While this is the first study to directly examine the role of the gut microbiome in cocaine-mediated behavioral plasticity, it is not the first to use antibiotics to alter behavioral responses to cocaine. Multiple previous studies demonstrated that systemic injections of cephalosporin antibiotics decrease reinstatement of cocaine self-administration363738, possibly through upregulation of the GLT-1 glutamate transporter at the synapse39. However, none of these studies examined changes in levels of gut bacteria, so the possible involvement of the gut microbiome in cephalosporin actions is unknown. In our study we saw behavioral effects of antibiotics only when they were given orally (Fig. 3), and thus were directly applied to the gut microbiota. Systemic injections of the antibiotics used in our study did not lead to any behavioral phenotype (Fig. 4), suggesting that it was their ability to reduce gut bacteria that lead to their behavioral effects.
