Effect of administration of the nicotinic acetylcholine receptor antagonist BTMPS, during nicotine self-administration, on lever responding induced by context long after withdrawal

The use-dependent, nicotinic acetylcholine receptor antagonist bis-(2,2,6,6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was studied for its potential to reduce the self-administration of nicotine in rats, as well as to reduce context-induced recidivistic-like behavior after a six-week period of cessation. Rats were allowed to self-administer nicotine (FR1 schedule) inside an operant chamber with a response lever active on a 24 h basis for 14 days. After the self-administration phase, the rats were returned to standard maintenance cages for a period of six weeks. At the end of six weeks the rats were returned to the operant chambers for 7 days and lever responses were recorded under conditions identical to the original self-administration phase, except that lever responses were not rewarded. Daily administration (s.c.) of BTMPS produced a dose-dependent decrease in the self-administration of nicotine 55-80% compared to control animals, and significantly decreased context-induced lever responding initiated six weeks after cessation (35-78% reduction vs. controls). Decreasing the BTMPS regimen to administration once every 3 days was not effective in reducing nicotine self-administration, but lever responding induced during the return to the operant chambers 6 weeks later was significantly decreased (40% reduction vs. controls). Therefore BTMPS can selectively reduce both self-administration of nicotine and long-term recidivistic-like behavior depending upon the dose regimen. Since BTMPS does not evoke anti-nicotinic effects under normal physiological conditions, these data support a proof of concept for the safe use of such compounds in the treatment of tobacco abuse.