CNS Dopamine Transmission Mediated by Noradrenergic Innervation

Smith, Caroline C.; Greene, Robert

doi:10.1523/jneurosci.6486-11.2012

Cited by 165 publications

(148 citation statements)

References 50 publications

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“…Our findings that LC neurons corelease dopamine in the dorsal hippocampus are consistent with the earlier finding that LC neurons also corelease dopamine in the prefrontal cortex and drive dopamine-dependent activity in the hippocampus (19,21). Moreover, the current findings provide anatomical support for the documented functional distinctions between the dorsal and ventral hippocampus (17).…”

Section: Discussionsupporting

confidence: 91%

“…The LC dopamine signal drives the selective attention underlying spatial learning and memory. Numerous reports suggest that the VTA is the main source of dopamine to the dorsal hippocampus (12)(13)(14), whereas others suggest that the LC supplies the hippocampus with dopamine (19)(20)(21). The present results reconcile the discrepancy between dense dopamine receptor expression and sparse VTA dopamine axon networks in the dorsal hippocampus and support the hypothesis that dopaminergic tone in the dorsal hippocampus arises from neurons of the LC.…”

Section: Discussionsupporting

confidence: 81%

“…However, the possibility exists that the D1/D5 receptor is activated by a ligand other than dopamine or undergoes receptor-receptor interactions. Norepinephrine has a K d of 50 μM at the dopamine D1 receptor (32), and the possibility exists that norepinephrine action at the dopamine D1 receptor is responsible for the effects reported by Smith and Greene (21). In fact, norepinephrine promotes cAMP accumulation in embryonic retinas via the dopamine D1/D5 receptor (33), and norepinephrine-induced increases in adenyl cyclase activity in retinal homogenates can be reversed by the dopamine D1/D5 receptor antagonist (34).…”

Section: Discussionmentioning

confidence: 96%

“…Taken together, there are some groups who argue that the VTA is the main source of dopamine to the dorsal hippocampus (12)(13)(14) and others who support the idea that dopamine is released from LC neurons (19)(20)(21). These conflicting hypotheses leave unanswered the question of which brain region supplies the dorsal hippocampus with dopaminergic tone.…”

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confidence: 99%

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Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory

Kempadoo

Mosharov

Choi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

497

507

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Dopamine neurotransmission in the dorsal hippocampus is critical for a range of functions from spatial learning and synaptic plasticity to the deficits underlying psychiatric disorders such as attentiondeficit hyperactivity disorder. The ventral tegmental area (VTA) is the presumed source of dopamine in the dorsal hippocampus. However, there is a surprising scarcity of VTA dopamine axons in the dorsal hippocampus despite the dense network of dopamine receptors. We have explored this apparent paradox using optogenetic, biochemical, and behavioral approaches and found that dopaminergic axons and subsequent dopamine release in the dorsal hippocampus originate from neurons of the locus coeruleus (LC). Photostimulation of LC axons produced an increase in dopamine release in the dorsal hippocampus as revealed by high-performance liquid chromatography. Furthermore, optogenetically induced release of dopamine from the LC into the dorsal hippocampus enhanced selective attention and spatial object recognition via the dopamine D1/D5 receptor. These results suggest that spatial learning and memory are energized by the release of dopamine in the dorsal hippocampus from noradrenergic neurons of the LC. The present findings are critical for identifying the neural circuits that enable proper attention selection and successful learning and memory.dopamine | locus coeruleus | hippocampus | memory | attention D opamine is a neurotransmitter released throughout the brain to encode salience and facilitate the formation of associative memory (1, 2). When released into the dorsal hippocampus, dopamine binds to D1/D5 receptors to promote attention, episodic memory formation, spatial learning, and synaptic plasticity (3-5). Successful spatial learning requires that hippocampal place cells, location-encoding pyramidal neurons (6), display consistent and stable patterns of neural activity, a process that can be enhanced by selective attention to spatial cues and by dopamine agonists (7,8). Conversely, dopamine receptor blockade attenuates the ability of spatial attention to stabilize the firing pattern of hippocampal place cells (8). The role of dopamine in driving attentional processes is highlighted by the fact that methylphenidate, one of the most common treatments for attention-deficit hyperactivity disorder (ADHD), improves attention by increasing synaptic availability of dopamine in the hippocampus, as well as in the prefrontal cortex and striatum (9-11). These findings suggest that dopamine is critical for the selective attention underlying spatial learning and memory.For decades, the ventral tegmental area (VTA) has been the presumed source of hippocampal dopamine. However, in recent years, the source of dopamine in the dorsal hippocampus has become less clear. McNamara et al. (12) argued that a dopaminergic projection from the VTA to the dorsal hippocampus promoted hippocampal reactivation during sleep and stabilized memory. However, only 10% of the sparse projection from the VTA to the hippocampus contains dopamine, raising the...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory

Kempadoo

Mosharov

Choi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

497

507

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“…However, studies have shown that VTA projections to dorsal hippocampus are scarce, whereas LC projections are abundant (8,12,13). In addition, dopamine, which is the most prominently implicated neuromodulator in novelty signaling (14), was demonstrated to be released from the LC, along with norepinephrine in the cortex (15) and in the hippocampus (8,12,16). Therefore, we hypothesized that the LC input to the CA3 network plays a pivotal role in single-trial learning of novel experience.…”

mentioning

confidence: 98%

Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context

Wagatsuma

Okuyama

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

215

181

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The memory for a new episode is formed immediately upon experience and can last up to a lifetime. It has been shown that the hippocampal network plays a fundamental role in the rapid acquisition of a memory of a one-time experience, in which the novelty component of the experience promotes the prompt formation of the memory. However, it remains unclear which neural circuits convey the novelty signal to the hippocampus for the singletrial learning. Here, we show that during encoding neuromodulatory input from locus coeruleus (LC) to CA3, but not CA1 or to the dentate gyrus, is necessary to facilitate novel contextual learning. Silencing LC activity during exposure to a novel context reduced subsequent reactivation of the engram cell ensembles in CA3 neurons and in downstream CA1 upon reexposure to the same context. Calcium imaging of the cells reactivated in both novel and familiar contexts revealed that suppression of LC inputs at the time of encoding resulted in more variable place fields in CA3 neurons. These results suggest that neuromodulatory input from LC to CA3 is crucial for the formation of a persistent memory in the hippocampus.

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Selective inhibition of dopamine‐beta‐hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex

et al. 2015

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IntroductionDisulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine‐beta‐hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine‐induced increase. Concomitantly, in rats with cocaine self‐administration history, cocaine‐seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release.MethodsNoradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti‐DBH‐saporin (aDBH‐sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat–cocaine combination on extracellular DA levels and their regulation by α2‐adrenoceptors.ResultsFifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat–cocaine combination, while it was ineffective in denervated rats.ConclusionsThis research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2‐autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat‐induced DA release.

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CNS Dopamine Transmission Mediated by Noradrenergic Innervation

Cited by 165 publications

References 50 publications

Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory

Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory

Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context

Selective inhibition of dopamine‐beta‐hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex

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