title: Assessment of the abuse liability of ABT-288, a novel histamine H₃ receptor antagonist.
abstract: BACKGROUND
  Histamine H3 receptor antagonists, such as ABT-288, have been shown to possess cognitive-enhancing and wakefulness-promoting effects. On the surface, this might suggest that H3 antagonists possess psychomotor stimulant-like effects and, as such, may have the potential for abuse.
  
  
  OBJECTIVE
  The aim of the present study was to further characterize whether ABT-288 possesses stimulant-like properties and whether its pharmacology gives rise to abuse liability.
  
  
  METHODS
  The locomotor-stimulant effects of ABT-288 were measured in mice and rats, and potential development of sensitization was addressed. Drug discrimination was used to assess amphetamine-like stimulus properties, and drug self-administration was used to evaluate reinforcing effects of ABT-288. The potential development of physical dependence was also studied.
  
  
  RESULTS
  ABT-288 lacked locomotor-stimulant effects in both rats and mice. Repeated administration of ABT-288 did not result in cross-sensitization to the stimulant effects of d-amphetamine in mice, suggesting that there is little overlap in circuitries upon which the two drugs interact for motor activity. ABT-288 did not produce amphetamine-like discriminative stimulus effects in drug discrimination studies nor was it self-administered by rats trained to self-administer cocaine. There were no signs of physical dependence upon termination of repeated administration of ABT-288 for 30 days.
  
  
  CONCLUSIONS
  The sum of these preclinical data, the first of their kind applied to H3 antagonists, indicates that ABT-288 is unlikely to possess a high potential for abuse in the human population and suggests that H3 antagonists, as a class, are similar in this regard.
authors: Department of Preclinical Safety-Development Sciences, AbbVie, Inc., 1 N. Waukegan Rd., North Chicago, IL 60064, USA. thomas.hudzik@abbvie.com
authors: Thomas J
authors: TJ
authors: Hudzik
authors: Ana
authors: A
authors: Basso
authors: Janel M
authors: JM
authors: Boyce-Rustay
authors: William
authors: W
authors: Bracken
authors: Kaitlin E
authors: KE
authors: Browman
authors: Karla
authors: K
authors: Drescher
authors: Timothy A
authors: TA
authors: Esbenshade
authors: Lise I
authors: LI
authors: Loberg
authors: James J
authors: JJ
authors: Lynch
authors: Jorge D
authors: JD
authors: Brioni
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects; D004334:Drug Administration Schedule; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012646:Self Administration; D019966:Substance-Related Disorders / Q000453:epidemiology; D013997:Time Factors
chemical_list: C576396:2-(4'-(5-methylhexahydropyrrolo(3,4-b)pyrrol-1-yl)biphenyl-4-yl)-2H-pyridazin-3-one; D054828:Histamine H3 Antagonists; D011724:Pyridazines; D011758:Pyrroles; D003042:Cocaine; D003913:Dextroamphetamine