Cocaine exposure increases norepinephrine in the gut facilitating gamma-proteobacteria colonization, which leads to a depletion of glycine from the host’s gut, blood and cerebrospinal fluid, and facilitates cocaine-induced addiction-like behaviors in mice, such as increased locomotion and exploration. Reduced glycine impacts glutamatergic synapses that make the animals more prone to develop addiction. The mechanisms reported in the current study could help modulate reward-related brain circuits that contribute to substance use disorders.