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

National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 01/2010; 30(1):218-29. DOI: 10.1523/JNEUROSCI.3884-09.2010
Source: PubMed


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 adeno-associated 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 (+)/VGluT2 (+) 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.

    • "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). "
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    ABSTRACT: Cocaine is habit-forming because of its ability to enhance dopaminergic neurotransmission in the forebrain. In addition to neuronal inputs, forebrain dopamine circuits are modulated by hormonal influences; one of these is leptin, an adipose-derived hormone that attenuates the rewarding effects of food and hunger-associated brain stimulation reward. Here we report reciprocal inhibition between the reward-related effects of leptin and the reward-related effects of cocaine in rats: First, we report that cocaine and the expectancy of cocaine each depress plasma leptin levels. Second, we report that exogenous leptin, given systemically or directly into the ventral tegmental area, attenuates (i) the ability of cocaine to elevate dopamine levels in nucleus accumbens (ii) the ability of cocaine to establish a conditioned place preference, and (iii) the ability of cocaine-predictive stimuli to prolong responding in extinction of cocaine-seeking. Thus while leptin represents an endogenous antagonist of the habit-forming and habit-sustaining effects of cocaine, this antagonism is attenuated by cocaine and comes to be attenuated by the expectancy of cocaine.Neuropsychopharmacology accepted article preview online, 05 August 2015. doi:10.1038/npp.2015.230.
    No preview · Article · Aug 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • ", project heavily to several limbic structures, including the nucleus accumbens (NAcc), amygdala, and prefrontal cortex (PFC). In the rat, both GABAergic and glutamatergic neurons form local synapses in the VTA (Omelchenko and Sesack, 2009; Dobi et al., 2010) and project in parallel with the DA neurons to limbic regions (Swanson, 1982; Van Bockstaele and Pickel, 1995; Carr and Sesack, 2000a; Yamaguchi et al., 2011). Studies of VTA function have focused largely on the DA projections from the VTA, because these neurons are the most abundant VTA cell type. "
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    ABSTRACT: The role of dopaminergic (DA) projections from the ventral tegmental area (VTA) in appetitive and rewarding behavior has been widely studied, but the VTA also has documented DA-independent functions. Several drugs of abuse, including nicotine, act on VTA GABAergic neurons, and most studies have focused on local inhibitory connections. Relatively little is known about VTA GABA projection neurons and their connections to brain sites outside the VTA. In this study, we employed viral-vector mediated cell-type specific anterograde tracing, classical retrograde tracing and immunohistochemistry to characterize VTA GABA efferents throughout the brain. We found that VTA GABA neurons project widely to forebrain and brainstem targets, including the ventral pallidum, lateral and magnocellular preoptic nuclei, lateral hypothalamus and lateral habenula. Minor projections also go to central amygdala, mediodorsal thalamus, dorsal raphe and deep mesencephalic nuclei, and sparse projections go to prefrontal cortical regions and to nucleus accumbens shell and core. Importantly, these projections differ from the major VTA DA target regions. Retrograde tracing studies confirmed results from the anterograde experiments and differences in projections from VTA subnuclei. Retrogradely-labeled GABA neurons were not numerous and most non-TH/retrogradely labeled cells lacked GABAergic markers. Many non-DA/retrogradely labeled cells projecting to several areas express VGluT2. VTA GABA and glutamate neurons project throughout the brain, most prominently to regions with reciprocal connections to the VTA. These data indicate that VTA GABA and glutamate neurons may have more dopamine-independent functions than previously recognized. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2014 · The Journal of Comparative Neurology
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    • "These neurons differed in cell morphology from the dopaminergic neurons and exhibited an expression of CaMKIIα-mCherry. Based on the results above, it is inferred that those nondopaminergic neurons were probably simple glutamatergic neurons, consistent with previous reports that glutamatergic neurons were present in the VTA [19, 31]. According to previous reports, the exists a type of glutamatergic neurons in the VTA region that release VGluT2 but do not release dopamine, and they exhibit different electrophysiological properties and neuronal projections apart from the VTA neurons coexpressing glutamine and dopamine [32]. "
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    ABSTRACT: The ventral tegmental area (VTA) plays an important role in motivation and motor activity of mammals. Previous studies have reported that electrical stimulations of the VTA's neuronal projections were able to upregulate the locomotor activity of behaving rats. However, which types of neurons in the VTA that take part in the activation remain elusive. In this paper we employed optogenetic technique to selectively activate the excitatory neurons expressing CaMKII α in the VTA region and induced a higher locomotor activity for free behaving rats. Further behavioral studies indicated that reward learning mediated in the enhancement of the rat locomotor activity. Finally the immunohistochemistry studies explored that the excitatory neurons under the optogenetic activation in VTA were partly dopaminergic that may participate as a vital role in the optogenetic activation of the locomotor activity. In total, our study provided an optogenetic approach to selectively upregulate the locomotor activity of free behaving rats, thus facilitating both neuroscience researches and neural engineering such as animal robotics in the future.
    Full-text · Article · Mar 2014
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