Assessment of the abuse liability of ABT-288, a novel histamine H sub(3) receptor antagonist

Rationale: Histamine H sub(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 sub(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 sub(3) antagonists, indicates that ABT-288 is unlikely to possess a high potential for abuse in the human population and suggests that H sub(3) antagonists, as a class, are similar in this regard.