Abstract
There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A) receptor activation through stimulation of metabotropic glutamate2/3 (mGlu2/3) receptors in the prefrontal cortex. Here we show that constitutive deletion of the mGlu2 gene profoundly attenuates an effect of 5-HT2A 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 mGlu2/3 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 mGlu2/3 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-HT2A 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-HT2A receptor function.
Highlights
Metabotropic glutamate receptors have been implicated in a wide variety of effects with clinical implications
The mGlu2 receptor positive allosteric modulator (PAM), CBiPES (10–30 mg/kg), when given to DOI-treated CD-1 mice, produced a mean of 2.3 head twitches at 30 mg/kg, a 60% reduction from DOI and vehicle-treated animals (Figure 1B)
LY379268 (Figure 1C), the orthosteric metabotropic glutamate2/3 (mGlu2/3) receptor agonist, was very potent at decreasing the mean head twitches produced by DOI [F(3,20) = 8.51, p < 0.001]
Summary
Metabotropic glutamate receptors (mGluRs) have been implicated in a wide variety of effects with clinical implications. The group II mGlu and mGlu receptor subtypes have been shown in a wide range of animal studies to have effects in models predictive of antidepressant activity (Chaki et al, 2004; Yasuhara et al, 2006; Nikiforuk et al, 2010; Fell et al, 2011), anxiolytic activity (Klodzinska et al, 2002; Schoepp et al, 2003; Galici et al, 2006) and antipsychotic activity (Moghaddam and Adams, 1998; Johnson et al, 2005; RorickKehn et al, 2007) These preclinical predictions have been confirmed for orthosteric mGlu2/3 receptor agonists in the treatment of schizophrenia, though in a limited subpopulation of patients (Patil et al, 2007; Kinon et al, 2015). A permissive role of the mGlu receptor in these effects is supported by several studies where mGlu receptor positive allosteric modulators (PAMs) suppressed head twitches induced by phenethylamine hallucinogens (Benneyworth et al, 2007; Lavreysen et al, 2015; Griebel et al, 2016)
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