Tobacco contributes to more deaths in the US each year than HIV, illicit drugs, alcohol, motor vehicle accidents, and firearm-related fatalities combined. While the commercialization of therapies for smoking cessation has enhanced abstinence, long-term abstinence rates are low. Kappa opiate receptor (KOR) antagonism has the potential to address the mood alterations that are associated with nicotine withdrawal, including irritability, anxiety, and depression. KORs are upregulated by chronic substance exposure and are thought to participate in mediating stress-induced reinstatement of drug-seeking behavior. Data to date support an emerging consensus that KOR antagonists have antidepressant-like effects, reduce excessive substance consumption, and reduce behaviors and signs of drug withdrawal (nicotine, alcohol, heroin). The availability of a highly selective, orally active, once-daily, well-tolerated kappa antagonist like CERC-501 would represent a promising treatment alternative for substance use disorders including nicotine dependence. Clinical studies to date suggest that CERC-501 safely and selectively blocks KOR in healthy adult humans. In animal studies, CERC-501 has demonstrated antidepressant-like effects and reduces the hyperalgesia, somatic signs and open field behaviors of nicotine-withdrawn rats. Cerecor's plans for CERC-501 include its registration as an aid to smoking cessation treatment. The primary objective of the proposal is to generate data in a Phase 1b/2a human laboratory study demonstrating that CERC-501 increases the ability to resist smoking relative to placebo, as measured by time to first cigarette and number of self-administered cigarettes in non-treatment seeking heavy smokers (Specific Aim 1). The experimental paradigm proposed herein has been previously developed and validated by others (McKee, et al 2012; Roche, et al 2014) to measure smoking lapse behaviors (time to first cigarette; number of cigarettes smoked) in smokers undergoing abstinence from cigarette smoking in a controlled environment. The model appears to be sensitive to risk factors for `real world' smoking relapse, the severity of nicotine dependence, and the degree of hedonic effect achieved with smoking. Healthy, heavy smokers are proposed to be dosed under staff observation daily with CERC-501 to steady state, and then admitted to a clinical research ward for overnight nicotine abstinence. After 18 hours of abstinence, the subjects will be presented with a smoking cue, and rewarded for every 5 minutes that they are able to abstain from smoking. Once the time to lapse has been established, they will be allowed to smoke ad libitum. The impact of CERC-501 on state measures of nicotine withdrawal, mood, anhedonia, anxiety, and craving, as well as its safety and tolerability in this cohort will be assessed (Specific Aims 2 and 3).