in exploratory behavior may reflect increased 
synaptic dopamine and secondary actions mediated by dopamine drd1 and drd4 
receptors.