Biased Oxytocinergic Modulation of Midbrain Dopamine Systems
Open accessAbstract
The release of dopamine (DA) regulates rewarding behavior and motor actions through striatum-targeting efferents from ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Here, we map and functionally characterize axonal projections from oxytocin neurons in the hypothalamic paraventricular nucleus to midbrain DA regions. Electrophysiological recordings of DA neurons reveal that both the application of oxytocin and optogenetic stimulation of oxytocinergic terminals suffice to increase DA neuron activity in the VTA but downregulate it in SNc. This biased modulation is mediated by oxytocin and vasopressin G-protein-coupled receptors. Oxytocin release directly activates DA neurons and indirectly inhibits them through local GABA neurons, but the relative magnitudes of the two mechanisms differ in VTA and SNc. Oxytocin-modulated DA neurons give rise to canonical striatal projections. Since hypothalamic oxytocinergic projections also target the striatum, oxytocin is poised to bias the balance of DA tone through multiple sites in vertebrate reward circuits.
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Oxytocin suppressed the spontaneous firing of substantia nigra dopamine neurons.
“In contrast to the increase of spontaneous firing of VTA dopamine neurons, oxytocin suppressed the spontaneous firing of substantia nigra dopamine neurons”
From Oxytocin, Neural Plasticity, and Social Behavior (2021) · cites this paper as Xiao et al. 2017
The Results section (“Opposing effects of Oxt on the activity of VTA and SNc DA neurons”) reports that oxytocin inhibited spontaneous firing in lateral SNc dopamine neurons. The claim generalizes this to SNc dopamine neurons overall, but the same passage reports no significant firing-rate change in medial SNc dopamine neurons. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOXT exerts precise control over DA neurons.
“Furthermore, OXT exerts precise control over DA neurons (Xiao et al., 2017).”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as Xiao et al., 2017
OXT release directly activates dopaminergic neurons and indirectly inhibits them via local GABAergic interneurons, with relative magnitudes differing in the VTA and SNc.
“OXT release directly activates dopaminergic neurons and indirectly inhibits them via local GABAergic interneurons, but the relative magnitudes of the two mechanisms differ in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc; Xiao et al., 2017).”
From Music's context-dependent influence on oxytocin, social bonding, and emotion regulation: a systematic review (2026) · cites this paper as Xiao et al., 2017
When OXT increases, it may promote dopaminergic signaling and enhance the output of the striatum.
“When OXT increases, it may promote dopaminergic signaling (Xiao et al., 2017) and enhance the output of the striatum.”
From Music's context-dependent influence on oxytocin, social bonding, and emotion regulation: a systematic review (2026) · cites this paper as Xiao et al., 2017
In slice recording experiments, OXT application increased firing rates in VTA-DA neurons but decreased firing rates in lateral SNc-DA neurons.
“In slice recording experiments, the OXT application increased firing rates in VTA-DA neurons but decreased firing rates in lateral substantia nigra pars compacta (SNc)-DA neurons.”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as Xiao et al., 2017
The enhancement of VTA-DA neuron firing by light stimulation was blocked by an OXT receptor antagonist, indicating direct modulation by OXT.
“The enhancement of VTA-DA neuron firing by light stimulation was blocked by an OXT receptor antagonist, indicating direct modulation by OXT.”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as Xiao et al., 2017
Optogenetic stimulation of OXT fibres enhanced VTA-DA neuron activity while reducing activity in lateral SNc-DA neurons.
“Optogenetic stimulation of OXT fibres also showed opposing effects, enhancing VTA-DA neuron activity while reducing activity in lateral SNc-DA neurons.”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as Xiao et al., 2017
The antagonist alone could not prevent light-induced inhibition of SNc-DA neurons.
“However, the antagonist alone could not prevent light-induced inhibition of SNc-DA neurons.”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as Xiao et al., 2017
The light-induced inhibition of SNc-DA neurons was mediated indirectly via local GABA neurons, as it was reduced in the presence of GABA receptor antagonists.
“This inhibition was found to be mediated indirectly via local GABA neurons, as it was reduced in the presence of GABA receptor antagonists.”
From Convergence of oxytocin and dopamine signalling in neuronal circuits: Insights into the neurobiology of social interactions across species (2024) · cites this paper as Xiao et al., 2017
Oxytocin in the VTA activates oxytocin receptors on dopamine neurons and regulates their activity, suggesting that oxytocin in the VTA gates social reward.
“Oxytocin in the VTA activates oxytocin receptors on DA neurons regulates their activity, suggesting that oxytocin in the VTA gates social reward (Hung et al., 2017; Tang et al., 2014; Xiao et al., 2017).”
From Oxytocin neurons mediate the effect of social isolation via the VTA circuits (2022) · cites this paper as Xiao et al., 2017
The release of oxytocin in the VTA increases DA neuron firing within the VTA.
“Previously, the release of oxytocin in the VTA was shown to increase DA neuron firing within the VTA (Xiao et al., 2017).”
From Oxytocin neurons mediate the effect of social isolation via the VTA circuits (2022) · cites this paper as Xiao et al., 2017
PVN-VTA oxytocinergic projections are crucially involved in social behaviors.
“Because PVN-VTA oxytocinergic projections are crucially involved in social behaviors (Hung et al., 2017; Xiao et al., 2017)”
From Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder (2019) · cites this paper as Xiao et al., 2017
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References 77 · Cited by 292
Research works printed but not linked: 1
- Song Z, Borland JM, Larkin TE, O’Malley M, Albers HE (2016). Activation of oxytocin receptors, but not arginine-vasopressin (AVP) receptors, in the ventral tegmental area of male Syrian hamsters is essential for the reward-like properties of social interactions. Psychoneuroendocrinology 74, 164– 72. 27632574 PMC6417503
- Authors
- Xiao, L., Priest, M. F., Nasenbeny, J., Lu, T., & Kozorovitskiy, Y.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Kozorovitskiy, Yevgenia
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 95
- Issue
- 2
- Pages
- 368-384.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7881764
- OpenAlex
- W2731941304
- Cited by
- 292
- References
- 77
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 30 · 2023: 32 · 2022: 39 · 2021: 47 · 2020: 46 · 2019: 15 · 2018: 32 · 2017: 10
- FWCI
- 40.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Beckman Young Investigator Award
- William and Bernice E. Bumpus Young Innovator Award
- Rita Allen Foundation Scholar Award
- NARSAD Young Investigator and P&S Fund Grant
- NIH (T32 AG20506)
- Arnold O. Beckman Postdoctoral Fellowship
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- oxytocin, dopaminergic neurons, ventral tegmental area, substantia nigra pars compacta, paraventricular nucleus, vasopressin receptor, GABAergic interneurons, reward systems, midbrain dopamine system, optogenetic stimulation
- MeSH terms
- Animals, Corpus Striatum, Dopamine, Mesencephalon, Mice, Transgenic, Neurons, Oxytocin, Reward, Substantia Nigra, Neostriatum, Ventral Tegmental Area
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