The research and training described in this Mentored Research Scientist Development (K01) Award application will provide the candidate with the skills necessary to become an independent investigator in the development of novel treatment targets in addictions. A multidisciplinary training and mentoring program is proposed at the Yale University School of Medicine that will help assist in the transition to independent research by providing structured mentoring, supervision and didactic techniques to address the following training goals: a) treatment development and clinical outcomes in addictions, b) advanced training in drug development pharmacology, and c) data analytical techniques relevant to experimental psychopharmacological studies with repeated time-points and longitudinal multilevel drug use outcomes. In order to achieve these career training goals, an innovative research proposal has been designed to use pregnenolone (PREG) as a mechanistic probe to increase levels of the potent GABA potentiating neuroactive steroid allopregnanolone (ALLO) and examine (a) its effects on provoked stress and drug-cue induced craving, and physiological, cognitive, emotional responses to stress and drug cue craving states, b) the safety and pharmacokinetic (PK) / pharmacodynamic (PD) profile of various doses of PREG and its conversion profile to downstream neuroactive steroids, and (c) explore its effects on daily cocaine craving, mood symptoms and cocaine use outcomes for 8 weeks; and also explore gender differences in each of these aims. The knowledge obtained from this MRSDA project would inform us on the role of PREG and ALLO in emotional, physiological and neuroendocrine arousal in response to stress and drug-cue exposure which are important predictors of relapse; its safety and PK/PD, and its metabolism into downstream neuroactive steroids which have not been previously tested in CUD; its effects on individual cocaine craving and drug use in ecologically valid environments of cocaine users; and gender differences that may exist in these outcomes. All of these are novel and never before addressed questions in cocaine addiction. The hands-on design and execution of the proposed research, combined with the structured mentoring, supervision and didactic training, will allow the candidate to meet much needed training goals, and generate preliminary data on pregnenolone and other neurosteroid analogs as novel and potential treatment targets in cocaine addiction for the design and submission of an R01 proposal in Year 04 of MRSDA training. Hence, this MRSDA will be a crucial stepping stone in the candidate's progression toward scientific independence.
. Cocaine use disorder (CUD) is a serious public health problem, yet no approved medications exist for its treatment. The proposed research will identify the role of pregnenolone, and its pharmacologic profile, in cocaine craving and drug use as well as in the disrupted physiological, hypothalamic-pituitary-adrenal (HPA) axis arousal and emotional changes associated with stress- and drug cue-induced craving states in men and women with CUD. Understanding the mechanisms underlying GABAergic neuroactive steroids in CUD can aid in the development of better treatment targets, thereby reducing the burden faced by individuals with this disorder and society as whole.