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Background: There is evidence that mGlu2/3 receptors regulate 5-HT 2A 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-HT 2A 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-HT 2A 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-HT 2A -mediated behavior, in mice. The selective 5-HT 2A antagonist M100907 completely blocked the HTR induced by 25CN-NBOH, whereas the selective 5-HT 2C 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-HT 2A 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-HT 2A receptor activation.

The author of this article wanted to change the Acknowledgments section to: These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran's Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding and functional data were generously.

Rationale: The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds., Objective: In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT 2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens., Methods: Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT 2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT 2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes., Results: ECPLA has high affinity for most serotonin receptors, α 2 -adrenoceptors, and D 2 -like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT 2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED 50 ) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED 50  = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED 50  = 421.7 nmol/kg) was slightly less potent than ECPLA., Conclusions: These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.