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The serotonin 5-HT2A receptor agonist TCB-2: a behavioral and neurophysiological analysis

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Abstract

Rationale

There are few reports on the high-affinity 5-HT2A agonist (4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).

Objectives

Here we provide the first behavioral and neurophysiological profile of TCB-2 in C57BL/6J mice, with direct comparisons to the 5-HT2A/2C agonist (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), in addition to determinations of 5-HT2A mediation via pretreatment with the selective 5-HT2A antagonist MDL 11,939.

Results

In a dose-dependent manner, TCB-2 induced head twitches, decreased food consumption in food-deprived mice, induced hypothermia, and increased corticosterone levels, with no effects on locomotor activity or anxiety-like behaviors in the open field. Similar effects were observed in side-by-side dose–response comparisons with DOI; although at the highest dose tested (5.0 mg/kg), TCB-2 induced significantly fewer head twitches, and a significantly enhanced hypothermic response, versus DOI. Pretreatment with MDL 11,939 blocked head twitches and temperature change following TCB-2 and DOI, confirming 5-HT2A mediation of these responses. Although MDL 11,939 pretreatment blocked DOI-induced suppression of feeding, MDL 11,939 had no effect on TCB-2-induced suppression of feeding. Previous studies show that 5-HT2A function is altered by changes in serotonin transporter (SERT) expression and function. In SERT knockout (−/−) mice, TCB-2-induced head twitches and hypothermia were greatly diminished compared to SERT wild-type (+/+) mice.

Conclusions

The current studies are important, as they are the first to assess the effects of TCB-2 in mice, and are among the first to report the behavioral and neurophysiological effects of this conformationally restricted phenethylamine analog compound, which has 65-fold greater effects on signaling via the phosphoinositide versus arachidonic acid pathways.

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Acknowledgements

The authors thank Dr. Pablo R. Moya for his assistance with this manuscript, and Su-Jan Huang and Teresa J. Tolliver for their continued assistance with animal care and genotyping. This research was supported by the NIMH Intramural Research program. All experiments adhered to the guidelines of the National Institutes of Health, and were approved by the National Institute of Mental Health Animal Care and Use Committee. The authors have nothing to disclose.

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Correspondence to Meredith A. Fox.

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This research was supported by the NIMH Intramural Research program.

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Fox, M.A., French, H.T., LaPorte, J.L. et al. The serotonin 5-HT2A receptor agonist TCB-2: a behavioral and neurophysiological analysis. Psychopharmacology 212, 13–23 (2010). https://doi.org/10.1007/s00213-009-1694-1

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