Orbitofrontal-striatal potentiation underlies stimulant induced hyperactivity

Stimulants are one of the most widely prescribed classes of pharmaceuticals, but it is unclear which brain pathways underlie their therapeutic and adverse actions. Here, with real-time monitoring of circuit plasticity, we demonstrate that psychostimulants strengthen orbitofrontal (OFC) to dorsomedial striatum (DMS) pathway synapses, and increase striatal output in awake mice. In vivo high-frequency stimulation of OFC-DMS pathway blocked stimulant-induced potentiation and the expression of locomotor sensitization, thereby directly linking OFC-DMS plasticity to hyperactivity.