Dopamine Neurons Make Glutamatergic SynapsesIn Vitro

Abstract

Interactions between dopamine and glutamate play prominent roles in memory, addiction, and schizophrenia. Several lines of evidence have suggested that the ventral midbrain dopamine neurons that give rise to the major CNS dopaminergic projections may also be glutamatergic. To examine this possibility, we double immunostained ventral midbrain sections from rat and monkey for the dopamine-synthetic enzyme tyrosine hydroxylase and for glutamate; we found that most dopamine neurons immunostained for glutamate, both in rat and monkey. We then used postnatal cell culture to examine individual dopamine neurons. Again, most dopamine neurons immunostained for glutamate; they were also immunoreactive for phosphate-activated glutaminase, the major source of neurotransmitter glutamate. Inhibition of glutaminase reduced glutamate staining. In single-cell microculture, dopamine neurons gave rise to varicosities immunoreactive for both tyrosine hydroxylase and glutamate and others immunoreactive mainly for glutamate, which were found near the cell body. At the ultrastructural level, dopamine neurons formed occasional dopaminergic varicosities with symmetric synaptic specializations, but they more commonly formed nondopaminergic varicosities with asymmetric synaptic specializations. Stimulation of individual dopamine neurons evoked a fast glutamatergic autaptic EPSC that showed presynaptic inhibition caused by concomitant dopamine release. Thus, dopamine neurons may exert rapid synaptic actions via their glutamatergic synapses and slower modulatory actions via their dopaminergic synapses. Together with evidence for glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, the present results suggest that glutamatergic cotransmission may be the rule for central monoaminergic neurons.

VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation

“…The feature of glutamate cotransmission of DA neurons has been debated during the past two decades, ever since the first demonstration that TH-positive neurons are immunoreactive for phosphate-activated glutaminase (27) and the demonstration that TH-labeled neurons in single-cell cultures generate a fast excitatory current (7). However, the functional role of such dual glutamatergic/dopaminergic signaling by a subset of the classical DA neurons in the VTA is unknown.…”

“…For example, most serotonin (5-HT) neurons and many cholinergic neurons express VGLUT3 (2,6). The ability of 5-HT, cholinergic, and dopamine (DA) neurons to release glutamate at synapses has been demonstrated in vitro (7)(8)(9).…”

Cellular and synaptic mechanisms of nicotine addiction

“…Thus, other glutamatergic inputs appear to be responsible for the direct excitation of the mesoaccumbens DA projections. One intriguing possibility is that glutamate release within the VTA may come from DA neurons themselves as has been demonstrated in vitro (Sulzer et al, 1998).…”

The effect of striatal dopamine depletion on striatal and cortical glutamate: A mini-review

“…Second, we did not examine indirect or secondary measures of changes in glutamate levels given dopamine depletion -such as genetic expression changes or changes in glutamate precursor or metabolite levels. Third, evidence suggests that midbrain dopamine neurons (particularly in the VTA)may not only release dopamine, but also co-release glutamate Rayport, 2001;Sulzer et al, 1998). In fact, co-transmission of several neurotransmitters may occur for all monoaminergic neurons (El Mestikawy et al, 2011;Nusbaumet al, 2001;Trudeau, 2004).…”