Skip to main content
SpringerLink
Log in

Role of atypical opiates in OCD. Experimental approach through the study of 5-HT2A/C receptor-mediated behavior

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

Abstract

Rationale

The selective serotonin (5-HT) reuptake inhibitors (SSRIs) represent the first-line pharmacotherapy for obsessive–compulsive disorder (OCD), and atypical antipsychotic drugs, which block 5-HT2A receptors, are used in augmentation strategies. Opiate drugs are also effective in treatment-refractory OCD and Tourette syndrome. The 5-HT2A-related behavior (i.e., head twitch) has been related with tics, stereotypes, and compulsive symptoms observed in Tourette syndrome and OCD.

Objectives

The aim of this study was to explore whether 5-HT2A-related behavior is affected by atypical opiate drugs.

Materials and methods

Head-twitch response was induced in mice by administration of either 5-hydroxytryptophan (5-HTP) or the 5-HT2A/C agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Dose–effect curves of atypical opiate drugs [(±)-tramadol, (−)-methadone and levorphanol], morphine, and other psychoactive drugs (fluvoxamine, desipramine, nefazodone, and clozapine) were performed. Opioid mechanisms were investigated by administration of naloxone.

Results

All the opiates tested reduced both 5-HTP and DOI-induced behavior in a naloxone-reversible fashion, atypical opiates being more effective. The effects of the other drugs depended on the protocol, clozapine being the most effective.

Conclusions

Combined 5-HT and opioid properties result in a greater efficacy in antagonizing 5-HT2A-related behavior. These results provide behavioral evidence to support convergent effects of the 5-HT and opioid systems in discrete brain areas, offering the potential for therapeutic advances in the management of refractory stereotypes and compulsive behaviors.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  • Adams KH, Hansen ES, Pinborg LH, Hasselbalch SG, Svarer C, Holm S, Bolwig TG, Knudsen GM (2005) Patients with obsessive–compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei. Int J Neuropsychopharmacol 8:391–401

    Article  PubMed  CAS  Google Scholar 

  • Atmaca M, Kuloglu M, Tezcan E, Gecici O (2002) Quetiapine augmentation in patients with treatment resistant obsessive–compulsive disorder: a single-blind, placebo-controlled study. Int Clin Psychopharmacol 17:115–119

    Article  PubMed  CAS  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  PubMed  CAS  Google Scholar 

  • Basselin M, Chang L, Seemann R, Bell JM, Rapoport SI (2005) Chronic lithium administration to rats selectively modifies 5-HT2A/2C receptor-mediated brain signaling via arachidonic acid. Neuropsychopharmacology 30:461–472

    Article  PubMed  CAS  Google Scholar 

  • Bergqvist PB, Dong J, Blier P (1999) Effect of atypical antipsychotic drugs on 5-HT2 receptors in the rat orbito-frontal cortex: an in vivo electrophysiological study. Psychopharmacology (Berl) 143:89–96

    Article  CAS  Google Scholar 

  • Berney A, Sookman D, Leyton M, Young SN, Benkelfat C (2006) Lack of effects on core obsessive–compulsive symptoms of tryptophan depletion during symptom provocation in remitted obsessive–compulsive disorder patients. Biol Psychiatry 59:853–857

    Article  PubMed  CAS  Google Scholar 

  • Codd EE, Shank RP, Schupsky JJ, Raffa RB (1995) Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 274:1263–1270

    PubMed  CAS  Google Scholar 

  • Corne SJ, Pickering R, Warner BJ (1963) A method for assessing the effect of drugs on the central actions of drugs on the central action of 5-hydroxytriptamine. Br J Pharmacol 20:106–120

    CAS  Google Scholar 

  • Darmani NA, Gerdes CF (1995) Temporal differential adaptation of head-twitch and ear-scratch responses following administration of challenge doses of DOI. Pharmacol Biochem Behav 50:545–550

    Article  PubMed  CAS  Google Scholar 

  • Darmani NA, Martin BR, Pandey U, Glennon RA (1990) Pharmacological characterization of ear-scratch response in mice as a behavioral model for selective 5-HT2-receptor agonists and evidence for 5-HT1B- and 5-HT2-receptor interactions. Pharmacol Biochem Behav 37:95–99

    Article  PubMed  CAS  Google Scholar 

  • De Montis GM, Devoto P, Tagliamonte A (1982) Possible antidepressant activity of methadone. Eur J Pharmacol 79:145–146

    Article  PubMed  Google Scholar 

  • Delgado PL, Moreno FA (1998) Hallucinogens, serotonin and obsessive–compulsive disorder. J Psychoact Drugs 30:359–366

    CAS  Google Scholar 

  • Dougherty DD, Rauch SL, Jenike MA (2004) Pharmacotherapy for obsessive–compulsive disorder. J Clin Psychol 60:1195–1202

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Evenden JL, Ryan CN (1999) The pharmacology of impulsive behaviour in rats VI: the effects of ethanol and selective serotonergic drugs on response choice with varying delays of reinforcement. Psychopharmacology (Berl) 146:413–421

    Article  CAS  Google Scholar 

  • Fanelli J, Montgomery C (1998) Use of the analgesic tramadol in antidepressant potentiation. Psychopharmacol Bull 32:442

    Google Scholar 

  • Friedlander L, Desrocher M (2006) Neuroimaging studies of obsessive–compulsive disorder in adults and children. Clin Psychol Rev 26:32–49

    Article  PubMed  Google Scholar 

  • Gaynor CM, Handley SL (2001) Effects of nicotine on head-shakes and tryptophan metabolites. Psychopharmacology (Berl) 153:327–333

    Article  CAS  Google Scholar 

  • Gessner PK, Page IH (1962) Behavioral effects of 5-methoxy-N,N dimethyltryptamine, other tryptamines and L.S.D. Am J Physiol 203:167

    CAS  Google Scholar 

  • Goldsmith TB, Shapira NA, Keck PE, Jr. (1999) Rapid remission of OCD with tramadol hydrochloride. Am J Psychiatry 156:660–661

    PubMed  CAS  Google Scholar 

  • Graybiel AM, Canales JJ (2001) The neurobiology of repetitive behaviors: clues to the neurobiology of Tourette syndrome. Adv Neurol 85:123–131

    PubMed  CAS  Google Scholar 

  • Hayslett RL, Tizabi Y (2005) Effects of donepezil, nicotine and haloperidol on the central serotonergic system in mice: implications for Tourette’s syndrome. Pharmacol Biochem Behav 81:879–886

    Article  PubMed  CAS  Google Scholar 

  • Hollander E, Baldini Rossi N, Sood E, Pallanti S (2003) Risperidone augmentation in treatment-resistant obsessive–compulsive disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol 6:397–401

    Article  PubMed  CAS  Google Scholar 

  • Hopwood SE, Owesson CA, Callado LF, McLaughlin DP, Stamford JA (2001) Effects of chronic tramadol on pre- and post-synaptic measures of monoamine function. J Psychopharmacol 15:147–153

    Article  PubMed  CAS  Google Scholar 

  • Ichikawa J, Meltzer HY (1995) DOI, a 5-HT2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum. Brain Res 698:204–208

    Article  PubMed  CAS  Google Scholar 

  • Insel TR, Pickar D (1983) Naloxone administration in obsessive–compulsive disorder: report of two cases. Am J Psychiatry 140:1219–1220

    PubMed  CAS  Google Scholar 

  • Iwarson K, Lindberg L, Waller T (1994) Common non-surgical techniques and procedures. In: Svendsen P, Hau J (eds) Handbook of laboratory animal science. Selection and handling of animals in biomedical research. CRC, Boca Raton (Florida), pp 229–272

    Google Scholar 

  • Karno M, Golding JM, Sorenson SB, Burnam MA (1988) The epidemiology of obsessive–compulsive disorder in five US communities. Arch Gen Psychiatry 45:1094–1099

    PubMed  CAS  Google Scholar 

  • Kawakami Y, Kitamura Y, Araki H, Kitagawa K, Suemaru K, Shibata K, Gomita Y (2005) Effects of monoamine reuptake inhibitors on wet-dog shakes mediated by 5-HT2A receptors in ACTH-treated rats. Pharmacol Biochem Behav 81:65–70

    Article  PubMed  CAS  Google Scholar 

  • Kennett GA, Lightowler S, de Biasi V, Stevens NC, Wood MD, Tulloch IF, Blackburn TP (1994a) Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function. Neuropharmacology 33:1581–1588

    Article  CAS  Google Scholar 

  • Kennett GA, Wood MD, Glen A, Grewal S, Forbes I, Gadre A, Blackburn TP (1994b) In vivo properties of SB 200646A, a 5-HT2C/2B receptor antagonist. Br J Pharmacol 111:797–802

    CAS  Google Scholar 

  • Kent JM (2000) SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 355:911–918

    Article  PubMed  CAS  Google Scholar 

  • Keuler DJ, Altemus M, Michelson D, Greenberg B, Murphy DL (1996) Behavioral effects of naloxone infusion in obsessive–compulsive disorder. Biol Psychiatry 40:154–156

    Article  PubMed  CAS  Google Scholar 

  • Khanna S, John JP, Reddy LP (2001) Neuroendocrine and behavioral responses to mCPP in obsessive–compulsive disorder. Psychoneuroendocrinology 26:209–223

    Article  PubMed  CAS  Google Scholar 

  • Khazaal Y, Krenz S, Benmebarek M, Zullino DF (2006) Worsening of obsessive-compulsive symptoms under methadone tapering. Prog Neuropsychopharmacol Biol Psychiatry 30:30(7):1350–1352 (originally published online 21 April 2006 at http://www.sciencedirect.com)

    Google Scholar 

  • Kleven MS, Assie MB, Koek W (1997) Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT(2A/2C) antagonist anxiolytics. II. Drug discrimination and behavioral observation studies in rats. J Pharmacol Exp Ther 282:747–759

    PubMed  CAS  Google Scholar 

  • Koran LM, Aboujaoude E, Bullock KD, Franz B, Gamel N, Elliott M (2005) Double-blind treatment with oral morphine in treatment-resistant obsessive–compulsive disorder. J Clin Psychiatry 66:353–359

    Article  PubMed  CAS  Google Scholar 

  • Koskinen T, Haapalinna A, Sirvio J (2003) Alpha-adrenoceptor-mediated modulation of 5-HT2 receptor agonist induced impulsive responding in a 5-choice serial reaction time task. Pharmacol Toxicol 92:214–225

    Article  PubMed  CAS  Google Scholar 

  • Kraepelin E (1921) Manic-depressive insanity and Paranoia. E&S Livingstone, Edinburgh.

  • Kurlan R, Majumdar L, Deeley C, Mudholkar GS, Plumb S, Como PG (1991) A controlled trial of propoxyphene and naltrexone in patients with Tourette’s syndrome. Ann Neurol 30:19–23

    Article  PubMed  CAS  Google Scholar 

  • Leckman JF, Walker DE, Goodman WK, Pauls DL, Cohen DJ (1994) “Just right” perceptions associated with compulsive behavior in Tourette’s syndrome. Am J Psychiatry 151:675–680

    PubMed  CAS  Google Scholar 

  • Leysen JE (2004) 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord 3:11–26

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Ibor Alcocer MI, Ortiz Alonso T, Encinas Mejias M, Fernandez A, Maestu F, Lopez-Ibor Alino JJ (2000) New advances in neuroimaging in the diagnosis of obsessive–compulsive disorder. Actas Esp Psiquiatr 28:304–310

    PubMed  CAS  Google Scholar 

  • Mangold DL, Peyrot M, Giggey P, Wand GS (2000) Endogenous opioid activity is associated with obsessive–compulsive symptomology in individuals with a family history of alcoholism. Neuropsychopharmacology 22:595–607

    Article  PubMed  CAS  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, Aghajanian GK (1998a) 5-Hydroxytryptamine-induced excitatory postsynaptic currents in neocortical layer V pyramidal cells: suppression by mu-opiate receptor activation. Neuroscience 86:485–497

    Article  CAS  Google Scholar 

  • Marek GJ, Aghajanian GK (1998b) The electrophysiology of prefrontal serotonin systems: therapeutic implications for mood and psychosis. Biol Psychiatry 44:1118–1127

    Article  CAS  Google Scholar 

  • Marek GJ, Carpenter LL, McDougle CJ, Price LH (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28:402–412

    Article  PubMed  CAS  Google Scholar 

  • McConville BJ, Norman AB, Fogelson MH, Erenberg G (1994) Sequential use of opioid antagonists and agonists in Tourette’s syndrome. Lancet 343:601

    Article  PubMed  CAS  Google Scholar 

  • Meuldijk R, Colon EJ (1992) Methadone treatment of Tourette’s disorder. Am J Psychiatry 149:139–140

    PubMed  CAS  Google Scholar 

  • Mink JW (2001) Neurobiology of basal ganglia circuits in Tourette syndrome: faulty inhibition of unwanted motor patterns? Adv Neurol 85:113–122

    PubMed  CAS  Google Scholar 

  • Nurnberg HG, Keith SJ, Paxton DM (1997) Consideration of the relevance of ethological animal models for human repetitive behavioral spectrum disorders. Biol Psychiatry 41:226–229

    Article  PubMed  CAS  Google Scholar 

  • Ogata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, Ueta Y (2004) The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes. Anesth Analg 98:1401–1406

    Article  PubMed  CAS  Google Scholar 

  • Ongur D, Goff DC (2005) Obsessive–compulsive symptoms in schizophrenia: associated clinical features, cognitive function and medication status. Schizophr Res 75:349–362

    Article  PubMed  Google Scholar 

  • Pauls DL (1992) The genetics of obsessive compulsive disorder and Gilles de la Tourette’s syndrome. Psychiatr Clin North Am 15:759–766

    PubMed  CAS  Google Scholar 

  • Pawlowski L, Melzacka M (1986) Inhibition of head twitch response to quipazine in rats by chronic amitriptyline but not fluvoxamine or citalopram. Psychopharmacology (Berl) 88:279–284

    CAS  Google Scholar 

  • Pujol J, Soriano-Mas C, Alonso P, Cardoner N, Menchon JM, Deus J, Vallejo J (2004) Mapping structural brain alterations in obsessive–compulsive disorder. Arch Gen Psychiatry 61:720–730

    Article  PubMed  Google Scholar 

  • Rojas-Corrales MO, Berrocoso E, Gibert-Rahola J, Mico JA (2002) Antidepressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake, in helpless rats. Life Sci 72:143–152

    Article  PubMed  CAS  Google Scholar 

  • Rojas-Corrales MO, Berrocoso E, Gibert-Rahola J, Mico JA (2004) Antidepressant-like effect of tramadol and its enantiomers in reserpinized mice: comparative study with desipramine, fluvoxamine, venlafaxine and opiates. J Psychopharmacol 18:404–411

    Article  PubMed  CAS  Google Scholar 

  • Rojas-Corrales MO, Gibert-Rahola J, Mico JA (1998) Tramadol induces antidepressant-type effects in mice. Life Sci 63:PL175–180

    Article  PubMed  CAS  Google Scholar 

  • Sandyk R (1986a) Naloxone withdrawal exacerbates Tourette syndrome. J Clin Psychopharmacol 6:58–59

    Article  CAS  Google Scholar 

  • Sandyk R (1986b) Tourette syndrome: successful treatment with clonidine and oxycodone. J Neurol 233:178–179

    Article  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 

  • Shapira NA, Keck PE, Jr., Goldsmith TD, McConville BJ, Eis M, McElroy SL (1997a) Open-label pilot study of tramadol hydrochloride in treatment-refractory obsessive–compulsive disorder. Depress Anxiety 6:170–173

    Article  CAS  Google Scholar 

  • Shapira NA, McConville BJ, Pagnucco ML, Norman AB, Keck PE, Jr. (1997b) Novel use of tramadol hydrochloride in the treatment of Tourette’s syndrome. J Clin Psychiatry 58:174–175

    CAS  Google Scholar 

  • Shapira NA, Verduin ML, DeGraw JD (2001) Treatment of refractory major depression with tramadol monotherapy. J Clin Psychiatry 62:205–206

    Article  PubMed  CAS  Google Scholar 

  • Shapira NA, Ward HE, Mandoki M, Murphy TK, Yang MC, Blier P, Goodman WK (2004) A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive–compulsive disorder. Biol Psychiatry 55:553–555

    Article  PubMed  CAS  Google Scholar 

  • Spencer C (2000) The efficacy of intramuscular tramadol as a rapid-onset antidepressant. Aust N Z J Psychiatry 34:1032–1033

    Article  PubMed  CAS  Google Scholar 

  • Stahl SM (1998) Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry 59 Suppl 4:5–14

    PubMed  CAS  MathSciNet  Google Scholar 

  • Sun HL, Zheng JW, Wang K, Liu RK, Liang JH (2003) Tramadol reduces the 5-HTP-induced head-twitch response in mice via the activation of mu and kappa opioid receptors. Life Sci 72:1221–1230

    Article  PubMed  CAS  Google Scholar 

  • Swartz CM, Shen WW (1999) Is episodic obsessive compulsive disorder bipolar? A report of four cases. J Affect Disord 56:61–66

    Article  PubMed  CAS  Google Scholar 

  • Urraca N, Camarena B, Gomez-Caudillo L, Esmer MC, Nicolini H (2004) Mu opioid receptor gene as a candidate for the study of obsessive compulsive disorder with and without tics. Am J Med Genet B Neuropsychiatr Genet 127:94–96

    Article  PubMed  CAS  Google Scholar 

  • Vickers SP, Easton N, Malcolm CS, Allen NH, Porter RH, Bickerdike MJ, Kennett GA (2001) Modulation of 5-HT(2A) receptor-mediated head-twitch behaviour in the rat by 5-HT(2C) receptor agonists. Pharmacol Biochem Behav 69:643–652

    Article  PubMed  CAS  Google Scholar 

  • Warneke L (1997) A possible new treatment approach to obsessive–compulsive disorder. Can J Psychiatry 42:667–668

    PubMed  CAS  Google Scholar 

  • Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Lee CK, Newman SC, Oakley-Browne MA, Rubio-Stipec M, Wickramaratne PJ et al (1994) The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. J Clin Psychiatry 55 Suppl:5–10

    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 

  • Xu LF, Chu WJ, Qing XY, Li S, Wang XS, Qing GW, Fei J, Guo LH (2006) Protopine inhibits serotonin transporter and noradrenaline transporter and has the antidepressant-like effect in mice models. Neuropharmacology 50:934–940

    Article  PubMed  CAS  Google Scholar 

  • Zohar J, Mueller EA, Insel TR, Zohar-Kadouch RC, Murphy DL (1987) Serotonergic responsivity in obsessive–compulsive disorder. Comparison of patients and healthy controls. Arch Gen Psychiatry 44:946–951

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the financial support provided by “Fondo de Investigación Sanitaria” from the Ministry of Health of Spain (PI031430).

Author information

Authors and Affiliations

  1. Group of Research and Development in Neuropsychopharmacology, Department of Neuroscience, Faculty of Medicine, University of Cádiz, Plz Falla 9, 11003, Cádiz, Spain

    M. Olga Rojas-Corrales, Juan Gibert-Rahola & Juan A. Mico

Authors
  1. M. Olga Rojas-Corrales
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan Gibert-Rahola
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juan A. Mico
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan A. Mico.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rojas-Corrales, M.O., Gibert-Rahola, J. & Mico, J.A. Role of atypical opiates in OCD. Experimental approach through the study of 5-HT2A/C receptor-mediated behavior. Psychopharmacology 190, 221–231 (2007). https://doi.org/10.1007/s00213-006-0619-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-006-0619-5

Keywords

Search

Navigation