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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References
Aulakh CS, Mazzola-Pomietto P, Hulihan-Giblin BA, Murphy DL (1995) Lack of cross-tolerance for hypophagia induced by DOI versus m-CPP suggests separate mediation by 5-HT2A and 5-HT2C receptors, respectively. Neuropsychopharmacology 13:1–8
Basselin M, Fox MA, Chang L, Bell JM, Greenstein D, Chen M, Murphy DL, Rapoport SI (2009) Imaging elevated brain arachidonic acid signaling in unanesthetized serotonin transporter (5-HTT)-deficient mice. Neuropsychopharmacology 34:1695–1709
Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mossner R, Westphal H, Lesch KP (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655
Bill DJ, Knight M, Forster EA, Fletcher A (1991) Direct evidence for an important species difference in the mechanism of 8-OH-DPAT-induced hypothermia. Br J Pharmacol 103:1857–1864
Chang CW, Poteet E, Schetz JA, Gumus ZH, Weinstein H (2009) Towards a quantitative representation of the cell signaling mechanisms of hallucinogens: measurement and mathematical modeling of 5-HT1A and 5-HT2A receptor-mediated ERK1/2 activation. Neuropharmacology 56(Suppl 1):213–225
Faure C, Mnie-Filali O, Scarna H, Debonnel G, Haddjeri N (2006) Effects of the 5-HT7 receptor antagonist SB-269970 on rat hormonal and temperature responses to the 5-HT1A/7 receptor agonist 8-OH-DPAT. Neurosci Lett 404:122–126
Fox MA, Jensen CL, French HT, Stein AR, Huang SJ, Tolliver TJ, Murphy DL (2008) Neurochemical, behavioral, and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice. Psychopharmacology (Berl) 201:203–218
Geyer MA, Vollenweider FX (2008) Serotonin research: contributions to understanding psychoses. Trends Pharmacol Sci 29:445–453
Gonzalez-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R, Gingrich JA, Sealfon SC (2003) Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci 23:8836–8843
Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA (2007) Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53:439–452
Goodwin GM, De Souza RJ, Green AR (1985) The pharmacology of the hypothermic response in mice to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). A model of presynaptic 5-HT1 function. Neuropharmacology 24:1187–1194
Guscott MR, Egan E, Cook GP, Stanton JA, Beer MS, Rosahl TW, Hartmann S, Kulagowski J, McAllister G, Fone KC, Hutson PH (2003) The hypothermic effect of 5-CT in mice is mediated through the 5-HT7 receptor. Neuropharmacology 44:1031–1037
Hedlund PB, Danielson PE, Thomas EA, Slanina K, Carson MJ, Sutcliffe JG (2003) No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Proc Natl Acad Sci U S A 100:1375–1380
Heisler LK, Pronchuk N, Nonogaki K, Zhou L, Raber J, Tung L, Yeo GS, O'Rahilly S, Colmers WF, Elmquist JK, Tecott LH (2007) Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation. J Neurosci 27:6956–6964
Hemrick-Luecke SK, Evans DC (2002) Comparison of the potency of MDL 100, 907 and SB 242084 in blocking the serotonin (5-HT)(2) receptor agonist-induced increases in rat serum corticosterone concentrations: evidence for 5-HT(2A) receptor mediation of the HPA axis. Neuropharmacology 42:162–169
Hollister LE, Macnicol MF, Gillespie HK (1969) An hallucinogenic amphetamine analog (DOM) in man. Psychopharmacologia 14:62–73
Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815–826
Jennings KA, Sheward WJ, Harmar AJ, Sharp T (2008) Evidence that genetic variation in 5-HT transporter expression is linked to changes in 5-HT2A receptor function. Neuropharmacology 54:776–783
Krall CM, Richards JB, Rabin RA, Winter JC (2008) Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice. Pharmacol Biochem Behav 88:349–357
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531
Li Q, Wichems CH, Ma L, Van de Kar LD, Garcia F, Murphy DL (2003) Brain region-specific alterations of 5-HT2A and 5-HT2C receptors in serotonin transporter knockout mice. J Neurochem 84:1256–1265
Mazzola-Pomietto P, Aulakh CS, Wozniak KM, Hill JL, Murphy DL (1995) Evidence that 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors. Psychopharmacology (Berl) 117:193–199
McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE (2006) 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. J Med Chem 49:5794–5803
Morishima Y, Shibano T (1995) Evidence that 5-HT2A receptors are not involved in 5-HT-mediated thermoregulation in mice. Pharmacol Biochem Behav 52:755–758
Moya PR, Berg KA, Gutierrez-Hernandez MA, Saez-Briones P, Reyes-Parada M, Cassels BK, Clarke WP (2007) Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors. J Pharmacol Exp Ther 321:1054–1061
Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181
Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, Ginovart N, Tharmalingam S, Masellis M, Houle S, Meyer JH (2007) Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study. Biol Psychiatry 62:327–331
Qu Y, Villacreses N, Murphy DL, Rapoport SI (2005) 5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter. Psychopharmacology (Berl) 180:12–20
Rioux A, Fabre V, Lesch KP, Moessner R, Murphy DL, Lanfumey L, Hamon M, Martres MP (1999) Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter. Neurosci Lett 262:113–116
Salmi P, Ahlenius S (1998) Evidence for functional interactions between 5-HT1A and 5-HT2A receptors in rat thermoregulatory mechanisms. Pharmacol Toxicol 82:122–127
Schechter LE, Simansky KJ (1988) 1-(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerts an anorexic action that is blocked by 5-HT2 antagonists in rats. Psychopharmacology (Berl) 94:342–346
Schmid CL, Raehal KM, Bohn LM (2008) Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo. Proc Natl Acad Sci U S A 105:1079–1084
Snyder SH, Faillace LA, Weingartner H (1968) DOM (STP), a new hallucinogenic drug, and DOET: effects in normal subjects. Am J Psychiatry 125:113–120
Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D (1995) Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374:542–546
Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320:1–13
Van de Kar LD, Javed A, Zhang Y, Serres F, Raap DK, Gray TS (2001) 5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells. J Neurosci 21:3572–3579
Vickers SP, Dourish CT, Kennett GA (2001) Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors. Neuropharmacology 41:200–209
Weingartner H, Snyder SH, Faillace LA (1971) DOM (STP), a new hallucinogenic drug: specific perceptual changes. J Clin Pharmacol New Drugs 11:103–111
Weisstaub NV, Zhou M, Lira A, Lambe E, Gonzalez-Maeso J, Hornung JP, Sibille E, Underwood M, Itohara S, Dauer WT, Ansorge MS, Morelli E, Mann JJ, Toth M, Aghajanian G, Sealfon SC, Hen R, Gingrich JA (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313:536–540
Wendland JR, Moya PR, Kruse MR, Ren-Patterson RF, Jensen CL, Timpano KR, Murphy DL (2008) A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder. Hum Mol Genet 17:717–723
Willins DL, Meltzer HY (1997) Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J Pharmacol Exp Ther 282:699–706
Yamada J, Sugimoto Y, Horisaka K (1995) Serotonin2 (5-HT2) receptor agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibits chlorpromazine- and haloperidol-induced hypothermia in mice. Biol Pharm Bull 18:1580–1583
Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD (2008) Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency. J Pharmacol Exp Ther 327:316–323
Zhang Y, Damjanoska KJ, Carrasco GA, Dudas B, D'Souza DN, Tetzlaff J, Garcia F, Hanley NR, Scripathirathan K, Petersen BR, Gray TS, Battaglia G, Muma NA, Van de Kar LD (2002) Evidence that 5-HT2A receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (-)DOI. J Neurosci 22:9635–9642
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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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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DOI: https://doi.org/10.1007/s00213-009-1694-1