Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2^High receptors and marked supersensitivity to the dopamine agonist (+)PHNO

Abstract

The finding that the mGlu2/3 metabotropic glutamate receptor agonist, LY404039, improves clinical symptoms in schizophrenia warrants a search for a possible interaction between mGlu2/3 receptors and dopamine D2 receptors. Here, this topic is examined in striatal tissue of mice lacking either mGlu2 or mGlu3 receptor. Such mice are known to be behaviorally supersensitive to dopamine receptor agonists. Therefore, to determine the basis of this dopamine supersensitivity, the proportion of dopamine D2High receptors was measured in the striata of mGlu2 and mGlu3 receptor knockout mice. The proportion of D2High receptors was found to be elevated by 220% in the striata of both knockouts. To measure the functional dopamine supersensitivity, the D2 agonist (1)PHNO was used to stimulate the incorporation of GTP-g-S in the striatal homogenates in the presence of drugs that blocked the dopamine D1, D3, and D5 receptors. Compared with control striata, the mGlu2 receptor knockout tissues were 67-fold more sensitive to (1)PHNO, while the mGlu3 receptor knockout tissues were 17-fold more sensitive. These data suggest that group II mGlu receptors-mGlu2 receptors in particular-may normally regulate D2 receptors by reducing the proportion of high-affinity D2 receptors in membranes. Such regulation may contribute to the antipsychotic action of mGlu2/3 receptor agonists.

Comprehensive behavioral study of mGluR3 knockout mice: implication in schizophrenia related endophenotypes

“…This possibility has also been supported by in vitro and in vivo experimental evidence in which group II mGluRs negatively modulated dopamine release in the limbic and cortical regions [5]. Seeman et al [32] revealed that D2 receptor was 17-fold more sensitive in mGluR3 knockout striate homogenates compared with control. There is also a possibility that D2 receptor hypersensitivity may cause hyper locomotor activity of mGluR3 mice in this study.…”

Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice

“…One relevant finding in the mGlu2 −/− mice is that despite no changes in striatal tissue levels of dopamine (current data and [7]) and no baseline dialysate changes in glutamate or dopamine [7], these mice exhibit enhancement of cocaine-induced extracellular dopamine and glutamate in the NAc [7]. There is also evidence that a greater proportion of dopamine D2 receptors are in a high-affinity state in mGlu2 −/− and mGlu3 −/− mice, which may be indicative of a subtle difference in dopaminergic function [31]. By the same token, the unchanged baseline levels of noradrenaline, 5-HT and cortical dopamine in mGlu2/3 −/− mice reported here do not preclude the occurrence of functionally significant alterations in monoamine signalling.…”

Metabotropic glutamate receptors as therapeutic targets for schizophrenia

“…Recently, it was shown that combined, sub-effective doses of the mGlu2/3 agonist (1S,2R,5R,6R)-2-amino-4- oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY379268) and the 5HT2A receptor antagonist, (R)-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M100907), are efficacious in an animal model predictive of antipsychotic activity (Uslaner et al 2009a). Other intriguing associations with group II mGluRs have been discovered that are relevant to current models of schizophrenia including the upregulation of high-affinity D2 dopamine receptors in the striatum of mGlu 2 and mGlu 3 knockout mice (Seeman et al 2009). Observations such as these warrant further investigation and should be kept in mind when considering a possible multi-target approach for treatment of psychosis (Wong et al 2010).…”