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. Author manuscript; available in PMC: 2022 Jul 8.
Published in final edited form as: Annu Rev Neurosci. 2021 Apr 6;44:359–381. doi: 10.1146/annurev-neuro-102320-102847

Figure 3.

Figure 3

Different modes of oxytocinergic modulation. (a) Proposed mechanism of oxytocin receptor GPCR signaling. A G protein activates PLC to degrade PIP2 into IP3 and DAG. Depleting membrane PIP2 closes KCNQ channels, increasing resistance and depolarizing neurons. DAG activates PKC to phosphorylate spike channels (Tirko et al. 2018). (b, left) In first-order modulation, oxytocin directly depolarizes some principal excitatory cells such as CA2 pyramidal neurons (Tirko et al. 2018). (Middle) In second-order modulation, oxytocin reduces inhibitory transmission by either increasing spontaneous firing or impairing GABA release (Owen et al. 2013). (Right) In third-order modulation, or modulation of modulation, oxytocin receptors on serotoninergic terminals impact serotonin signaling in nucleus accumbens (top) (Dölen et al. 2013), and oxytocin increases VTA dopamine neuron firing but decreases SNc dopamine neuron firing (bottom) (Xiao et al. 2017). Abbreviations: 5-HT, 5-hydroxytryptamine; DAG, diacylglycerol; DAn, dopamine neuron; GABA, γ aminobutyric acid; GPCR, G protein–coupled receptor; IP3, inositol triphosphate; KCNQ, M-type K+ channel; MSN, medium spiny neuron; OXTR, oxytocin receptor; P, phosphorylation; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PVN, paraventricular nucleus of the hypothalamus; SNc, substantia nigra pars compacta; TGOT, [Thr4, Gly7]-oxytocin; VTA, ventral tegmental area.