Nicotine intake constitutes a principal mechanism for tobacco addiction. Adequate treatment of smoking addiction remains problematic. Part of the problem with devising effective treatment is a poor understanding of the pharmacologic aspects of nicotine that underlie addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also causes pronounced receptor desensitization. It is not currently known how much of each of nicotine's two actions at the receptor level - stimulation vs. desensitization, contribute to its particular behavioral effects, including reinforcement and addiction. Sazetidine-A is a novel compound that provides potent desensitization of a4B2 nicotinic receptors. Our preliminary studies have shown the promise of sazetidine-A. We have shown that Sazetidine-A significantly reduces nicotine self-administration both with acute and chronic administration. The proposed neurobehavioral studies will broaden the sazetidine-A characterization, determining the dose and time-effect function at which the maximum efficacy in reducing extended access nicotine self-administration is reached and the doses at which side effects are seen. Sex-differences in response will be determined in all phases of the study. Sazetidine-A efficacy in reducing relapse to nicotine self-administration with challenges of nicotine priming, conditioned cues and stress will be determined. Newly developed compounds in the Sazetidine class of nicotinic desensitizing agents will be screened for blockade of nicotine-induced sensitization of locomotor hyperactivity. Those compounds and doses effective in this screen will be tested for efficacy in significantly reducing nicotine self-administration and helping to prevent relapse. The intended beneficial outcome of this research is to determine the most effective way to use nicotinic desensitizing agents to reduce dependence on tobacco and facilitate cessation.
Tobacco use and nicotine addiction are an immense public health problem, and the health costs associated with smoking are estimated as $75 billion per year in the U.S. Current treatments for nicotine addiction are not adequate. The goal of this NCDDDG is to develop smoking cessation drugs to help the nearly 50 million people in N. America and 1 billion people worldwide end their addiction to nicotine and stop smoking.
|Hussmann, G Patrick; DeDominicis, Kristen E; Turner, Jill R et al. (2014) Chronic sazetidine-A maintains anxiolytic effects and slower weight gain following chronic nicotine without maintaining increased density of nicotinic receptors in rodent brain. J Neurochem 129:721-31|
|Burke, Dennis A; Heshmati, Pooneh; Kholdebarin, Ehsan et al. (2014) Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats. Eur J Pharmacol 741:132-9|
|Liu, Yong; Paige, Mikell; Olson, Thao T et al. (2014) Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A. Bioorg Med Chem Lett 24:2954-6|
|Levin, Edward D (2013) Complex relationships of nicotinic receptor actions and cognitive functions. Biochem Pharmacol 86:1145-52|
|Levin, Edward D; Cauley, Marty; Rezvani, Amir H (2013) Improvement of attentional function with antagonism of nicotinic receptors in female rats. Eur J Pharmacol 702:269-74|
|Levin, Edward D; Sexton, Hannah G; Gordon, Karen et al. (2013) Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor *2-/- and *7-/- mice. Eur J Pharmacol 718:167-72|
|Rezvani, Amir H; Cauley, Marty; Xiao, Yingxian et al. (2013) Effects of chronic sazetidine-A, a selective ?4?2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats. Psychopharmacology (Berl) 226:35-43|
|Liu, Yong; Richardson, Janell; Tran, Thao et al. (2013) Chemistry and pharmacological studies of 3-alkoxy-2,5-disubstituted-pyridinyl compounds as novel selective ýý4ýý2 nicotinic acetylcholine receptor ligands that reduce alcohol intake in rats. J Med Chem 56:3000-11|
|Rezvani, Amir H; Timofeeva, Olga; Sexton, Hannah G et al. (2012) Effects of sazetidine-A, a selective ?4?2* nicotinic receptor desensitizing agent, on body temperature regulation in mice and rats. Eur J Pharmacol 682:110-7|
|Rezvani, Amir H; Cauley, Marty; Sexton, Hannah et al. (2011) Sazetidine-A, a selective ?4?2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague-Dawley rats. Psychopharmacology (Berl) 215:621-30|