title: Preclinical evaluation of the abuse potential of Pitolisant, a histamine H₃ receptor inverse agonist/antagonist compared with Modafinil.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Bioprojet-Biotech, Saint Grégoire Cedex, France.
authors.forename: M
authors.initials: M
authors.lastname: Uguen
authors.forename: D
authors.initials: D
authors.lastname: Perrin
authors.forename: S
authors.initials: S
authors.lastname: Belliard
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: P M
authors.initials: PM
authors.lastname: Beardsley
authors.forename: J M
authors.initials: JM
authors.lastname: Lecomte
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced* / Q000517:prevention & control; D001522:Behavior, Animal / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000009:adverse effects; D000697:Central Nervous System Stimulants / Q000009:adverse effects; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004353:Drug Evaluation, Preclinical; D054314:Drug Inverse Agonism; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D017442:Histamine Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000378:metabolism*; D064690:Wakefulness-Promoting Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D015507:Drugs, Investigational; D017442:Histamine Agonists; D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3; D064690:Wakefulness-Promoting Agents; C516975:pitolisant; D000077408:Modafinil; D004298:Dopamine