Elsevier

Neuroscience Letters

Volume 493, Issue 3, 15 April 2011, Pages 76-79
Neuroscience Letters

Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists

https://doi.org/10.1016/j.neulet.2011.01.046Get rights and content

Abstract

Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [3H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens.

Research highlights

► Head-twitch behavior induced by hallucinogenic 5HT2A agonists is abolished in mGlu2-KO mice. ► Cellular response induced by hallucinogenic 5HT2A agonists is abolished in mGlu2-KO mice. ► This suggests the 5HT2A-mGlu2 complex as necessary for the responses induced by hallucinogens.

Section snippets

Acknowledgements

NIMH 5R01MH084894 (J.G.M.), NIDA P01 DA12923 (S.C.S.), NARSAD (J.G.M.), and the Maltz Family Foundation (J.G.M.) participated in the funding of this study. We are grateful to Dr. J.A. Gingrich for his gift of 5-HT2AR-KO mice. J.L.M was the recipient of a postdoctoral fellowship from Ministerio de Ciencia e Innovación, Spain.

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