Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Jun 15;1641(Pt B):217-33.
doi: 10.1016/j.brainres.2016.01.005. Epub 2016 Jan 11.

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex

Bo Xing  1 , Yan-Chun Li  1 , Wen-Jun Gao  2
Affiliations
Review

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex

Bo Xing et al. Brain Res. .

Abstract

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System.

Keywords: Dopamine; Neuromodulator; Norepinephrine; Prefrontal cortex; Psychiatric disorders.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Simplified modulatory effects of NE and DA on prefrontal cortical excitatory synapses. At presynaptic sites, NE and DA can inhibit glutamate release through activation of α2 receptors and D1 receptors, respectively, to control the opening of Ca2+ channels. At postsynaptic sites, both NE and DA can enhance AMPAR- and NMDAR-mediated excitatory currents through β receptor- and D1 receptor-activated cAMP-PKA signaling pathways, respectively. In addition, by inhibiting cAMP-PKA signaling, NE and DA can decrease excitatory currents through activation of α2 receptors and D2 receptors, respectively. Activation of D2 receptors also blocks excitatory currents by recruiting Akt-GSK3 signaling.
Figure 2
Figure 2
Simplified summary of the modulatory effects of NE and DA on prefrontal cortical inhibitory synapses. At presynaptic sites, NE and DA can inhibit GABA release by activating α2 receptors and D2 receptors, respectively; whereas NE also enhance GABA release through activation of α1 or β adrenergic receptors. At postsynaptic sites, NE and DA increase GABAA receptor-mediated inhibitory current through β receptors and D1 receptors by activating camp-PKA signaling pathway. NE and DA also recruit α2 receptors and D2 receptors, respectively, leading to inhibition of cAMP-PKA signaling and thus decreased GABAA receptor-mediated inhibitory current. Activation of D2 receptors also triggers Akt-GSK3 signaling to decrease GABAA receptor-mediated inhibitory current.
Figure 3
Figure 3
Schematic model showing the complementary NE and DA effects on the synaptic transmission in PFC local circuitry. DA differentially affects the monosynaptic connections between P and NP, depending on the pre- and postsynaptic target neurons. In contrast, NE has opposite effects on P-P, P-NP and NP-P connections. Note: P, pyramidal neuron; NP, non-pyramidal neuron.
Figure 4
Figure 4
Schematic graph shows the potential roles of Akt/GSK-3β signaling in DA and NE modulation of synaptic functions in the PFC. At presynaptic sites, activation of Akt down-regulates the expression of NET, which will result in an elevation of both DA and NE. At postsynaptic sites, activation of D1 receptors activates, but activation of D2 receptors inhibits, the cAMP/PKA/DARPP-32 signaling pathway to regulate both glutamatergic and GABAgeric receptor function. In addition, activation of D2 receptors also triggers β-arrestin2 binding with PP2A and Akt to form a complex. Within the complex, PP2A dephosphorylates and deactivates Akt, resulting in an activation of GSK-3β, which in turn down-regulates glutamatergic and GABAgeric receptor function. In addition to DA receptors, Akt/GSK-3β is probably also involved in β receptor-mediated regulation of synaptic transmission. Similarly, β receptors activate, but α2 receptors inhibit, the cAMP/PKA/DARPP-32 signaling pathway. In addition, activation of either α2 receptors or D2 receptors also stimulates PLC/PKC and PLC/IP3/Ca2 signaling, which will result in down-regulation of both glutamatergic and GABAgeric receptor function.
See this image and copyright information in PMC

References

    1. Agster KL, et al. Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex. J Comp Neurol. 2013;521:2195–207. - PMC - PubMed
    1. Andersen SL. Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD). Behav Brain Res. 2002;130:197–201. - PubMed
    1. Aoki C, et al. Perikaryal and synaptic localization of alpha 2A-adrenergic receptor-like immunoreactivity. Brain Res. 1994;650:181–204. - PubMed
    1. Aoki C, et al. Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons. Cereb Cortex. 1998a;8:269–77. - PubMed
    1. Aoki C, Venkatesan C, Kurose H. Noradrenergic modulation of the prefrontal cortex as revealed by electron microscopic immunocytochemistry. Adv Pharmacol. 1998b;42:777–80. - PubMed

Publication types

LinkOut - more resources