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Cell-based reporters reveal in vivo dynamics of dopamine and norepinephrine release in murine cortex.

ABSTRACT: The neuronal coding of stimulus-to-action sequences is believed to involve the release of dopamine (DA) and norepinephrine (NE). The electrochemical similarity of these monoamines, however, confounds real-time measurements of their release. Here we report cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) that use the specificity of G protein-coupled receptors (GPCRs) to discriminate nanomolar concentrations of DA and NE. CNiFERs were implanted into the frontal cortex of mice to measure the timing of neurotransmitter release during classical conditioning with the use of two-photon microscopy. The onset of DA release correlated with that of licking and shifted from the time of the reward toward that of the cue upon conditioning. In contrast, concurrent release of NE did not correlate with licking or the cue. This generation of CNiFERs provides unique tools to assess the release of monoamines. The molecular design of these CNiFERs may be generalized to realize CNiFERs for any molecule that activates a GPCR.

SUBMITTER: Muller A

PROVIDER: S-EPMC4245316 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Cell-based reporters reveal in vivo dynamics of dopamine and norepinephrine release in murine cortex.

Muller Arnaud A Joseph Victory V Slesinger Paul A PA Kleinfeld David D

Nature methods 20141026 12

The neuronal coding of stimulus-to-action sequences is believed to involve the release of dopamine (DA) and norepinephrine (NE). The electrochemical similarity of these monoamines, however, confounds real-time measurements of their release. Here we report cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) that use the specificity of G protein-coupled receptors (GPCRs) to discriminate nanomolar concentrations of DA and NE. CNiFERs were implanted into the frontal cortex of mice ...[more]

PMID: 25344639

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Project description: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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Cell-based reporters reveal in vivo dynamics of dopamine and norepinephrine release in murine cortex.

Publications

Cell-based reporters reveal in vivo dynamics of dopamine and norepinephrine release in murine cortex.

Similar Datasets

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