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Blockade of the mGlu5 receptor decreases basal and stress-induced cortical norepinephrine in rodents

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Abstract

Rationale

Glutamate, the major excitatory neurotransmitter in the brain mediates its effects by both ionotropic and metabotropic receptor subtypes. Recently, the search for selective ligands for glutamate receptor subtypes has led to the discovery of 2-methyl-6-(phenylethynyl)pyridine (MPEP), an antagonist specific for metabotropic glutamate receptor 5 (mGlu5). This receptor is highly expressed in limbic forebrain regions and is thought to modulate anxiety-related processes. The noradrenergic nucleus locus coeruleus (LC) is an important mediator of stress responses and dysfunction of this system is implicated in affective disorders such as anxiety and depression.

Objectives

We sought to assess the effects of mGlu5 receptor antagonists, MPEP and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on cortical norepinephrine (NE) levels.

Methods

In vivo microdialysis and high-pressure liquid chromatography with electrochemical detection (HPLC-ED) were used to assess the effects of mGlu5 antagonism on extracellular NE in the frontal cortex, a major terminal field of the LC.

Results

Blockade of the mGlu5 receptor elicited significant reductions in extracellular NE in the frontal cortex. The benzodiazepine diazepam also reduced cortical NE. Furthermore, MPEP administration attenuated stress-induced increases in extracellular NE.

Conclusions

Taken together, these data show that MPEP and MTEP, through their blockade of the mGlu5, reduce extracellular norepinephrine, the impact of which may contribute to their anxiolytic actions.

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Authors and Affiliations

  1. Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA, 19129, USA

    Michelle E. Page & Paul Szeliga

  2. Nervous System Research, Novartis Institutes for BioMedical Sciences, Novartis Pharma AG, Basel, Switzerland

    Fabrizio Gasparini & John F. Cryan

  3. Department of Neurosurgery, Thomas Jefferson University, 1025 Walnut Street, Room 516, Philadelphia, PA, 19107, USA

    Michelle E. Page

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  1. Michelle E. Page
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  2. Paul Szeliga
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Correspondence to Michelle E. Page.

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Page, M.E., Szeliga, P., Gasparini, F. et al. Blockade of the mGlu5 receptor decreases basal and stress-induced cortical norepinephrine in rodents. Psychopharmacology 179, 240–246 (2005). https://doi.org/10.1007/s00213-005-2142-5

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  • DOI: https://doi.org/10.1007/s00213-005-2142-5

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