Depression of substantia nigra dopamine transmission is driven by retrograde neurotensin release and is enhanced by methamphetamine self-administration

Midbrain dopamine neurons play central roles in reward learning and motivated behavior, and inhibition at somatodendritic dopamine D2 receptor (D2R) synapses blunts psychostimulant reinforcement. Release of the neuropeptide neurotensin in the midbrain increases following methamphetamine exposure and induces long-term depression of D2R synaptic currents (LTD DA ), however the source of neurotensin that drives LTD DA is not known. Here we show that LTD DA is driven by neurotensin released by dopamine neurons. Optogenetic stimulation of dopamine neurons was sufficient to induce LTD DA in the substantia nigra, but not the ventral tegmental area, and was dependent on neurotensin receptors, postsynaptic calcium, and vacuolar-type H + -ATPase activity in the postsynaptic cell. Further, LTD DA was enhanced in mice that had self-administered methamphetamine. These findings reveal a novel form of signaling between dopamine neurons involving release of the peptide neurotensin, which may act as a feed forward mechanism to increase dopamine neuron excitability and methamphetamine self-administration.