Glutamatergic and Nonglutamatergic Neurons of the Ventral Tegmental Area Establish Local Synaptic Contacts with Dopaminergic and Nondopaminergic Neurons

Abstract

The ventral tegmental area (VTA) contributes to reward and motivation signaling. In addition to the well established populations of dopamine (DA) or GABA VTA neurons, glutamatergic neurons were recently discovered in the VTA. These glutamatergic neurons express the vesicular glutamate transporter 2, VGluT2. To investigate whether VTA glutamatergic neurons establish local synapses, we tagged axon terminals from resident VTA neurons by intra-VTA injection of Phaseolus vulgaris leucoagglutinin (PHA-L) or an adenoassociated virus encoding wheat germ agglutinin (WGA) and by immunoelectron microscopy determined the presence of VGluT2 in PHA-L-or WGA-positive terminals. We found that PHA-L-or WGA-positive terminals from tagged VTA cells made asymmetric or symmetric synapses within the VTA. VGluT2 immunoreactivity was detected in the vast majority of PHA-L-or WGA-positive terminals forming asymmetric synapses. These results indicate that both VTA glutamatergic and nonglutamatergic (likely GABAergic) neurons establish local synapses. To examine the possible DAergic nature of postsynaptic targets of VTA glutamatergic neurons, we did triple immunolabeling with antibodies against VGluT2, tyrosine hydroxylase (TH), and PHA-L. From triple-labeled tissue, we found that double-labeled PHA-L (ϩ)/VGluT2 (ϩ) axon terminals formed synaptic contacts on dendrites of both TH-positive and TH-negative cells. Consistent with these anatomical observations, in whole-cell slice recordings of VTA neurons we observed that blocking action potential activity significantly decreased the frequency of synaptic glutamatergic events in DAergic and non-DAergic neurons. These observations indicate that resident VTA glutamatergic neurons are likely to affect both DAergic and non-DAergic neurotransmission arising from the VTA.

Amylin Modulates the Mesolimbic Dopamine System to Control Energy Balance

“…The VTA contains sizable non-DA neuronal populations (eg, glutamate, GABA) (Dobi et al, 2010), and testing the potential co-expression of the AmyR with different neurotransmitter phenotypes may provide clues as to other mechanisms involved in the acute energy balance effects of VTA amylin signaling. Although the energy balance effects of VTA sCT are almost completely reversed by NAc core administration of DA receptor agonists in HFD-maintained rats, sCT-induced hypophagia and body weight loss are attenuated but not reversed by intra-core D1 þ D2 receptor agonism in chow-fed rats.…”

Reciprocal Inhibitory Interactions Between the Reward-Related Effects of Leptin and Cocaine

“…Among these are changes in excitatory transmission to the ventral tegmental area (VTA; Saal et al, 2003), origin of the mesocorticolimbic dopamine system, and a critical link between reward-predictive cues and brain reward circuitry (You et al, 2007). This system is responsive not only to a variety of glutamatergic inputs from local (Dobi et al, 2010) and distal (Geisler et al, 2007) neuronal sources, but also to a number of state variables mediated by blood-borne factors including leptin (Figlewicz et al, 2003;Krugel et al, 2003;Hommel et al, 2006;Liu et al, 2011;Thompson and Borgland, 2013). Leptin is an endogenous inhibitor of food reward (Figlewicz et al, 2007;Domingos et al, 2011) that has both direct (Fulton et al, 2006a;Krugel et al, 2003;Leinninger et al, 2009;Davis et al, 2011;Domingos et al, 2011) and indirect (Leinninger et al, 2009) effects on brain reward function and that is depressed in heroin addicts (Housová et al, 2005) and fluctuates abnormally during craving for alcohol (Kiefer et al, 2005) or nicotine (al 'Absi et al, 2011).…”

Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

“…The switch from tonic to phasic firing is controlled by glutamate signaling at its ionotropic receptors. Activation of glutamatergic afferents (Geisler et al, 2007;Grace and Bunney, 1984;Omelchenko and Sesack, 2009), and possibly VM VGluT2-containing interneurons (Dobi et al, 2010), control the transition from peacemaker tonic to phasic burst firing of DA neurons. In contrast, blockade of VM ionotropic glutamate receptors disrupts burst firing (Charlety et al, 1991;Chergui et al, 1993).…”