| Cigarette smoking is the leading preventable cause of death worldwide with no successful treatment options for the majority of individuals wishing to quit. To improve treatment efficacy and individualize treatment strategies in patients wishing to quit smoking there is a critical need to identify novel, rapidly translatable pharmacotherapeutics, identify genetic correlates of tobacco dependence and treatment response that may guide cessation therapy, and describe the etiology of the coincident behavior of smoking and drinking so that interventions may be realized for co-abuse.;We leveraged a larval zebrafish behavioral model based on locomotor activation to address this clinical need. Our aims were to: (1) identify bioactive compounds already approved or available for human consumption that have potential as novel smoking cessation therapeutics; (2) identify and describe genes involved in the acute nicotine response and varenicline treatment that may be important contributors to tobacco dependence risk and treatment outcomes; and (3) determine how nicotine and ethanol interact, influencing the acute perception of drug reward associated with these coincidentally used and abused drugs. We have identified candidate medications, apomorphine, betaxolol, clonazepam, diazepam, lorazepam, topiramate, and zolpidem, and herbal supplements, valerian root, kava, skullcap, and American ginseng, for the treatment of tobacco dependence. We identified novel genes, znrd1 and gabra3, that may be involved in the acute perception of nicotine and in varenicline treatment effects, and described the impact on these responses of loss of the alpha 4 nicotinic receptor subunit. We also describe an interaction of nicotine and ethanol that may be important to understanding the coincident behaviors of smoking and drinking alcohol.;The majority of smokers wish to quit, but very few are successful even with the most efficacious treatment strategies. By adding to the armamentarium novel medications for the treatment of tobacco dependence, elucidating the genetic contributors to dependence liability and treatment outcomes, and interpreting the comorbid conditions influencing smoking behavior we may individualize the treatment of tobacco dependence and put an end to the single greatest preventable cause of death in world. |
