Signaling in dopamine D2 receptor-oxytocin receptor heterocomplexes and its relevance for the anxiolytic effects of dopamine and oxytocin interactions in the amygdala of the rat
Open accessAbstract
Dopamine D2 receptor (D2R)-oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. In this work the hypothesis is tested using cotransfected HEK293 cells whether allosteric reciprocal D2R-OTR interactions can enhance signaling of D2R-OTR heterocomplexes along the CREB, MAPK and PLC pathways and whether the anxiolytic effects of OT may involve facilitatory D2R-OTR interactions within the central amygdaloid nucleus (CeA). Oxytocin enhanced the D2-like agonist quinpirole induced inhibition of the AC-PKA-pCREB signaling cascade and increased its signaling over the RAS-MAPK-pELK pathway. Quinpirole enhanced the oxytocin induced increases in the activity of the PLCbeta-IP3-calcineurin and RAS-MAPK-pELK cascades. Bilateral infusion of oxytocin (0.9-150ng/side) into the CeA of the rat elicited anxiolytic effects in the Shock-Probe Burying test, an unconditioned model of fear/anxiety. This action was not observed when oxytocin (25ng/side) was simultaneously co-infused with raclopride (neither 250 nor 500ng/side), a D2/D3 antagonist, into the CeA. Based on the current findings, the blockade of the anxiolytic effects of oxytocin by the simultaneous intra-CeA administration of raclopride can be explained by a lack of facilitatory protomer interactions in D2R-OTR heterocomplexes. Dysfunction and/or disruption of such interactions in the central amygdala may lead to anxiety development. Restoration of such interactions may represent a new strategy for development of novel anxiolytic drugs.
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In the striatum, OXTR activation on astrocytes inhibits glutamate release, and D2R-OXTR heterocomplexes facilitate dopaminergic signaling.
“In the striatum, OXTR activation on astrocytes inhibits glutamate release (Amato et al., 2022), and D2R-OXTR heterocomplexes facilitate dopaminergic signaling (Hernandez-Mondragon et al., 2023; Pérez de la Mora et al., 2016).”
From Music's context-dependent influence on oxytocin, social bonding, and emotion regulation: a systematic review (2026) · cites this paper as Pérez de la Mora et al., 2016
The potential receptor-receptor interactions may involve an enhancing effect of D2R-OXTR heterocomplexes on CREB, MAPK, and PLC signaling pathways.
“it may also be possible that in agreement with de la Mora et al. (2016), the potential receptor–receptor interactions may involve an enhancing effect of D2R–OXTR heterocomplexes on CREB, MAPK, and PLC signaling pathways”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as de la Mora et al., 2016
The anxiolytic effects of oxytocin infusion into CeA were abolished by simultaneous administration of OTA, an OXTR antagonist.
“Such effects were abolished by the simultaneous administration of OTA, an OXTR antagonist (Elands et al., 1988).”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as de la Mora et al., 2016
Oxytocin infusion (above 25 ng/side) into the CeA triggered anxiolytic effects in rats in the shock-probe burying test.
“results from our laboratory (de la Mora et al., 2016) showed that oxytocin infusion (above 25 ng/side) into the CeA triggered anxiolytic effects in rats when using the shock-probe burying test.”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as de la Mora et al., 2016
Simultaneous intra-amygdaloid infusion of noneffective doses of quinpirole and oxytocin elicited anxiolytic effects.
“the simultaneous infusion of noneffective doses of quinpirole (current work) and OXT (de la Mora et al., 2016) also elicited anxiolytic effects.”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as de la Mora et al., 2016
Co-injection of oxytocin with raclopride and prior raclopride administration prevented oxytocin-induced anxiolytic effects.
“both the co-injection of oxytocin with raclopride (de la Mora et al., 2016) and the previous raclopride administration (Laszlo et al., 2020) prevented the oxytocin-induced anxiolytic effects”
From Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat relevance for anxiolytic actions (2023) · cites this paper as de la Mora et al., 2016
D2R-OXTR heterocomplexes were validated by BRET in HEK293 cells after co-transfection with D2RRluc and OXTRGFP2.
“These results were validated by using the BRET technique in HEK293 cells after co-transfection with D2RRluc and OXTRGFP2 (de la Mora et al., 2016).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as de la Mora et al., 2016
The OXTR forms heteroreceptor complexes with dopamine D2R, 5-HT2AR, and 5-HT2CR protomers.
“In this review, we will deal with the discovered OXTR heteroreceptor complexes and their function, in which the dopamine D2R protomers (Romero-Fernandez et al., 2013; de la Mora et al., 2016), 5-HT2AR and 5-HT2CR protomers (Chruścicka et al., 2019, 2021; Wallace Fitzsimons et al., 2019) participate”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as de la Mora et al., 2016
The anxiolytic effects of quinpirole and oxytocin microinjections into the central amygdala were blocked by co-infusion with the D2R-like antagonist raclopride.
“The anxiolytic effects were blocked by co-infusion with a D2R-like antagonist raclopride in the central amygdala (de la Mora et al., 2016).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as de la Mora et al., 2016
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References 63 · Cited by 63
Research works printed but not linked: 1
- G. Paxinos, C. Watson, The Rat Brain in Stereotaxical Coordinates, second ed. Academic Press, San Diego, California, USA, 1986.
- Authors
- de la Mora, M. P., Pérez-Carrera, D., Crespo-Ramírez, M., Tarakanov, A., Fuxe, K., & Borroto-Escuela, D. O.
- Affiliations
- Universidad Nacional Autónoma de México (MX)
- Russian Academy of Sciences (RU)
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 1862
- Issue
- 11
- Pages
- 2075-2085
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2460814375
- Cited by
- 63
- References
- 63
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 4 · 2023: 8 · 2022: 9 · 2021: 8 · 2020: 3 · 2019: 5 · 2018: 11 · 2017: 3 · 2016: 1
- FWCI
- 10.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Swedish Research Council (348-2014-4396)
- Dirección General de Asuntos del Personal Académico (DGAPA) de la Universidad Nacional Autónoma de México (IN204314)
- Consejo Nacional de Ciencia y Tecnología (220173)
- Swedish Medical Research Council (04X-715)
- AFA Försäkring (130328)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- dopamine D2 receptor, oxytocin receptor, central amygdala, quinpirole, CREB signaling, MAPK signaling, RAS/MAPK pathway, raclopride, anxiety, anxiolytic drug development
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