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

Hallucinogenic drugs like LSD, mescaline, and psilocybin all bind strongly to the serotonin 5-HT(2A) receptor. Drugs that affect metabotropic glutamate 2/3 (mGlu2/3) receptors can alter the cellular and behavioral effects of hallucinogens. In mice, chronic treatment (21 days) with the mGlu2/3 receptor antagonist LY341495 (1.5 mg/kg) reduced the hallucinogenic-like effects of LSD (0.24 mg/kg). This treatment decreased binding of a radiolabeled tracer to 5-HT(2A) receptors in the somatosensory cortex of normal mice, but not in mice lacking the mGlu2 receptor. It also reduced head-twitch behavior and the expression of certain genes (c-fos, egr-1, egr-2) that are normally triggered by hallucinogenic drugs. These results suggest that repeatedly blocking mGlu2 receptors dampens the 5-HT(2A) receptor-mediated effects of LSD.

Study at a glance

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-HT(2A) 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 (0.24mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [(3)H]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-HT(2A) 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-HT(2A) receptor-dependent hallucinogenic effects of LSD.