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.
|DeDominicis, Kristen E; Sahibzada, Niaz; Olson, Thao T et al. (2017) The (?4)3(?2)2 Stoichiometry of the Nicotinic Acetylcholine Receptor Predominates in the Rat Motor Cortex. Mol Pharmacol 92:327-337|
|Dezfuli, Ghazaul; Kellar, Kenneth J; Dretchen, Kenneth L et al. (2016) Evidence for the role of ?2* nAChR desensitization in regulating body weight in obese mice. Neuropharmacology 110:165-174|
|Forcelli, Patrick A; Turner, Jill R; Lee, Bridgin G et al. (2016) Anxiolytic- and antidepressant-like effects of the methadone metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP). Neuropharmacology 101:46-56|
|Tuan, Edward W; Horti, Andrew G; Olson, Thao T et al. (2015) AT-1001 Is a Partial Agonist with High Affinity and Selectivity at Human and Rat ?3?4 Nicotinic Cholinergic Receptors. Mol Pharmacol 88:640-9|
|Kong, Hyesik; Song, Jun-ke; Yenugonda, Venkata Mahidhar et al. (2015) Preclinical studies of the potent and selective nicotinic ?4?2 receptor ligand VMY-2-95. Mol Pharm 12:393-402|
|Afshordel, Sarah; Wood, Wellington Gibson; Igbavboa, Urule et al. (2014) Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein levels in aged mouse brain. J Neurochem 129:732-42|
|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|
|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|
|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|
Showing the most recent 10 out of 23 publications