Norepinephrine in vertebrates and its invertebrate analog, octopamine, regulate the activity of neural circuits. We find that, when hungry, Drosophila larvae switch activity in type II octopaminergic motor neurons (MNs) to high-frequency bursts, which coincide with locomotion-driving bursts in type I glutamatergic MNs that converge on the same muscles. Optical quantal analysis across hundreds of synapses simultaneously reveals that octopamine potentiates glutamate release by tonic type Ib MNs, but not phasic type Is MNs, and occurs via the G(q)-coupled octopamine receptor (OAMB). OAMB is more abundant in type Ib terminals and acts through diacylglycerol and its target Unc13A, a key component of the glutamate release machinery. Potentiation varies significantly-by up to 1,000%-across synapses of a single Ib axon, with synaptic Unc13A levels determining both release probability and potentiation. We propose that a dual molecular mechanism-an upstream neuromodulator receptor and a downstream transmitter release controller-fine-tunes catecholaminergic modulation so that strong tonic synapses exhibit large potentiation, while weaker tonic and all phasic synapses maintain consistency, yielding a sophisticated regulation of locomotor behavior.