Dopamine (DA) release from striatum is fundamental for rewarding, reinforcement, and drug addiction.There are two pathways toward the activity-induced dopamine release in striatum: the direct (but distant) dopamine transmission (dDT) pathway from the midbrain via forebrain bundle ascending pathway, and the indirect (but local) axo-axonic pathway from cholinergic transmission to DA transmission (CTDT), [1-4]).Cocaine is well known to enhance extracellular DA level by blocking dopamine transporter (DAT),but it remains elusive whether cocaine affects DA level by other mechanisms in the striatum.Using optogenetic stimulation to selective activate Chls in brain slices, we measured the local CTDT-induced DA release and found that CTDT was potently inhibited by cocaine in both dorsal striatum and nucleus accumbens.This inhibition was mediated by neither DAT nor blockade of action potential, but caused by the inhibition of nAChRs on DA terminals.We also showed that cocaine oppositely modulated striatal DA overfiow from the distant dDT pathway (facilitation) and the local CTDT pathway (inhibition).Our findings provide a novel essential mechanism and target for treating cocaine addiction.