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Struthers AM, Wilkinson JL, Dwoskin LP, Crooks PA, Bevins RA: Mecamylamine, dihydro-beta-erythroidine, and dextromethorphan block conditioned responding evoked by the conditional stimulus effects of nicotine. Genes Brain Behav. 2009 Apr;8(3):257-66. Epub 2008 Dec 11.
Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors play in the CS effects of nicotine (0.4mg/kg) using antagonists with differential selectivity for beta2*, alpha7*, alpha6beta2*, and alpha3beta4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-beta-erythroidine (DHbetaE) dose-dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHbetaE, each blocked conditioned responding when given 5min before testing and still blocked conditioned responding when administered 200min before testing. Two novel bis-picolinium analogs (N, N'-(3, 3'-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N'-(decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion was used to target alpha3beta4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1mg/kg). These results indicate that beta2* and potentially alpha3beta4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids. |
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