Defining Neurobiological Links Between Substance Use and Mental Illness

Study Description: Tobacco smoking leads to 480,000 deaths and a loss of $300 billion a year in the U.S. Individuals with major depressive disorder (MDD) are more vulnerable for experiencing these burdens as they are twice as likely to use nicotine versus the general population. The current work will explain the neurobiological basis of this enhanced risk and will define potential targets for lessening the impact of nicotine on those with MDD. This research plan will take the innovative approach of evaluating nicotine s effects in non-smokers with and without MDD. In contrast to focusing on nicotine dependent individuals, which introduces confounds due to chronic use, this design will directly show the domains in which the neurobiological impact of nicotine is greater in those with MDD, providing a mechanistic framework for enhanced risk. To further characterize the links between nicotine use and mental illness, a second arm of the protocol will evaluate the impact of mental health comorbidities on the neurobiological impact of nicotine in individuals who use nicotine regularly. This secondary arm of the protocol will provide a more complete picture of why individuals with mental health comorbidities are at higher risk of nicotine dependence than the general population. Objectives: The primary objective of the first study arm is to determine the differential neurobiological impact of a nicotinic agonist on those with and without current major depressive disorder. Whether such effects are linked with specific symptoms of MDD will be assessed as will the potential modifying influence of biological sex. Those with a lifetime history of MDD will be assessed as well given evidence that reduced reward responsivity is a trait that persists even when one no longer meets current MDD criteria. The primary objective of the second study arm is to determine the impact of nicotine-modulated changes in brain function, cognition, and affect between those who do and do not chronically use nicotine. Psychiatric symptoms will be evaluated along dimensions of internalizing (e.g., depression, anxiety), thought disorders (e.g. psychosis), and externalizing (e.g., impulsivity, ADHD) to characterize the full spectrum of mental health symptoms that may influence the neurobiological impact of nicotine. Endpoints: Brain function will be assessed in several ways: 1) Resting-state fMRI will determine pharmacologically mediated group-specific differences in functional brain organization and inherent dynamic functioning 2) Task-based fMRI will determine pharmacologically mediated group-specific differences in reward function, affective processing, and interceptive awareness. These same measures will further be assessed considering specific symptoms of MDD and biological sex. In the arm of individuals using nicotine, brain function will be assessed using task and resting-state fMRI to determine the associations between mental health symptom dimensions and pharmacologically mediated associations with (1) functional brain organization and inherent dynamic functioning and (2) reward function, cue-reactivity, affective processing, and interoceptive awareness.