Neurobehavioral Mechanisms Linking Childhood Adversity to Increased Risk for Smoking

The purpose of this study is to evaluate how certain childhood experiences influences brain function and responses to nicotine exposure in a group of nonsmoking young adults. The investigators assess responses to nicotine exposure by giving participants a small amount of nicotine or placebo, and then asking them to answer questionnaires. The investigational drugs used in this study are a nicotine nasal spray (i.e., Nicotrol) and/or a nasal spray placebo (made of common kitchen ingredients, including a very tiny amount of pepper extract also called capsaicin). The investigators assess brain function through function magnetic resonance imaging (fMRI), which is a noninvasive procedure that uses a magnetic field to take pictures of your brain while you are performing certain tasks. This study will help us to learn more about why some childhood experiences (adverse childhood experiences, or ACEs) contribute to increased risk for smoking and other substance use.

Individuals with a history of adverse childhood experiences (ACEs) are more likely to smoke cigarettes than those without, but little is known about the factors that account for this increased risk. This study will examine brain function in regions related to reward processing and inhibitory control, along with reactions to initial nicotine exposure to help explain why ACEs lead to increased risk for smoking. In this study, young adult non-smokers ages 18-21 (n=150) with a history of exposure to ACEs ranging from 0 to 4 or more will be enrolled to attend 7 visits including an MRI scan and administration of a nicotine nasal spray. Participants will complete an in-person screening visit, followed by a training visit to provide training for the MRI tasks and to acclimate them to the mock MRI scanner. They will then complete a functional neuroimaging scanning session to examine brain reactivity during a monetary reward task, an inhibitory control task, and during rest. Participants will then attend 3 separate visits in which subjective reactions to a nasal spray containing 0, .5, or 1 mg doses of nicotine will be measured. During a final choice session participants will choose to self-administer nicotine or placebo nasal spray. Breath and urine samples will be collected at each visit to test for recent smoking, alcohol use, or illicit drug use. Plasma samples will be collected at each fixed-dose session to assess nicotine and cotinine levels. All nicotine administration will occur during laboratory sessions, and the study physician will be on site or on call during all visits.

All participants will sample the three doses of nicotine spray in a counter-balanced crossover design.

Participants will be administered 2 nasal sprays with a combined nicotine content of 0mg nicotine, 0.1mL

Participants will be administered 2 nasal sprays with a combined nicotine content of 0.5 mg nicotine, 0.1mL

Participants will be administered 2 nasal sprays with a combined nicotine content of 1.0 mg nicotine, 0.1mL

subjective effects will be measured by the Nicotine Effects Questionnaire at the end of each fixed dose session. This scale measure positive reactions, negative reactions, and dizziness on a scale from 0-3 where 0 is none and 3 is intense.

subjective effects will be measured on a visual analog scale at the end of each fixed dose session. Ratings will be provided on a scale of 0=not at all to 100=an awful lot.

reinforcing effects will be measured by the number of choices for nicotine spray (range 0-8) during the forced choice session.

Percent blood oxygen level-dependent (BOLD) signal change during anticipation of monetary gain versus baseline during the Reward Guessing Task will be extracted from the bilateral ventral striatum

Percent BOLD signal change during "rare go" versus "no-go" trials during the Go/No-Go Task will be extracted from the right inferior frontal gyrus

Inclusion Criteria: generally healthy 18-21 years of age never smoked a full cigarette or used an equivalent amount of other nicotine or tobacco products no tobacco exposure in the past 3 years expired air CO level ≤ 3 ppm corroboration of non-smoking status from 2 collateral reporters breath alcohol value = 0.000 Exclusion Criteria: use of illegal drugs as measured by urine drug screen reported history of illicit drug use > 10 times lifetime lifetime history of alcohol use disorder binge drinking > 5 times per month over the past 3 months history of serious mental illness including bipolar or psychotic disorders significant medical or unstable psychiatric disorders systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg heart rate ≥ 100 bpm use of psychoactive medications (e.g., antidepressants, opioid analgesics, etc.) in the past 6 months presence of conditions that would make fMRI unsafe (e.g., pacemaker) brain abnormality (including but not limited to stroke, brain tumor, and seizure disorder) history of serious traumatic brain injury claustrophobia lack of firm resolve to refrain from cigarette, e-cigarette or other tobacco use in the coming year pregnant, trying to become pregnant, or breastfeeding inability to understand written and/or spoken English language inability to attend all experimental sessions