Assessment of the abuse liability of ABT-288, a novel histamine H3 receptor antagonist

• Published in: Psychopharmacology 2013-07, Vol.228 (2), p.187-197
• Main Authors: Hudzik, Thomas J., Basso, Ana, Boyce-Rustay, Janel M., Bracken, William, Browman, Kaitlin E., Drescher, Karla, Esbenshade, Timothy A., Loberg, Lise I., Lynch, James J., Brioni, Jorge D.
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cocaine - administration & dosage; Dextroamphetamine - administration & dosage; Dextroamphetamine - pharmacology; Discrimination Learning - drug effects; Drug Administration Schedule; Histamine H3 Antagonists - administration & dosage; Histamine H3 Antagonists - pharmacology; Histamine H3 Antagonists - toxicity; Humans; Male; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Pyridazines - administration & dosage; Pyridazines - pharmacology; Pyridazines - toxicity; Pyrroles - administration & dosage; Pyrroles - pharmacology; Pyrroles - toxicity; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reinforcement Schedule; Self Administration; Substance-Related Disorders - epidemiology; Time Factors
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-013-3027-7

Rationale Histamine H 3 receptor antagonists, such as ABT-288, have been shown to possess cognitive-enhancing and wakefulness-promoting effects. On the surface, this might suggest that H 3 antagonists possess psychomotor stimulant-like effects and, as such, may have the potential for abuse. Objectives 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 H 3 antagonists, indicates that ABT-288 is unlikely to possess a high potential for abuse in the human population and suggests that H 3 antagonists, as a class, are similar in this regard.