High-frequency axonal bursts mediate bidirectional modulation of dopamine signaling by nicotinic receptors

Nicotinic acetylcholine receptors (nAChRs) facilitate striatal dopamine transmission but also suppress dopamine release during high-frequency stimulation, suggesting they act as as low pass filters of dopamine release. Because axonal excitability is key a determinant of transmission, we combined axonal recordings and calcium imaging to define the physiological conditions under which nAChRs bidirectionally control dopaminergic axons. Activation of cholinergic interneuron (CINs) recruited nAChRs to enhance dopaminergic axon signals under moderate activation but suppressed signals after strong high-frequency stimulation. Axonal recordings revealed that single-pulse striatal stimulation triggered a rapid (~125 Hz) burst of 2-3 nAChR-driven spikes in dopaminergic axons followed by a brief refractory period that inhibited further axon spiking. In sum, we show that nAChRs mainly enhance local excitability of striatal dopaminergic axons but also trigger axonal bursting that suppresses axonal excitability. This mechanism expands the computational power of dopaminergic axons and explains the apparent nAChR-mediated low-pass filtering of dopamine release.