Skip to main content
Springer Nature Link
Log in

Characterization of the head-twitch response induced by hallucinogens in mice

Detection of the behavior based on the dynamics of head movement

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The head-twitch response (HTR) is a rapid side-to-side rotational head movement that occurs in rats and mice after administration of serotonergic hallucinogens and other 5-HT2A agonists. The HTR is widely used as a behavioral assay for 5-HT2A activation and to probe for interactions between the 5-HT2A receptor and other transmitter systems.

Objective

High-speed video recordings were used to analyze the head movement that occurs during head twitches in C57BL/6J mice. Experiments were also conducted in C57BL/6J mice to determine whether a head-mounted magnet and a magnetometer coil could be used to detect the HTR induced by serotonergic hallucinations based on the dynamics of the response.

Results

Head movement during the HTR was highly rhythmic and occurred within a specific frequency range (mean head movement frequency of 90.3 Hz). Head twitches produced wave-like oscillations of magnetometer coil voltage that matched the frequency of head movement during the response. The magnetometer coil detected the HTR induced by the serotonergic hallucinogens 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25, 0.5, and 1.0 mg/kg, i.p.) and lysergic acid diethylamide (LSD; 0.05, 0.1, 0.2, and 0.4 mg/kg, i.p.) with extremely high sensitivity and specificity. Magnetometer coil recordings demonstrated that the non-hallucinogenic compounds (+)-amphetamine (2.5 and 5.0 mg/kg, i.p.) and lisuride (0.8, 1.6, and 3.2 mg/kg, i.p.) did not induce the HTR.

Conclusions

These studies confirm that a magnetometer coil can be used to detect the HTR induced by hallucinogens. The use of magnetometer-based HTR detection provides a high-throughput, semi-automated assay for this behavior, and offers several advantages over traditional assessment methods.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Abbas AI, Yadav PN, Yao WD, Arbuckle MI, Grant SG, Caron MG, Roth BL (2009) PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors. J Neurosci 29:7124–7136

    Article  PubMed  CAS  Google Scholar 

  • Adams LM, Geyer MA (1985) Patterns of exploration in rats distinguish lisuride from lysergic acid diethylamide. Pharmacol Biochem Behav 23:461–468

    Article  PubMed  CAS  Google Scholar 

  • Arnt J, Hyttel J (1989) Facilitation of 8-OHDPAT-induced forepaw treading of rats by the 5-HT2 agonist DOI. Eur J Pharmacol 161:45–51

    Article  PubMed  CAS  Google Scholar 

  • Bedard P, Pycock CJ (1977) “Wet-dog” shake behaviour in the rat: a possible quantitative model of central 5-hydroxytryptamine activity. Neuropharmacology 16:663–670

    Article  PubMed  CAS  Google Scholar 

  • Benneyworth MA, Xiang Z, Smith RL, Garcia EE, Conn PJ, Sanders-Bush E (2007) A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol Pharmacol 72:477–484

    Article  PubMed  CAS  Google Scholar 

  • Beraneck M, McKee JL, Aleisa M, Cullen KE (2008) Asymmetric recovery in cerebellar-deficient mice following unilateral labyrinthectomy. J Neurophysiol 100:945–958

    Article  PubMed  CAS  Google Scholar 

  • Canal CE, Morgan D (2012) Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Anal 4:556–576

    Google Scholar 

  • Canal CE, Olaghere da Silva UB, Gresch PJ, Watt EE, Sanders-Bush E, Airey DC (2010) The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen. Psychopharmacology 209:163–174

    Article  PubMed  CAS  Google Scholar 

  • Corne SJ, Pickering RW (1967) A possible correlation between drug-induced hallucinations in man and a behavioural response in mice. Psychopharmacologia 11:65–78

    Article  PubMed  CAS  Google Scholar 

  • Corne SJ, Pickering RW, Warnet BT (1963) A method for assessing the effects of drugs on the central actions of 5-hydroxytryptamine. Br J Pharmacol Chemother 20:106–120

    Article  PubMed  CAS  Google Scholar 

  • Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I (2008) Agonist-directed trafficking of signaling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells. Eur J Pharmacol 594:32–38

    Article  PubMed  CAS  Google Scholar 

  • Darmani NA (1998) The silent and selective 5-HT1A antagonist, WAY 100635, produces via an indirect mechanism, a 5-HT2A receptor-mediated behaviour in mice during the day but not at night. J Neural Transm 105:635–643

    Article  PubMed  CAS  Google Scholar 

  • Darmani NA, Martin BR, Pandey U, Glennon RA (1990) Do functional relationships exist between 5-HT1A and 5-HT2 receptors? Pharmacol Biochem Behav 36:901–906

    Article  PubMed  CAS  Google Scholar 

  • Darmani NA, Mock OB, Towns LC, Gerdes CF (1994) The head twitch response in the least shrew (Cryptotis parva) is a 5-HT2- and not a 5-HT1C-mediated phenomenon. Pharmacol Biochem Behav 48:383–396

    Article  PubMed  CAS  Google Scholar 

  • Darmani NA, Pandya DK (2000) Involvement of other neurotransmitters in behaviors induced by the cannabinoid CB1 receptor antagonist SR 141716A in naive mice. J Neural Transm 107:931–945

    Article  PubMed  CAS  Google Scholar 

  • Dickerson AK, Mills ZG, Hu DL (2012) Wet mammals shake at tuned frequencies to dry. J R Soc Interface 9:3208–3218

    Google Scholar 

  • Dursun SM, Handley SL (1996) Similarities in the pharmacology of spontaneous and DOI-induced head shakes suggest 5-HT2A receptors are active under physiological conditions. Psychopharmacology 128:198–205

    Article  PubMed  CAS  Google Scholar 

  • Egashira N, Shirakawa A, Okuno R, Mishima K, Iwasaki K, Oishi R, Fujiwara M (2011) Role of endocannabinoid and glutamatergic systems in DOI-induced head-twitch response in mice. Pharmacol Biochem Behav 99:52–58

    Article  PubMed  CAS  Google Scholar 

  • Fantegrossi WE, Harrington AW, Eckler JR, Arshad S, Rabin RA, Winter JC, Coop A, Rice KC, Woods JH (2005) Hallucinogen-like actions of 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) in mice and rats. Psychopharmacology 181:496–503

    Article  PubMed  CAS  Google Scholar 

  • Fantegrossi WE, Harrington AW, Kiessel CL, Eckler JR, Rabin RA, Winter JC, Coop A, Rice KC, Woods JH (2006) Hallucinogen-like actions of 5-methoxy-N, N-diisopropyltryptamine in mice and rats. Pharmacol Biochem Behav 83:122–129

    Article  PubMed  CAS  Google Scholar 

  • Fantegrossi WE, Reissig CJ, Katz EB, Yarosh HL, Rice KC, Winter JC (2008) Hallucinogen-like effects of N, N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents. Pharmacol Biochem Behav 88:358–365

    Article  PubMed  CAS  Google Scholar 

  • Fantegrossi WE, Simoneau J, Cohen MS, Zimmerman SM, Henson CM, Rice KC, Woods JH (2010) Interaction of 5-HT2A and 5-HT2C receptors in R(−)-2,5-dimethoxy-4-iodoamphetamine-elicited head twitch behavior in mice. J Pharmacol Exp Ther 335:728–734

    Article  PubMed  CAS  Google Scholar 

  • Fone KC, Johnson JV, Bennett GW, Marsden CA (1989) Involvement of 5-HT2 receptors in the behaviours produced by intrathecal administration of selected 5-HT agonists and the TRH analogue (CG 3509) to rats. Br J Pharmacol 96:599–608

    Article  PubMed  CAS  Google Scholar 

  • Fox MA, Stein AR, French HT, Murphy DL (2010) Functional interactions between 5-HT2A and presynaptic 5-HT1A receptor-based responses in mice genetically deficient in the serotonin 5-HT transporter (SERT). Br J Pharmacol 159:879–887

    Article  PubMed  CAS  Google Scholar 

  • Garcia EE, Smith RL, Sanders-Bush E (2007) Role of Gq protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. Neuropharmacology 52:1671–1677

    Article  PubMed  CAS  Google Scholar 

  • Gerber R, Barbaz BJ, Martin LL, Neale R, Williams M, Liebman JF (1985) Antagonism of l-5-hydroxytryptophan-induced head-twitching in rats by lisuride: a mixed 5-hydroxytryptamine agonist–antagonist? Neurosci Lett 60:207–213

    Article  PubMed  CAS  Google Scholar 

  • Gewirtz JC, Marek GJ (2000) Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23:569–576

    Article  PubMed  CAS  Google Scholar 

  • González-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-HT2A receptor-mediated signaling pathways to affect behavior. Neuron 53:439–452

    Article  PubMed  Google Scholar 

  • González-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

    PubMed  Google Scholar 

  • Halberstadt AL, Geyer MA (2010) LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor. Psychopharmacology 208:179–189

    Article  PubMed  CAS  Google Scholar 

  • Halberstadt AL, Geyer MA (2011) Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 61:364–381

    Article  PubMed  CAS  Google Scholar 

  • Halberstadt AL, Koedood L, Powell SB, Geyer MA (2011) Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice. J Psychopharmacol 25:1548–1561

    Article  PubMed  CAS  Google Scholar 

  • Handley SL, Dursun SM (1992) Serotonin and Tourette’s syndrome: movements such as head-shakes and wet-dog shakes may model human tics. Adv Biosci 85:235–253

    CAS  Google Scholar 

  • Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, Matos RC, Tran TB, Whaley R, Glennon RA, Hert J, Thomas KL, Edwards DD, Shoichet BK, Roth BL (2009) Predicting new molecular targets for known drugs. Nature 462:175–181

    Article  PubMed  CAS  Google Scholar 

  • Klein AB, Santini MA, Aznar S, Knudsen GM, Rios M (2010) Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice. Neuroscience 169:1007–1016

    Article  PubMed  CAS  Google Scholar 

  • Kłodzinska A, Bijak M, Tokarski K, Pilc A (2002) Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice. Pharmacol Biochem Behav 73:327–332

    Article  PubMed  Google Scholar 

  • Lambe EK, Aghajanian GK (2007) Prefrontal cortical network activity: opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation. Neuroscience 145:900–910

    Article  PubMed  CAS  Google Scholar 

  • Lucki I, Minugh-Purvis N (1987) Serotonin-induced head shaking behavior in rats does not involve receptors located in the frontal cortex. Brain Res 42:403–406

    Article  Google Scholar 

  • Marek GJ (2003) Behavioral evidence for mu-opioid and 5-HT2A receptor interactions. Eur J Pharmacol 474:77–83

    Article  PubMed  CAS  Google Scholar 

  • Marek GJ (2009) Activation of adenosine1 (A1) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats. Neuropharmacology 56:1082–1087

    Article  PubMed  CAS  Google Scholar 

  • Mason HC, Mason BT, Moos WS (1955) Total-head (brain) X irradiation of mice and primary factors involved. Br J Radiology 28:495–507

    Article  CAS  Google Scholar 

  • Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J (2011a) Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett 493:76–79

    Article  PubMed  CAS  Google Scholar 

  • Moreno JL, Kurita M, Holloway T, López J, Cadagan R, Martínez-Sobrido L, García-Sastre A, González-Maeso J (2011b) Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT2A and mGlu2 receptors in the adult offspring. J Neurosci 31:1863–1872

    Article  PubMed  CAS  Google Scholar 

  • Nabeshima T, Ishikawa K, Yamaguchi K, Furukawa H, Kameyama T (1987) Phencyclidine-induced head-twitch responses as 5-HT2 receptor-mediated behavior in rats. Neurosci Lett 76:335–338

    Article  PubMed  CAS  Google Scholar 

  • Neumeyer JL, Kula NS, Bergman J, Baldessarini RJ (2003) Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines. Eur J Pharmacol 474:137–140

    Article  PubMed  CAS  Google Scholar 

  • Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181

    Article  PubMed  CAS  Google Scholar 

  • Richmond FJ, Loeb GE (1992) Electromyographic studies of neck muscles in the intact cat: II. Reflexes evoked by muscle nerve stimulation. Exp Brain Res 88:59–66

    Article  PubMed  CAS  Google Scholar 

  • Schindler EA, Dave KD, Smolock EM, Aloyo VJ, Harvey JA (2012) Serotonergic and dopaminergic distinctions in the behavioral pharmacology of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Pharmacol Biochem Behav 101:69–76

    Article  PubMed  CAS  Google Scholar 

  • Schmid CL, Bohn LM (2010) Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a ß-arrestin2/Src/Akt signaling complex in vivo. J Neurosci 30:13513–13524

    Article  PubMed  CAS  Google Scholar 

  • 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 USA 105:1079–1084

    Article  PubMed  CAS  Google Scholar 

  • Schreiber R, Brocco M, Audinot V, Gobert A, Veiga S, Millan MJ (1995) (1-(2,5-Dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. J Pharmacol Exp Ther 273:101–112

    PubMed  CAS  Google Scholar 

  • Siegel RK, Lee MA, Jarvik ME (1972) A device for analyzing drug-induced responses in freely moving mice. J Exp Anal Behav 18:415–418

    Article  PubMed  CAS  Google Scholar 

  • Silva MT, Calil HM (1975) Screening hallucinogenic drugs: systematic study of three behavioral tests. Psychopharmacologia 42:163–171

    Article  PubMed  CAS  Google Scholar 

  • Starr BS, Starr MS (1986) Grooming in the mouse is stimulated by the dopamine D1 agonist SKF 38393 and by low doses of the D1 antagonist SCH 23390, but is inhibited by dopamine D2 agonists, D2 antagonists and high doses of SCH 23390. Pharmacol Biochem Behav 24:837–839

    Article  PubMed  CAS  Google Scholar 

  • Tadano T, Hozumi M, Satoh N, Oka R, Hishinuma T, Mizugaki M, Arai Y, Yasuhara H, Kinemuchi H, Niijima F, Nakagawasai O, Tan-no K, Kisara K (2001) Central serotonergic mechanisms on head twitch response induced by benzodiazepine receptor agonists. Pharmacology 62:157–162

    Article  PubMed  CAS  Google Scholar 

  • Watson NV, Gorzalka BB (1992) Concurrent wet dog shaking and inhibition of male rat copulation after ventromedial brainstem injection of the 5-HT2 agonist DOI. Neurosci Lett 141:25–29

    Article  PubMed  CAS  Google Scholar 

  • Weiner DM, Burstein ES, Nash N, Croston GE, Currier EA, Vanover KE, Harvey SC, Donohue E, Hansen HC, Andersson CM, Spalding TA, Gibson DF, Krebs-Thomson K, Powell SB, Geyer MA, Hacksell U, Brann MR (2001) 5-Hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 299:268–276

    PubMed  CAS  Google Scholar 

  • Wentzel SE, Konow N, German RZ (2011) Regional differences in hyoid muscle activity and length dynamics during mammalian head shaking. J Exp Zool A Ecol Genet Physiol 315:111–120

    Article  PubMed  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Yamamoto T, Ueki S (1975) Behavioral effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in rats and mice. Eur J Pharmacol 32:156–162

    Article  PubMed  CAS  Google Scholar 

  • Young JW, Goey AK, Minassian A, Perry W, Paulus MP, Geyer MA (2010) GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior. Psychopharmacology 208:443–454

    Article  PubMed  CAS  Google Scholar 

  • Zhang C, Marek GJ (2008) AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes. Prog Neuropsychopharmacol Biol Psychiatry 32:62–71

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by National Institute on Drug Abuse Awards R01 DA002925 and F32 DA025412, and the Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0804, USA

    Adam L. Halberstadt & Mark A. Geyer

  2. Research Service, VA San Diego Healthcare System, San Diego, CA, USA

    Mark A. Geyer

Authors
  1. Adam L. Halberstadt
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Mark A. Geyer
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Adam L. Halberstadt.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. S1

Magnetometer coil responses induced by grooming behavior. a Voltage response of the magnetometer coil during grooming. b Periodogram showing the spectral density of the magnetometer response to grooming (TIFF 929 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Halberstadt, A.L., Geyer, M.A. Characterization of the head-twitch response induced by hallucinogens in mice. Psychopharmacology 227, 727–739 (2013). https://doi.org/10.1007/s00213-013-3006-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3006-z

Keywords

pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy