Ventral Tegmental Area Glutamate Neurons: Electrophysiological Properties and Projections

The ventral tegmental area (VTA) has a central role in the neural processes that underlie motivation and behavioral reinforcement. Although thought to contain only dopamine and GABA neurons, the VTA also includes a recently discovered population of glutamate neurons identified through the expression of the vesicular glutamate transporter VGLUT2. A subset of VGLUT2+ VTA neurons corelease dopamine with glutamate at terminals in the NAc, but others do not express dopaminergic markers and remain poorly characterized. Using transgenic mice that express fluorescent proteins in distinct cell populations, we now find that both dopamine and glutamate neurons in the medial VTA exhibit a smaller hyperpolarization-activated current (Ih) than more lateral dopamine neurons and less consistent inhibition by dopamine D2 receptor agonists. In addition, VGLUT2+ VTA neurons project to the nucleus accumbens (NAc), lateral habenula, ventral pallidum (VP), and amygdala. Optical stimulation of VGLUT2+ projections expressing channelrhodopsin-2 further reveals functional excitatory synapses in the VP as well as the NAc. Thus, glutamate neurons form a physiologically and anatomically distinct subpopulation of VTA projection neurons.

• Publication year

  2012

• Venue

  Journal of Neuroscience

• Publication date

  2012-10-24

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1523/JNEUROSCI.3128-12.2012PMID 23100428PMCID PMC3685320
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Neurotransmitter corelease: mechanism and physiological role.

  2012cited by this paper
• The glutamatergic component of the mesocortical pathway emanating from different subregions of the ventral midbrain.

  2012influential reference
• From glutamate co-release to vesicular synergy: vesicular glutamate transporters

  2011cited by this paper
• Mesocorticolimbic Glutamatergic Pathway

  2011influential reference
• From glutamate co-release to vesicular synergy: vesicular glutamate transporters.

  2011cited by this paper
• Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli.

  2011cited by this paper
• Negative Reward Signals from the Lateral Habenula to Dopamine Neurons Are Mediated by Rostromedial Tegmental Nucleus in Primates

  2011cited by this paper
• NMDA Receptors on Non-Dopaminergic Neurons in the VTA Support Cocaine Sensitization

  2010cited by this paper
• A transgenic mouse line for molecular genetic analysis of excitatory glutamatergic neurons.

  2010cited by this paper
• Glutamatergic Signaling by Mesolimbic Dopamine Neurons in the Nucleus Accumbens

  2010cited by this paper
• Dopaminergic Terminals in the Nucleus Accumbens But Not the Dorsal Striatum Corelease Glutamate

  2010influential reference
• Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo.

  2010influential reference
• In vitro identification and electrophysiological characterization of dopamine neurons in the ventral tegmental area.

  2010cited by this paper
• Glutamatergic and Nonglutamatergic Neurons of the Ventral Tegmental Area Establish Local Synaptic Contacts with Dopaminergic and Nondopaminergic Neurons

  2010cited by this paper
• Ultrastructural analysis of local collaterals of rat ventral tegmental area neurons: GABA phenotype and synapses onto dopamine and GABA cells

  2009cited by this paper
• Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli

  2009cited by this paper
• A robust and high-throughput Cre reporting and characterization system for the whole mouse brain

  2009influential reference
• Phasic Firing in Dopaminergic Neurons Is Sufficient for Behavioral Conditioning

  2009influential reference
• Faculty Opinions recommendation of Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system.

  2008cited by this paper
• Developmental and Target-Dependent Regulation of Vesicular Glutamate Transporter Expression by Dopamine Neurons

  2008cited by this paper
• eview entral pallidum roles in reward and motivation

  2008cited by this paper
• Novel neurons in ventral tegmental area fire selectively during the active phase of the diurnal cycle

  2008cited by this paper
• Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system.

  2008influential reference
• Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat

  2008cited by this paper
• Midbrain Dopamine Neurons: Projection Target Determines Action Potential Duration and Dopamine D2 Receptor Inhibition

  2008cited by this paper
• Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex.

  2007influential reference
• Lateral habenula as a source of negative reward signals in dopamine neurons

  2007cited by this paper
• Glutamatergic neurons are present in the rat ventral tegmental area

  2007cited by this paper
• Topographical organization of GABAergic neurons within the ventral tegmental area of the rat

  2007cited by this paper
• Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement.

  2007influential reference
• Particular subpopulations of midbrain and hypothalamic dopamine neurons express vesicular glutamate transporter 2 in the rat brain

  2006influential reference
• The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons?

  2006influential reference
• Characterization of a mouse strain expressing Cre recombinase from the 3′ untranslated region of the dopamine transporter locus

  2006influential reference
• VGLUTs: 'exciting' times for glutamatergic research?

  2006cited by this paper
• Neurochemical modulation of ingestive behavior in the ventral pallidum

  2006cited by this paper
• The Ventral Pallidum and Hedonic Reward: Neurochemical Maps of Sucrose “Liking” and Food Intake

  2005cited by this paper
• Mesocortical Dopamine Neurons Operate in Distinct Temporal Domains Using Multimodal Signaling

  2005cited by this paper
• VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate.

  2004cited by this paper
• Uniform Inhibition of Dopamine Neurons in the Ventral Tegmental Area by Aversive Stimuli

  2004cited by this paper
• Dopamine Neurons Mediate a Fast Excitatory Signal via Their Glutamatergic Synapses

  2004cited by this paper
• A gene expression atlas of the central nervous system based on bacterial artificial chromosomes

  2003influential reference
• Hyperpolarization-activated cation currents: from molecules to physiological function.

  2003cited by this paper
• A subset of ventral tegmental area neurons is inhibited by dopamine, 5-hydroxytryptamine and opioids.

  1997cited by this paper
• Queer current and pacemaker: the hyperpolarization-activated cation current in neurons.

  1996cited by this paper
• Opioids excite dopamine neurons by hyperpolarization of local interneurons

  1992cited by this paper
• Two types of neurone in the rat ventral tegmental area and their synaptic inputs.

  1992cited by this paper
• Two cell types in rat substantia nigra zona compacta distinguished by membrane properties and the actions of dopamine and opioids

  1989influential reference
• The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat.

  1982cited by this paper
• [Dopamine (3-hydroxytyramine) in the central nervous system and its relation to the Parkinson syndrome in man].

  1962cited by this paper
• Dopamin (3-Hydroxytyramin) im Zentralnervensystem und seine Beziehung zum Parkinson-Syndrom des Menschen

  1962cited by this paper

• Untangling dopamine and glutamate in the ventral tegmental area

  2025cites this paper
• Ghrelin Recruits the Endocannabinoid System to Modulate Food Reward

  2025cites this paper
• Understanding the connection between stress and sleep: From underlying mechanisms to therapeutic solutions.

  2025cites this paper
• Upregulation of NR2A in Glutamatergic VTA Neurons Contributes to Chronic Visceral Pain in Male Mice

  2025cites this paper
• Dopaminergic tone inhibits spontaneous glutamate release and augments homeostatic synaptic plasticity.

  2025cites this paper
• Adaptive Hypervigilance Following Chronic Social Aggression: A Synapse-Specific, Subcortical Mechanism.

  2025cites this paper
• From valence encoding to motivated behavior: a focus on the nucleus accumbens circuitry.

  2025cites this paper
• Circuit-selective pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception.

  2025cites this paper
• Drug-induced changes in connectivity to midbrain dopamine cells revealed by rabies monosynaptic tracing

  2025cites this paper
• Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses

  2025cites this paper
• Differential effects of acute and chronic fluoxetine on c-Fos expression in specific subpopulations of midbrain dopaminergic neurons.

  2025cites this paper
• From memory disorders to the development of depression: A system approach

  2025cites this paper
• Single-cell sequencing of rodent ventral pallidum reveals diverse neuronal subtypes with noncanonical interregional continuity

  2025cites this paper
• A septal-ventral tegmental area circuit drives exploratory behavior.

  2024cites this paper
• Midbrain glutamatergic circuit mechanism of resilience to socially transferred allodynia in male mice

  2024cites this paper
• Optogenetics in Mood Disorders

  2024cites this paper
• Proportion and distribution of neurotransmitter-defined cell types in the ventral tegmental area and substantia nigra pars compacta

  2024cites this paper
• Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses

  2024cites this paper
• Single-cell sequencing of rodent ventral pallidum reveals diverse neuronal subtypes with non-canonical interregional continuity

  2024cites this paper
• S-3,4-DCPG, a potent orthosteric agonist for the mGlu8 receptor, facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats.

  2024cites this paper
• Amphetamine Injection into the Nucleus Accumbens and Electrical Stimulation of the Ventral Tegmental Area in Rats After Novelty Test—Behavioral and Neurochemical Correlates

  2024cites this paper
• Neuronal heterogeneity in the ventral tegmental area: distinct contributions to reward circuitry and motivated behavior

  2024cites this paper
• The Formation and Function of the VTA Dopamine System

  2024cites this paper
• The maternal vGluT2 and embryonic mGluR3 signaling relay system controls offspring wing dimorphism in pea aphid

  2024cites this paper
• Heterogeneity of mesencephalic dopaminergic neurons: From molecular classifications, electrophysiological properties to functional connectivity

  2024cites this paper
• Monosynaptic ventral tegmental area glutamate projections to the locus coeruleus enhance aversive processing

  2024cites this paper
• Proportion and distribution of neurotransmitter-defined cell types in the ventral tegmental area and substantia nigra pars compacta

  2024influential citation
• Targeting the ventral pallidum in obesity

  2024cites this paper
• Functional Adaptation in the Brain Habenulo–Mesencephalic Pathway During Cannabinoid Withdrawal

  2024cites this paper
• Neural circuit-selective, multiplexed pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception

  2024cites this paper
• Methylphenidate induces a different response in the dorsal raphe as compared to ventral tegmental area and locus coeruleus: behavioral and concomitant neuronal recordings in adult rats

  2023cites this paper
• Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration

  2023cites this paper
• Dopamine, Norepinephrine and Serotonin Participate Differently in Methylphenidate Action in Concomitant Behavioral and Ventral Tegmental Area, Locus Coeruleus and Dorsal Raphe Neuronal Study in Young Rats

  2023cites this paper
• Ventral tegmental area glutamate neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate opioid-seeking behavior

  2023cites this paper
• An excitatory projection from the basal forebrain to the ventral tegmental area that underlies anorexia-like phenotypes.

  2023cites this paper
• Modulation of dopamine from ventral tegmental area neurons by the LC-REM-OFF and PPT-REM-ON neurons in REMS regulation in freely moving rats.

  2023cites this paper
• Somatostatin-Expressing Neurons in the Ventral Tegmental Area Innervate Specific Forebrain Regions and Are Involved in Stress Response

  2023cites this paper
• epithalamic lateral habenula promotes rewarding behaviours independently

  2023cites this paper
• Ventral Tegmental Area Glutamatergic Neurons Facilitated Emergence From Isoflurane Anesthesia Involves Excitation of Lateral Septum GABA-ergic Neurons in Mice

  2023cites this paper
• Pharmacological evaluation of lateral habenula and rostromedial tegmental nucleus in the expression of ethanol-induced place preference

  2023cites this paper
• An Excitatory Projection from the Basal Forebrain to the Ventral Tegmental Area Underlying Anorexia-like Phenotypes

  2023cites this paper
• Ventral Tegmental Area Glutamate Neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate prescription opioid-seeking behavior

  2022cites this paper
• Distinct cell populations of ventral tegmental area process motivated behavior

  2022cites this paper
• Pharmacological modulation of ventral tegmental area neurons elicits changes in trigeminovascular sensory processing and is accompanied by glycemic changes: Implications for migraine

  2022cites this paper
• Neurobiological and Neuropharmacological Aspects of Food Addiction.

  2022cites this paper
• Modafinil Administration to Preadolescent Rat Impairs Non-Selective Attention, Frontal Cortex D2 Expression and Mesolimbic GABA Levels

  2022cites this paper
• Anatomy and Function of Ventral Tegmental Area Glutamate Neurons

  2022influential citation
• Control of Behavioral Arousal and Defense by a Glutamatergic Midbrain-Amygdala Pathway in Mice

  2022cites this paper
• Neural circuits provide insights into reward and aversion

  2022cites this paper
• The Ventral Tegmental Area and Nucleus Accumbens as Circadian Oscillators: Implications for Drug Abuse and Substance Use Disorders

  2022cites this paper
• Unbiased stereological estimates of dopaminergic and GABAergic neurons in the A10, A9, and A8 subregions in the young male Macaque

  2022cites this paper
• Neurobiological Mechanisms of Nicotine Reward and Aversion

  2022cites this paper
• Blockade of 5-Hydroxytryptamine 2A Receptor Attenuates Precipitation of Naloxone-Induced Withdrawal Symptoms in Opioid-Exposed Mice

  2022cites this paper
• Mesoaccumbal glutamate neurons drive reward via glutamate release, but aversion via dopamine co-release

  2022cites this paper
• Ventral tegmental area glutamate neurons mediate nonassociative consequences of stress

  2022cites this paper
• Gene knockdown of HCN2 ion channels in the ventral tegmental area reduces ethanol consumption in alcohol preferring rats

  2022cites this paper
• Methylphenidate cross-sensitization with amphetamine is dose dependent but not age dependent.

  2022cites this paper
• Deletion of VGLUT2 in Midbrain Dopamine Neurons Attenuates Dopamine and Glutamate Responses to Methamphetamine in Mice.

  2021cites this paper
• Contributions of Neuroimmune and Gut-Brain Signaling to Vulnerability of Developing Substance Use Disorders.

  2021cites this paper
• Ventral pallidum cellular and pathway specificity in drug seeking.

  2021cites this paper
• Astrocytes in the ventral pallidum extinguish heroin seeking through GAT-3 upregulation and morphological plasticity at D1-MSN terminals

  2021cites this paper
• Midbrain Dopamine Neurons Defined by TrpV1 Modulate Psychomotor Behavior

  2021cites this paper
• Prevention of glutamate excitotoxicity in lateral habenula alleviates ethanol withdrawal-induced somatic and behavioral effects in ethanol dependent mice.

  2021cites this paper
• A Whole-Brain Connectivity Map of VTA and SNc Glutamatergic and GABAergic Neurons in Mice

  2021cites this paper
• Modulating the Neuromodulators: Dopamine, Serotonin, and the Endocannabinoid System.

  2021cites this paper
• Oxytocin and Addiction: Potential Glutamatergic Mechanisms

  2021cites this paper
• An emerging map of glutamate delta 1 receptor in the forebrain.

  2021cites this paper
• Genetic Probe for Visualizing Glutamatergic Synapses and Vesicles by 3D Electron Microscopy

  2021cites this paper
• Glutaminergic Signaling in the Nucleus Accumbens Modulates the Behavioral Response to Acute and Chronic Methylphenidate

  2021cites this paper
• Sex Differences in the Glutamate System: Implications for Addiction.

  2020cites this paper
• Investigating the influence of perinatal nicotine exposure on genetic profiles of neurons in the sub-regions of the VTA

  2020cites this paper
• Glutamate homeostasis and dopamine signaling: implications for psychostimulant addiction behavior.

  2020cites this paper
• Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function

  2020cites this paper
• Frequency-dependent electrical stimulation of fimbria-fornix preferentially affects the mesolimbic dopamine system or prefrontal cortex.

  2020cites this paper
• Cocaine use disorder: A look at metabotropic glutamate receptors and glutamate transporters.

  2020cites this paper
• Determining the optimal expression method for dual-color imaging.

  2020cites this paper
• Early Life Stress- and Drug-Induced Histone Modifications Within the Ventral Tegmental Area

  2020cites this paper
• Salience processing by glutamatergic neurons in the ventral pallidum.

  2020cites this paper
• In DA Club of Reinforcement: Glutamate, It's Your Birthday.

  2020cites this paper
• Distracting stimuli evoke ventral tegmental area responses in rats during ongoing saccharin consumption

  2020cites this paper
• In silico Hierarchical Clustering of Neuronal Populations in the Rat Ventral Tegmental Area Based on Extracellular Electrophysiological Properties

  2020cites this paper
• A genetic probe for visualizing glutamatergic synapses and vesicles by 3D electron microscopy

  2020cites this paper
• A quantitative reward prediction error signal in the ventral pallidum

  2020cites this paper
• Neural Circuits for Reward.

  2020cites this paper
• Molecular Regulation in Dopaminergic Neuron Development. Cues to Unveil Molecular Pathogenesis and Pharmacological Targets of Neurodegeneration

  2020cites this paper
• VTA Glutamate Neuron Activity Drives Positive Reinforcement Absent Dopamine Co-release.

  2020cites this paper
• Whole‐brain efferent and afferent connectivity of mouse ventral tegmental area melanocortin‐3 receptor neurons

  2020cites this paper
• Vesicular neurotransmitter transporters in Drosophila melanogaster.

  2020cites this paper
• Oxytocin treatment for alcoholism: Potential neurocircuitry targets.

  2020cites this paper
• A Whole-Brain Map and Assay Parameter Analysis of Mouse VTA Dopaminergic Activation

  2020cites this paper
• Ethanol produces multiple electrophysiological effects on ventral tegmental area neurons in freely moving rats

  2020cites this paper
• Neurochemical Signaling of Reward and Aversion to Ventral Tegmental Area Glutamate Neurons

  2020cites this paper
• A quantitative reward prediction error signal in the ventral pallidum

  2020cites this paper
• An expanded palette of dopamine sensors for multiplex imaging in vivo

  2020cites this paper
• Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area

  2020cites this paper
• Ventral Tegmental Area GABA, glutamate, and glutamate-GABA neurons are heterogenous in their electrophysiological and pharmacological properties

  2020cites this paper
• Optogenetics: what it has uncovered in potential pathways of depression.

  2019cites this paper
• Differential Nicotinic Modulation of Glutamatergic and GABAergic VTA Microcircuits

  2019cites this paper
• Neurocircuitry of Reward and Addiction: Potential Impact of Dopamine–Glutamate Co-release as Future Target in Substance Use Disorder

  2019cites this paper
• Glutamate and dopamine in the VTA participate differently in the acute and chronic effect of methylphenidate.

  2019cites this paper