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.

Attenuation of Behavioral Effects of Cocaine by the Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)-pyridine in Squirrel Monkeys: Comparison with Dizocilpine

“…These qualitatively different pharmacological profiles make it unlikely that the cocaine-antagonist effects of MPEP were mediated principally via attenuation of NMDA receptor activity. MPEP also has been reported to inhibit norepinephrine transport (NET) and to mimic the effects of prototypic NET inhibitors on cellular activity in the amygdala and locus coeruleus of rats (Heidbreder et al, 2003). Although inhibition of NET could have contributed to some of the effects of MPEP in our study (e.g., reduced locomotion), it is not likely to be the mechanism underlying MPEP-induced attenuation of cocaine's behavioral effects.…”

Metabotropic Glutamate 5 Receptor Antagonism Is Associated with Antidepressant-Like Effects in Mice

“…port for the involvement of mGlu5 receptors in depression has come from a limited number of studies using MPEP. Because MPEP exhibits weak interactions with other receptors, such as mGlu4 (Mathiesen et al, 2003), NMDA receptors, and noradrenaline transporters (Heidbreder et al, 2003), MTEP was synthesized. MTEP is an MPEP analog with increased potency, in vivo selectivity , and improved bioavailability (Roppe et al, 2004).…”

The Metabotropic Glutamate 5 Receptor Antagonist 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine Reduces Ethanol Self-Administration in Multiple Strains of Alcohol-Preferring Rats and Regulates Olfactory Glutamatergic Systems

“…MPEP has also been shown to decrease cocaine self-administration in mice (Chiamulera et al, 2001) and rats (Tessari et al, 2004;Kenny et al, 2005;Lee et al, 2005), cocaineinduced place preference (McGeehan and Olive, 2003), nicotine self-administration (Paterson et al, 2003), and reinstatement of nicotine self-administration (Tessari et al, 2004). However, MPEP has been shown to have a number of off-target effects, notably antagonism of NMDA receptors (O'Leary et al, 2000), inhibition of the noradrenaline transporter (Heidbreder et al, 2003), and positive allosteric modulation of the mGlu4 receptor (Mathiesen et al, 2003). Therefore, we have used the more recently discovered MTEP (Brodkin et al, 2002a;Anderson et al, 2003;Cosford et al, 2003), which has greater selectivity for the mGlu5 receptor.…”