1 Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: santiago.cuesta@rutgers.edu.
2 Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET-UNR) and Plataforma Argentina de Biología Estructural y Metabolómica (PLABEM), Rosario, Santa Fe, Argentina.
3 Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
4 Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Canada; The Center of Excellence in Research on Orphan Diseases - Foundation Courtois, Université du Québec à Montréal, Montréal, QC, Canada; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC, Canada.
5 Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: vsperandio@wisc.edu.

Gut-microbiota membership is associated with diverse neuropsychological outcomes, including substance use disorders (SUDs). Here, we use mice colonized with Citrobacter rodentium or the human ?-Proteobacteria commensal Escherichia coli HS as a model to examine the mechanistic interactions between gut microbes and host responses to cocaine. We find that cocaine exposure increases intestinal norepinephrine levels that are sensed through the bacterial adrenergic receptor QseC to promote intestinal colonization of ?-Proteobacteria. Colonized mice show enhanced host cocaine-induced behaviors. The neuroactive metabolite glycine, a bacterial nitrogen source, is depleted in the gut and cerebrospinal fluid of colonized mice. Systemic glycine repletion reversed, and ?-Proteobacteria mutated for glycine uptake did not alter the host response to cocaine. ?-Proteobacteria modulated glycine levels are linked to cocaine-induced transcriptional plasticity in the nucleus accumbens through glutamatergic transmission. The mechanism outline here could potentially be exploited to modulate reward-related brain circuits that contribute to SUDs.