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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 mGlu 2  gene profoundly attenuates an effect of 5-HT 2A  receptor activation using the mouse head twitch response (HTR). MGlu 2  and mGlu 3  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 mGlu 2  receptor KO mice at a dose 10-fold higher than the peak effective dose in WT or mGlu 3  receptor KO mice. In addition, the mGlu 2/3  receptor agonist LY379268, and the mGlu 2  receptor positive allosteric modulator (PAM) CBiPES, potently blocked the HTR to DOI in WT and mGlu 3  receptor KO mice. Conversely, the mGlu 2/3  receptor antagonist LY341495 (10 mg/kg) increased the HTR produced by DOI (3 mg/kg) in mGlu 3  receptor KO mice. Finally, the mGlu 2  receptor potentiator CBiPES was able to attenuate the increase in the HTR produced by LY341495 in mGlu 3  receptor KO mice. Taken together, all of these results are consistent with the hypothesis that that DOI-induced head twitches are modulated by mGlu 2  receptor activation. These results also are in keeping with a critical autoreceptor function for mGlu 2  receptors in the prefrontal cortex with differential effects of acute vs. chronic perturbation (e.g., constitutive mGlu 2  receptor KO mice). The robust attenuation of DOI-induced head twitches in the mGlu 2  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 mGlu 2  receptor and/or selective mGlu 3  receptor agonists/PAMs/antagonists could provide an important tools in understanding glutamatergic modulation of prefrontal cortical 5-HT 2A  receptor function.

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