Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function

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Abstract

Background

Neurotensin (NT) is known to act on dopamine (DA) neurons at the somatodendritic level to regulate cell firing and secondarily enhance DA release. In addition, anatomical and indirect physiological data suggest the presence of NT receptors at the terminal level. However, a clear demonstration of the mechanism of action of NT on dopaminergic axon terminals is lacking. We hypothesize that NT acts to increase DA release by inhibiting the function of terminal D2 autoreceptors. To test this hypothesis, we used fast-scan cyclic voltammetry (FCV) to monitor in real time the axonal release of DA in the nucleus accumbens (NAcc).

Results

DA release was evoked by single electrical pulses and pulse trains (10 Hz, 30 pulses). Under these two stimulation conditions, we evaluated the characteristics of DA D ₂autoreceptors and the presynaptic action of NT in the NAcc shell and shell/core border region. The selective agonist of D ₂autoreceptors, quinpirole (1 μM), inhibited DA overflow evoked by both single and train pulses. In sharp contrast, the selective D ₂receptor antagonist, sulpiride (5 μM), strongly enhanced DA release triggered by pulse trains, without any effect on DA release elicited by single pulses, thus confirming previous observations. We then determined the effect of NT (8–13) (100 nM) and found that although it failed to increase DA release evoked by single pulses, it strongly enhanced DA release evoked by pulse trains that lead to prolonged DA release and engage D ₂autoreceptors. In addition, initial blockade of D ₂autoreceptors by sulpiride considerably inhibited further facilitation of DA release generated by NT (8–13).

Conclusion

Taken together, these data suggest that NT enhances DA release principally by inhibiting the function of terminal D ₂autoreceptors and not by more direct mechanisms such as facilitation of terminal calcium influx.

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Most cited references 38

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In vivo voltammetry is approaching the end of its second decade as a technique to explore extracellular concentrations in the brain. The issues of selectivity and sensitivity, which caused considerable discussion and confusion in the early 1980s, are now resolved. It is clear that in vivo voltammetry and dialysis are complimentary tools to understand neurotransmitter dynamics. The two chief advantages of voltammetry compared to dialysis, improved temporal resolution and reduced tissue damage, make this technique exceptionally well suited for providing information which is complementary to that obtained by single-unit recording and is uniquely capable of providing information on the short-term regulation of extracellular levels of biogenic amines.

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Inhibition of dopamine release via presynaptic D2 receptors: time course and functional characteristics in vivo.

Marianne Benoit-Marand, Emiliana Borrelli, Francois Gonon (2001)

Most neurotransmitters inhibit their own release through autoreceptors. However, the physiological functions of these presynaptic inhibitions are still poorly understood, in part because their time course and functional characteristics have not been described in vivo. Dopamine inhibits its own release through D2 autoreceptors. Here, the part played by autoinhibition in the relationship between impulse flow and dopamine release was studied in vivo in real time. Dopamine release was evoked in the striatum of anesthetized mice by electrical stimulation of the medial forebrain bundle and was continuously monitored by amperometry using carbon fiber electrodes. Control experiments performed in mice lacking D2 receptors showed no autoinhibition of dopamine release. In wild-type mice, stimulation at 100 Hz with two to six pulses linearly inhibited further release, whereas single pulses were inefficient. Dopaminergic neurons exhibit two discharge patterns: single spikes forming a tonic activity below 4 Hz and bursts of two to six action potentials at 15 Hz. Stimulation mimicking one burst (four pulses at 15 Hz) promoted extracellular dopamine accumulation and thus inhibited further dopamine release. This autoinhibition was maximal between 150 and 300 msec after stimulation and disappeared within 600 msec. This delayed and prolonged time course is not reflected in extracellular DA availability and thus probably attributable to mechanisms downstream from autoreceptor stimulation. Thus, in physiological conditions, autoinhibition has two important roles. First, it contributes to the attenuation of extracellular dopamine during bursts. Second, autoinhibition elicited by one burst transiently attenuates further dopamine release elicited by tonic activity.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Neurosci

Title: BMC Neuroscience

Publisher: BioMed Central

ISSN (Electronic): 1471-2202

Publication date Collection: 2009

Publication date (Electronic): 14 August 2009

Volume: 10

Page: 96

Affiliations

[1 ]Department of Pharmacology, Groupe de Recherche sur le Système Nerveux Central, Faculty of Medicine, Université de Montréal, Quebec, H3C 3J7, Canada

Article

Publisher ID: 1471-2202-10-96

DOI: 10.1186/1471-2202-10-96

PMC ID: 2745416

PubMed ID: 19682375

SO-VID: be43a959-7025-43ce-9b9a-019a0626faee

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.