Dopaminergic Terminals in the Nucleus Accumbens But Not the Dorsal Striatum Corelease Glutamate

Abstract

Coincident signaling by dopamine and glutamate is thought to be crucial for a variety of motivated behaviors. Previous work has suggested that some midbrain dopamine neurons are themselves capable of glutamate corelease, but this phenomenon remains poorly understood. Here, we expressed the light-activated cation channel Channelrhodopsin-2 (ChR2) in genetically defined midbrain dopamine neurons to stimulate exocytosis specifically from dopaminergic terminals in both the nucleus accumbens (NAc) shell and dorsal striatum of brain slices from adult mice. Optical activation resulted in robust glutamate-mediated EPSCs in all medium spiny neurons examined in the NAc shell. In contrast, optically evoked glutamatergic currents were nearly undetectable in the dorsal striatum. Further, we used a conditional knock-out mouse lacking vesicular glutamate transporter 2 (VGLUT2) specifically in dopamine neurons to determine whether VGLUT2 is required for the exocytotic release of glutamate from dopamine neurons. Our data show that conditional knock-out completely abolished all optically evoked glutamate release. These results provide definitive physiological evidence for VGLUT2-mediated glutamate release by mature dopamine neurons projecting to the NAc shell, but not to the dorsal striatum. Thus, the unique ability of NAc-projecting dopamine neurons to synchronously activate both dopamine and glutamate receptors may have crucial implications for the ability to respond to motivationally significant stimuli.

Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

“…A subset of DA neurons in the VTA co-releases DA and glutamate in the NAc shell (21)(22)(23). We recently showed that the release properties and the modulation by G i -coupled D 2 receptors are remarkably similar for DA and glutamate release from these terminals (20).…”

Prefrontal Cortical Kappa Opioid Receptors Attenuate Responses to Amygdala Inputs

“…It is also possible that KOR modulates other glutamatergic projections to the mPFC we did not explore here, such as the thalamus. A proportion of dopamine (DA) neurons co-express the glutamate transporter (Yamaguchi et al, 2011) and have been shown to co-release glutamate in the ventral striatum (Stuber et al, 2010;Tecuapetla et al, 2010). Electrical and chemical activation of the VTA produces fast glutamatergic synaptic responses in the mPFC (Lavin et al, 2005), suggesting that mesocortical DA neurons may also co-release glutamate.…”

Somatodendritic dopamine release: recent mechanistic insights

“…Long-standing evidence, primarily from cultured DA neurons, had indicated that glutamate could be synthesized and released by DA neurons [147,148]. Using optogenetic methods with selective expression of channelrhodopsin (ChR2) in DA neurons, several groups have now shown that glutamate released from DA axons produces glutamate receptor-dependent excitatory postsynaptic currents in striatal neurons in ex vivo slices [149][150][151][152][153][154] and mediates behavioural consequences in vivo [155]. Similar methods have shown that co-release of GABA from DA axons produces GABA A receptor-dependent IPSCs in striatal neurons, although DA neurons do not synthesize GABA but rather obtain it via plasma membrane uptake [152,156].…”