Chronic treatment with LY341495 decreases 5-HT2A receptor binding and hallucinogenic effects of LSD in mice

Abstract

Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT2A receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24 mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5 mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [3H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT2A agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT2A receptor-dependent hallucinogenic effects of LSD.

Psychedelics

“…Thus, chronic treatment with LY341495 decreases LSD-dependent head-twitch behavior as well as LSD-dependent induction of expression of c-fos, egr-1, and egr-2 in the mouse somatosensory cortex. In conclusion, data from Moreno et al (2013) support the hypothesis that chronic blockade of mGlu2 receptor-dependent signaling downregulates 5-HT 2A receptor binding in the mouse somatosensory cortex and its hallucinogen-like cellular signaling and behavioral effects. Given that mGlu2 receptors are located presynaptically, their blockade would lead to excessive glutamate release, potentially resulting in feedback downregulation of 5-HT 2A receptors expressed on the pyramidal apical dendrites.…”

“…This study by Moreno et al (2013) demonstrates that chronic treatment with the mGlu2/3 receptor inverse agonist LY341495 downregulates 5-HT 2A receptor binding in the mouse somatosensory cortex through a mechanism that requires expression of the mGlu2 receptor, because this effect was not observed in mGlu2 KO mice. The lower density of 5-HT 2A receptors correlates with changes in hallucinogen-like behavioral and cellular responses that require expression of the 5-HT 2A receptor in the mouse brain cortex.…”

“…That is, if a psychedelic (e.g., LSD) for some reason fails to downregulate 5-HT 2A receptors, glutamate receptors might adapt instead and thus prevent cortical overstimulation. Moreno et al (2013) H]LY341495 binding were assessed in the bilateral somatosensory cortex. The head-twitch behavioral response was also measured 1 day after the last injection with chronic LY341495.…”

“…Analysis of the maximum number of binding sites (B max ) by Moreno et al (2013) revealed a lower density of mGlu2/3 receptors in the somatosensory cortex from mice chronically treated with LY341495. The number of [ 3 H]ketanserin binding sites was also decreased in WT mice, but not in mGlu2-KO mice; there was no effect on K D .…”

Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment

“…On the other hand, the locomotor activity induced by the mGlu 2/3 R antagonist LY341495 is attenuated in 5-HT 2A -KO mice [74]. Moreover, chronic administration of the hallucinogenic 5-HT 2A agonist 2,5-Dimethoxy-4-bromoamphetamine (DOB) in mice attenuates the behavioral effects of the mGlu 2/3 R agonist LY379268 [95] whereas chronic treatment by LY341495 decreases 5-HT 2A binding and the hallucinogenic effects of LSD [96]. …”