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Preclinical evaluation of the abuse potential of P itolisant, a histamine H 3 receptor inverse agonist/antagonist compared with M odafinil
Author(s) -
Uguen M,
Perrin D,
Belliard S,
Ligneau X,
Beardsley PM,
Lecomte JM,
Schwartz JC
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12149
Subject(s) - nucleus accumbens , inverse agonist , pharmacology , sensitization , agonist , antagonist , dopamine , conditioned place preference , histamine , dopaminergic , psychology , chemistry , medicine , endocrinology , receptor , neuroscience
Background and Purpose Pitolisant, a histamine H 3 receptor inverse agonist/antagonist is currently under P hase 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 M odafinil, a psychostimulant currently used in the same indications. Experimental Approach Effects of P itolisant 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 M odafinil increased dopamine release. In rodents, P itolisant 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 M odafinil. Finally, P itolisant 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 P itolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of M odafinil.