AbstractHumans escalate their cigarette smoking over time, and a major obstacle in the field of pre‐clinical nicotine addiction research has been the inability to produce escalated nicotine self‐administration in rats. In experiment 1, male Wistar rats were trained to respond for nicotine in 2‐hour operant sessions, then exposed to chronic intermittent (12 hours/day) nicotine vapor and repeatedly tested for nicotine self‐administration at 8–12 hours of withdrawal. Rats were tested intermittently on days 1, 3 and 5 of the vapor exposure procedure, then tested with nicotine vapor exposure on 6–15 consecutive days. Rats exhibited transient increases in operant nicotine responding during intermittent testing, regardless of vapor condition, and this responding returned to baseline levels upon resumption of consecutive‐days testing (i.e. nicotine deprivation effect). Nicotine vapor‐exposed rats then escalated nicotine self‐administration relative to both their own baseline (∼200% increase) and non‐dependent controls (∼3× higher). In experiment 2, rats were exposed or not exposed to chronic intermittent nicotine vapor, then tested for spontaneous and precipitated somatic signs of nicotine withdrawal. Eight hours following removal from nicotine vapor, rats exhibited robust mecamylamine‐precipitated somatic signs of withdrawal. There was a strong correlation between nicotine flow rate and air–nicotine concentration, and the air–nicotine concentrations used in experiments 1 and 2 resemble concentrations experienced by human smokers. Collectively, these results suggest that chronic intermittent nicotine vapor inhalation produces somatic and motivational signs of nicotine dependence, the latter of which is evidenced by escalation of nicotine self‐administration.