The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen
- 280 Downloads
Hallucinogenic serotonin 2A (5-HT2A) receptor partial agonists, such as (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), induce a frontal cortex-dependent head-twitch response (HTR) in rodents, a behavioral proxy of a hallucinogenic response that is blocked by 5-HT2A receptor antagonists. In addition to 5-HT2A receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT2C receptors.
We tested for involvement of 5-HT2C receptors in the HTR induced by DOI.
Comparison of 5-HT2C receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI-induced HTR in knockout mice. Also, pretreatment with either the 5-HT2C receptor antagonist SB206553 or SB242084 eradicated a twofold difference in DOI-induced HTR between the standard inbred mouse strains C57BL/6J and DBA/2J, and decreased the DOI-induced HTR by at least 50% in both strains. None of several measures of 5-HT2A receptors in frontal cortex explained the strain difference, including 5-HT2A receptor density, Gαq or Gαi/o protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2. 5-HT2C receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT2C receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI.
We conclude that the HTR to DOI in mice is strongly modulated by 5-HT2C receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT2 receptors.
KeywordsSerotonin 2A receptor (5-HT2A) Serotonin 2C receptor (5-HT2C) Hallucinogens Head-twitch response (HTR) Phospholipase C (PLC) Phospholipase A (PLA)
We thank research assistants Katherine Smith, Dongmei Li, and Jason Abramo for diligent and careful work in the laboratory. The authors report no conflicts of interest. Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # NO1MH32004 (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.
- Abramoff MD, Magelhaes PJ, Ram SJ (2004) Image processing with ImageJ. Biophotonics Int 11(7):36–42Google Scholar
- Benedetti F, Barbini B, Bernasconi A, Fulgosi MC, Colombo C, Dallaspezia S, Gavinelli C, Marino E, Pirovano A, Radaelli D, Smeraldi E (2008) Serotonin 5-HT2A receptor gene variants influence antidepressant response to repeated total sleep deprivation in bipolar depression. Prog Neuropsychopharmacol Biol Psychiatry 32:1863–1866CrossRefPubMedGoogle Scholar
- Cussac D, Newman-Tancredi A, Duqueyroix D, Pasteau V, Millan MJ (2002) Differential activation of Gq/11 and Gi(3) proteins at 5-hydroxytryptamine(2C) receptors revealed by antibody capture assays: influence of receptor reserve and relationship to agonist-directed trafficking. Mol Pharmacol 62:578–589CrossRefPubMedGoogle Scholar
- Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I (2008) Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C -VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells. Eur J Pharmacol 594:32–38CrossRefPubMedGoogle Scholar
- Dunlop J, Lock T, Jow B, Sitzia F, Grauer S, Jow F, Kramer A, Bowlby MR, Randall A, Kowal D, Gilbert A, Comery TA, Larocque J, Soloveva V, Brown J, Roncarati R (2009) Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3, 5-dihydro-5-methyl-N-3-pyridinylbenzo[1, 2-b:4, 5-b']di pyrrole-1(2H)-carboxamide). J Pharmacol Exp Ther 328:766–776CrossRefPubMedGoogle Scholar
- Fiorella D, Helsley S, Lorrain DS, Rabin RA, Winter JC (1995a) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. III: the mechanistic basis for supersensitivity to the LSD stimulus following serotonin depletion. Psychopharmacology (Berl) 121:364–372CrossRefGoogle Scholar
- Fitzgerald LW, Conklin DS, Krause CM, Marshall AP, Patterson JP, Tran DP, Iyer G, Kostich WA, Largent BL, Hartig PR (1999) High-affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidence favoring the ternary complex and two-state models of agonist action. J Neurochem 72:2127–2134CrossRefPubMedGoogle Scholar
- Freedman DX, Boggan WO (1982) Biochemical pharmacology of psychotomimetics. Springer-Verlag, BerlinGoogle Scholar
- Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221CrossRefPubMedGoogle Scholar
- Paxinos G, Watson KBJ (2004) The mouse brain in stereotaxic coordinates, 2nd edn. Elsevier Academic Press, Amsterdam, BostonGoogle Scholar
- Quednow BB, Schmechtig A, Ettinger U, Petrovsky N, Collier DA, Vollenweider FX, Wagner M, Kumari V (2009) Sensorimotor gating depends on polymorphisms of the serotonin-2A receptor and catechol-o-methyltransferase, but not on neuregulin-1 Arg38Gln genotype: a replication study. Biol Psychiatry 66(6):614–620CrossRefPubMedGoogle Scholar
- Smith RL, Barrett RJ, Sanders-Bush E (2003) Discriminative stimulus properties of 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/−)DOI] in C57BL/6J mice. Psychopharmacology (Berl) 166:61–68Google Scholar
- 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 313:536–540CrossRefPubMedGoogle Scholar