Discriminative stimulus effects of a novel epibatidine analog RTI-102 in mice

Abstract

Aims: Developing effective drugs to promote smoking cessation is key to counteracting the potential health risks associated with cigarette smoking. RTI-102 is a low efficacy analog of the high affinity and high efficacy nicotinic acetylcholine receptor agonist epibatidine. To examine its effects in vivo, RTI-102 was studied in a drug discrimination procedure.

Methods: Male C57BL/6J mice (n = 8) discriminated nicotine (1 mg/kg, s.c.) from saline while responding under a fixed ratio 10 schedule of food presentation. Nicotine, epibatidine, and RTI-102 were studied alone and RTI-102 was studied in combination with nicotine.

Results: Nicotine and epibatidine both dose-dependently increased nicotine-appropriate responses to a maximum of 86% and 92%, respectively. The ED50 values were 0.86 mg/kg for nicotine and 0.0021 mg/kg for epibatidine. In contrast, RTI-102 could only produce a maximum of 49% nicotine-appropriate responses up to a dose that disrupted responding. When combined with the training dose (1 mg/kg) of nicotine, RTI-102 dose-dependently attenuated the discriminative stimulus effects of nicotine to 33% nicotine-appropriate responding.

Conclusions: The behavioral effects of nicotinic acetylcholine receptor ligands vary as a function of agonist efficacy, as evidenced by the high percentage of nicotine-appropriate responding produced by epibatidine and the lower percentage of nicotine-appropriate responding produced by RTI-102. Further evidence is provided by the antagonism of nicotine by RTI-102 to the level of effect produced by RTI-102 alone. Low efficacy is presumed to be critically important to the effectiveness of some smoking cessation drugs (e.g. varenicline), suggesting that RTI-102 could be developed for the same indication.

Financial support: Supported by NIH grant DA025267.