title: Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Biology, Center of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline Pharmaceuticals, 37135 Verona, Italy. Christian_A_Heidbreder@gsk.com
authors.forename: Christian A
authors.initials: CA
authors.lastname: Heidbreder
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bianchi
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Lacroix
authors.forename: Stefania
authors.initials: S
authors.lastname: Faedo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Perdona
authors.forename: Rosaria
authors.initials: R
authors.lastname: Remelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavanni
authors.forename: Francesco
authors.initials: F
authors.lastname: Crespi
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001667:Binding, Competitive; D003891:Desipramine / Q000494:pharmacology; D004563:Electrochemistry / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008839:Microelectrodes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D027981:Symporters / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000929:Antidepressive Agents, Tricyclic; D003891:Desipramine; D018691:Excitatory Amino Acid Antagonists; D005473:Fluoxetine; D007099:Imipramine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011725:Pyridines; D018092:Kainic Acid Receptors; D027981:Symporters; C493227:SLC6A2 protein, human; C493226:Slc6a2 protein, rat; C011386:nisoxetine; C121465:6-methyl-2-(phenylethynyl)pyridine