BACKGROUND AND PURPOSE: Pitolisant, a histamine H₃ receptor inverse 
agonist/antagonist is currently under Phase III clinical trials for treatment of 
excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse 
potential was investigated using in vivo models in rodents and monkeys and 
compared with those of Modafinil, a psychostimulant currently used in the same 
indications.
EXPERIMENTAL APPROACH: Effects of Pitolisant on dopamine release in the nucleus 
accumbens, on spontaneous and cocaine-induced locomotion, locomotor 
sensitization were monitored. It was also tested in three standard drug abuse 
tests i.e. conditioned place preference in rats, self-administration in monkeys 
and cocaine discrimination in mice as well as in a physical dependence model.
KEY RESULTS: Pitolisant did not elicit any significant changes in dopaminergic 
indices in rat nucleus accumbens whereas Modafinil increased dopamine release. 
In rodents, Pitolisant was without any effect on locomotion and reduced the 
cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no 
conditioned hyperlocomotion were evidenced with this compound in rats whereas 
significant effects were elicited by Modafinil. Finally, Pitolisant was devoid 
of any significant effects in the three standard drug abuse tests (including 
self-administration in monkeys) and in the physical dependence model.
CONCLUSIONS AND IMPLICATIONS: No potential drug abuse liability for Pitolisant 
was evidenced in various in vivo rodent and primate models, whereas the same 
does not seem so clear in the case of Modafinil.