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.2019 Feb;236(2):821-830.
doi: 10.1007/s00213-018-5118-y. Epub 2018 Nov 17.

Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen

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Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen

Adam L Halberstadt et al. Psychopharmacology (Berl).2019 Feb.

Abstract

Background: There is evidence that mGlu2/3 receptors regulate 5-HT2A signaling, interactions that have been theorized to play a role in the antipsychotic-like effects of mGlu2/3 agonists as well as the hallucinogenic effects of 5-HT2A agonists. One approach to unraveling this interaction is through the chronic administration of agonists at the two receptors, which should influence the functional properties of the targeted receptor due to receptor downregulation or desensitization and thereby alter crosstalk between the two receptors. In this study, we investigated whether chronic treatment with the mGlu2/3 agonist LY379268 would alter the behavioral response to a phenethylamine hallucinogen, 25CN-NBOH, which acts as a selective 5-HT2A agonist.

Methods: We first conducted a dose response of 25CN-NBOH (0.1, 0.3, 1, 3, or 10 mg/kg) to confirm the effects on head-twitch response (HTR) and then blockade studies with either the M100907 (0.1 mg/kg) or SB242084 (0.1, 0.3, or 1 mg/kg) to determine the contribution of 5-HT2A and 5-HT2C to 25CN-NBOH-induced HTR, respectively. To determine whether an mGlu2/3 agonist could block 25CN-NBOH-induced HTR, mice were pretreated with vehicle or LY379268 (0.1, 1, or 10 mg/kg) prior to 25CN-NBOH, and HTR was assessed. The effects of chronic LY379268 on 5-HT2A agonist-induced HTR were evaluated by treating mice with either vehicle or LY379268 (10 mg/kg) for 21 days and measuring 25CN-NBOH-induced HTR 48 h after the final LY379268 treatment. The following day (72 h after the final LY379268 treatment), the ability of acute LY379268 to block PCP-induced locomotor activity was assessed.

Results: 25CN-NBOH dose-dependently increased the HTR, a 5-HT2A-mediated behavior, in mice. The selective 5-HT2A antagonist M100907 completely blocked the HTR induced by 25CN-NBOH, whereas the selective 5-HT2C antagonist SB242084 had no effect on the HTR. Administration of LY379268 (10 mg/kg SC) attenuated the HTR induced by 1 mg/kg 25CN-NBOH by ~ 50%. Chronic treatment (21 days) with LY379268 also attenuated the HTR response to 25CN-NBOH when tested 48 h after the last dose of LY379268. In locomotor tests, acute LY379268 significantly attenuated PCP-induced locomotor activity in the chronic vehicle treatment group; by contrast, there was only a trend for an overall interaction in the chronic LY379268 group, with LY379268 blocking the locomotor-stimulating effects of PCP only during the last 20 min.

Conclusions: These data are consistent with a functional interaction between mGlu2/3 and 5-HT2A receptors, although the specific mechanism for the interaction is not known. These data support the hypothesis that mGlu2/3 receptors play a prominent role in modulating the behavioral response to 5-HT2A receptor activation.

Keywords: 5-HT2A; Hallucinogen; Head twitch; Metabotropic glutamate receptor; Serotonin; mGlu2/3.

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Conflict of interest statement

Disclosure/Conflict of interest

Mark Geyer holds an equity interest in San Diego Instruments.

Figures

Fig. 1
Fig. 1
Effect of 25CN-NBOH on the head twitch response. Data are presented as group means±SEM. *p<0.05 significantly different from vehicle control group.
Fig. 2
Fig. 2
Effect of M100,907 and SB242084 on 25CN-NBOH-induced head twitch response. Data as presented as group means±SEM. **p<0.01, significantly different from 25CN-NBOH alone.
Fig. 3
Fig. 3
Effect of LY379268 on 25CN-NBOH-induced head twitch response (A,B). Data are presented as group means±SEM. *p<0.05 significantly different from vehicle.
Fig. 4
Fig. 4
Effect of chronic LY379268 treatment on 25CN-NBOH-induced head twitch response. HTR response 48 hours after last chronic injection LY379268. Data presented as group means±SEM. *p<0.01, significantly different from comparison group.
Fig. 5
Fig. 5
LY379268 reversal of PCP-induced hyperlocomotion in mice treated chronically with vehicle (A) or LY379268 (B). (A) Locomotor activity (distance traveled) in mice after chronic treatment with saline. (B) Locomotor activity (distance traveled) in mice after chronic treatment with LY379268. Data are presented as group means±SEM for 20-min time blocks. *p<0.05, significantly different from VEH – PCP group.
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