Metabotropic Glutamate2 Receptors Play a Key Role in Modulating Head Twitches Induced by a Serotonergic Hallucinogen in Mice
Mark J. Benvenga, Stephen F. Chaney, Melvyn Baez, Thomas C. Britton, William J. Hornback, James A. Monn, Gerard J. Marek
Frontiers in Pharmacology March 15, 2018 DOI: 10.3389/fphar.2018.00208 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | mGlu2 and mGlu3 receptor knockout mice and age-matched ICR (CD-1) wild type mice |
| Interventions | DOI LY379268 CBiPES LY341495 |
| Dose | DOI 3 mg/kg; LY341495 10 mg/kg; DOI dose 10-fold higher than peak effective dose in WT or mGlu3 KO mice (exact value not stated) |
| Measures | head twitch response (HTR) |
| Topics | Serotonin |
| Citations | 26 |
| Key findings | Constitutive deletion of the mGlu2 gene nearly eliminated DOI-induced head twitches in mice, with DOI failing to produce significant head twitches at a dose 10-fold higher than the peak effective dose in wild type or mGlu3 knockout mice. The mGlu2/3 agonist LY379268 and the mGlu2 positive allosteric modulator CBiPES blocked DOI-induced head twitches, while the antagonist LY341495 increased them. The authors argue these results support a critical autoreceptor function for mGlu2 receptors in modulating prefrontal cortical 5-HT2A receptor activity. |
Abstract
There is substantial evidence that glutamate can modulate the effects of 5-hydroxytryptamine2A (5-HT2A) receptor activation through stimulation of metabotropic glutamate 2/3 (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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 16
- Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism Science Advances November 17, 2021
- Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment Neuropharmacology January 13, 2023
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo Scientific Reports October 3, 2019
- Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics. Molecular Psychiatry September 1, 2023
and 11 more in the library
Cites 16
- Reversal of Phencyclidine Effects by a Group II Metabotropic Glutamate Receptor Agonist in Rats Science August 28, 1998
- Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution. Current Biology April 13, 2016
- Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis Schizophrenia Bulletin October 6, 2012
- DOI-Induced Activation of the Cortex: Dependence on 5-HT2AHeteroceptors on Thalamocortical Glutamatergic Neurons Journal of Neuroscience December 1, 2000
- Increased thalamic resting‐state connectivity as a core driver of LSD‐induced hallucinations Acta Psychiatrica Scandinavica September 21, 2017
and 11 more in the library