Glutamatergic signaling by midbrain dopaminergic neurons: recent insights from optogenetic, molecular and behavioral studies

Although the notion that dopaminergic neurons utilize glutamate as a co-transmitter has long been supported by tantalizing molecular, immunocytochemical and electrophysiological evidence it has only been with the recent addition of optogenetic and other approaches that the existence and functional relevance of this mechanism could be unambiguously demonstrated. Here we discuss the possible mechanisms of action of glutamate released from mesoaccumbens dopaminergic neurons based on recently accumulated evidence. Surprisingly, rather then to confirm a role in conventional fast excitatory transmission, the latest evidence suggests that glutamate released from dopaminergic neurons may primarily act through different unconventional presynaptic and postsynaptic mechanisms.

► Midbrain dopaminergic neurons express VGluT2, enabling glutamate accumulation and release.
► VGluT2 knockout results in blunted behavioral responding to amphetamine and cocaine.
► VGluT2 knockout in dopamine neurons reduces dopamine content and release in the nucleus accumbens.
► Postsynaptic excitation of nucleus accumbens neurons by dopaminergic neurons is weak.
► The function of glutamatergic synaptic transmission by dopaminergic neurons remains unclear.