Metabotropic Glutamate₂ Receptors Play a Key Role in Modulating Head Twitches Induced by a Serotonergic Hallucinogen in Mice

There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine_2A (5-HT_2A) receptor activation through stimulation of metabotropic glutamate_2/3 (mGlu_2/3) receptors in the prefrontal cortex. Here we show that constitutive deletion of the mGlu₂ gene profoundly attenuates an effect of 5-HT_2A receptor activation using the mouse head twitch response (HTR). MGlu₂ and mGlu₃ receptor knockout (KO) as well as age-matched ICR (CD-1) wild type (WT) mice were administered (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and observed for head twitch activity. DOI failed to produce significant head twitches in mGlu₂ receptor KO mice at a dose 10-fold higher than the peak effective dose in WT or mGlu₃ receptor KO mice. In addition, the mGlu_2/3 receptor agonist LY379268, and the mGlu₂ receptor positive allosteric modulator (PAM) CBiPES, potently blocked the HTR to DOI in WT and mGlu₃ receptor KO mice. Conversely, the mGlu_2/3 receptor antagonist LY341495 (10 mg/kg) increased the HTR produced by DOI (3 mg/kg) in mGlu₃ receptor KO mice. Finally, the mGlu₂ receptor potentiator CBiPES was able to attenuate the increase in the HTR produced by LY341495 in mGlu₃ receptor KO mice. Taken together, all of these results are consistent with the hypothesis that that DOI-induced head twitches are modulated by mGlu₂ receptor activation. These results also are in keeping with a critical autoreceptor function for mGlu₂ receptors in the prefrontal cortex with differential effects of acute vs. chronic perturbation (e.g., constitutive mGlu₂ receptor KO mice). The robust attenuation of DOI-induced head twitches in the mGlu₂ receptor KO mice appears to reflect the critical role of glutamate in ongoing regulation of 5-HT_2A receptors in the prefrontal cortex. Future experiments with inducible knockouts for the mGlu₂ receptor and/or selective mGlu₃ receptor agonists/PAMs/antagonists could provide an important tools in understanding glutamatergic modulation of prefrontal cortical 5-HT_2A receptor function.