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The mechanisms through which blockade of metabotropic glutamate receptors 5 (mGluR5) results in anxiolytic and antidepressant effects are currently unknown. In the present study, we therefore hypothesized that the anxiolytic- and antidepressant-like profile of the noncompetitive mGluR5 receptor antagonist 2-ethyl-6-(phenylethynyl)-pyridine (MPEP) may be mediated by inhibition of the norepinephrine transporter (NET). Accordingly, we first examined the potency of MPEP to bind to or inhibit uptake at the NET as well as the dopamine and serotonin transporters (DAT and SERT, respectively). We also examined the simultaneous in vivo effects of MPEP and desipramine (DMI) on both NE-like oxidation current in the amygdala (AMY) and cell firing in the locus coeruleus (LC) by means of differential pulse voltammetry (DPV) coupled with electrophysiology. MPEP completely displaced the binding of [3H]-nisoxetine on human NET with a pKi of 6.63 +/- 0.02. In addition, MPEP was able to inhibit [3H]-NE uptake in LLCPK cells expressing human NET, with a pIC50 of 5.55 +/- 0.09. In vivo DPV data revealed that both MPEP (30 mg/kg i.p.) and DMI (10 mg/kg i.p.) significantly increased NE-like voltammetric responses levels in the AMY, whereas both compounds also significantly decreased cell firing monitored concomitantly from the second microelectrode in the LC. Collectively, the results of the present study provide potential new mechanisms through which MPEP exerts its anxiolytic and antidepressant effects.

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