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

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.

Identification of Three Residues Essential for 5-Hydroxytryptamine 2A-Metabotropic Glutamate 2 (5-HT2A·mGlu2) Receptor Heteromerization and Its Psychoactive Behavioral Function

“…We also showed that the head-twitch response induced by the hallucinogenic 5-HT 2A agonist DOI was significantly decreased in mGlu2-KO mice (50). These results suggest that the mGlu2 receptor is necessary to induce a 5-HT 2A -dependent head-twitch response.…”

Psychedelics

“…Moreno et al (2011) found that the DOI-or LSD-elicited HTR was completely abolished in mGluR2-KO mice. They also carried out [ 3 H]ketanserin saturation binding experiments in frontal cortex membranes from KO mice and found no decrease in K d or B max , compared with WT mice.…”

The Prevalence, Maintenance, and Relevance of G Protein–Coupled Receptor Oligomerization

“…One of the key examples has been to define the contribution of a potential 5-HT 2A -metabotropic glutamate reception subtype 2 (mGluR2) heteromer to both pharmacological and behavioral responses to a group of 5-HT 2A agonists that generate hallucinogenic effects. Intriguingly, although drugs such as 2,5-dimethoxy-4-iodoamphetamine are able to induce a head-twitch response in mice that requires expression of the 5-HT 2A receptor in cortical pyramidal neurons (Gonzalez-Maeso et al, 2007), this effect also requires expression of the mGluR2 receptor because it is also lacking in mGluR2 knockout animals (Moreno et al, 2011b). Moreover, this effect is restored in such animals by virally mediated reintroduction of the mGluR2 receptor .…”