Mapping Brain Glutamate in Humans: Sex Differences in Cigarette Smokers

Study Overview
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Brief Summary
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The proposed study will evaluate sex differences in whole-brain glutamate (Glu), with a focus on the dorsal anterior cingulate cortex (dACC), anterior insula, and thalamus, as well as how it is influenced by sex (males vs. females), smoking state (overnight abstinent vs. sated), and circulating ovarian hormones (estrogen and progesterone) in women. Glu will be measured in almost the entire brain, with special focus on the dorsal anterior cingulate cortex (dACC), anterior insula, and thalamus, all of which have been implicated in behavioral states linked to tobacco withdrawal, using an echo-planar spectroscopic imaging (EPSI) variant of magnetic resonance spectroscopy (MRS). Serum ovarian hormones (estrogen and progesterone) will be measured for female participants to determine relationships between brain Glu and this hormone. Whole-brain Glu will be measured in 60 smokers (30 men, 30 women) twice, after overnight ( 12 h) abstinence and after participants smoke the first cigarette of the day.

Official Title
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Mapping Brain Glutamate in Humans: Sex Differences in Cigarette Smokers

Conditions
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Cigarette Smoking, Tobacco Dependence, Sex

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Self-identified as only male or female Age 18-45 years (children <18 years will be excluded due to low prevalence of conventional cigarette smoking; female participants >45 years of age will be excluded to avoid effects of perimenopause and menopause in women; male participants >45 years of age will be excluded as well to ensure that male and female groups are matched on age English fluency demonstrated by verbal skills sufficient to participate in a conversation, including the ability to ask and answer questions at a level that assures adequate understanding of the study (a comprehension quiz will be given) Right handedness (evaluated using the Edinburgh Inventory) Generally in good health without cardiovascular, hepatic, renal, or autoimmune diseases, diabetes, or cancer Must have smoked for ≥1 year Must endorse inhaling while smoking Must smoke ≥10 cigarettes per day Must have expired CO >10 ppm and urinary cotinine ≥100 ng/ml at screening/intake Fulfillment of DSM-5 criteria for Tobacco Use Disorder Exclusion Criteria: Seeking treatment for nicotine dependence within 3 months of screening Medical condition that may compromise safety (based on history, physical exam) Neurological disorder that would compromise compliance and/or informed consent Major psychiatric disorder (e.g., Major Depression, Schizophrenia, Bipolar Disorder) per DSM-5 MINI Current drug use disorders other than Tobacco Use Disorder (as defined in DSM-5) Recent use of cocaine, opiates, benzodiazepines, or amphetamines as shown by urine test at the screening or testing sessions Smoke marijuana >3X/week (self-report) or positive marijuana urine test on a scan day (positive at screening allowed) Use of tobacco in forms other than cigarettes (e.g., snuff, chewing tobacco, e-cigarettes) >10 days in the month before screening Preference for menthol cigarettes, given sex differences in the effect of menthol on the rate of nicotine entry into the brain Pregnancy or nursing Presence in the body of metal that would compromise safety during MRI Claustrophobia Any other condition that would compromise safety

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Male<br> | |
| Female<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating Ovarian Hormone: Estrogen - in overnight abstinent smokers | Estrogen assayed via a blood sample | Measured before and after smoking a cigarette across a period of 2 hours | 
| Circulating Ovarian Hormone: Progesterone - in overnight abstinent smokers | Estrogen assayed via a blood sample | Measured before and after smoking a cigarette across a period of 2 hours | 
| Whole Brain Glutamate | Measured by EPSI acquisition in overnight abstinent smokers | Measured before and after smoking a cigarette across a period of 2 hours | 
| Nicotine Metabolite Ratio | Measured by blood sample | Measured before smoking a cigarette at a single timepoint | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urge to Smoke Scale (UTS) | This is a 10-item self-reporting questionnaire that measures cigarette craving | Measured before and after smoking a cigarette across a period of 2 hours | 
| Shiffman-Jarvik Withdrawal Scale (SJWS) | This is a 25-item self-reporting questionnaire that measures psychological withdrawal | Measured before and after smoking a cigarette across a period of 2 hours | 
| Positive and Negative Affect Schedule (PANAS) | This is a 20-item self-reporting questionnaire that measures positive and negative affect | Measured before and after smoking a cigarette across a period of 2 hours | 
| Spielberger State-Trait Anxiety (STAI) | This is a 20-item self-reporting questionnaire that measures anxiety | Measured before and after smoking a cigarette across a period of 2 hours |