LAUSR

Stress is known to influence smoking relapse. Experimental studies indicate that acute stress increases nicotine‐seeking behavior, yet neurobiological mechanisms remain poorly understood. Herein, we investigated disrupted excitatory neural activity in the dorsolateral prefrontal cortex (dlPFC) as a mechanism of stress‐induced nicotine‐seeking behavior. Non–treatment‐seeking cigarette smokers were screened for psychiatric, medical, and neuroimaging contraindications. Using a double‐blind, placebo‐controlled, randomized crossover design, participants (N = 21) completed two oral‐dosing sessions: stress (yohimbine 54 mg + hydrocortisone 10 mg) vs placebo (lactose 54 mg + lactose 10 mg). During each experimental session, working memory proficiency, dlPFC excitatory neural activity, nicotine‐seeking behavior, and subjective effects were measured. dlPFC excitatory neural activity was quantified via glutamate modulation during working memory performance using functional proton magnetic resonance spectroscopy. Nicotine‐seeking behavior was assayed using a cigarette puffs vs money choice progressive ratio task. Results indicated that yohimbine + hydrocortisone evoked a sustained physiological stress response (elevated heart rate, blood pressure, saliva cortisol, and saliva α‐amylase levels; ps < .05). Relative to placebo levels, acute stress increased nicotine‐seeking behavior (ps < .05), disrupted dlPFC glutamate modulation (p = .025), and impaired dlPFC function (working memory proficiency; ps < .05). The stress‐induced increase in nicotine‐seeking behavior was linearly related to the stress‐induced disruption of dlPFC glutamate modulation (R2 = 0.24‐0.37; ps < .05). These findings suggest that disrupted dlPFC excitatory neural activity is a neurobiological correlate of acute stress‐induced nicotine‐seeking behavior. These findings further emphasize the central role of the dlPFC in regulating drug‐seeking behavior. Future studies are needed to evaluate interventions to improve dlPFC resilience to acute stress effects, including neurostimulation, working memory training, and “anti‐stress” medications.