, Volume 203, Issue 4, pp 781–792

Sigma1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice

  • J. Kitanaka
  • N. Kitanaka
  • T. Tatsuta
  • F. S. Hall
  • G. R. Uhl
  • K. Tanaka
  • N. Nishiyama
  • Y. Morita
  • M. Takemura
Original Investigation



The effects of sigma receptor antagonists on methamphetamine (METH)-induced stereotypy have not been examined. We examined the effects of sigma antagonists on METH-induced stereotypy in mice.


The administration of METH (10 mg/kg) to male ddY mice induced stereotyped behavior consisting of biting (90.1%), sniffing (4.2%), head bobbing (4.1%), and circling (1.7%) during an observation period of 1 h. Pretreatment of the mice with BMY 14802 (α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol; 1, 5, and 10 mg/kg), a non-specific sigma receptor antagonist, significantly increased METH-induced sniffing (19.2%, 30.5%, and 43.8% of total stereotypical behavior) but decreased biting (76.6%, 66.9%, and 49.3% of total stereotypical behavior) in a dose-dependent manner. This response was completely abolished by (+)-SKF 10,047 ([2S-(2α,6α,11R)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol; 4 and 10 mg/kg), a putative sigma1 receptor agonist, and partially by PB 28 (1-cyclohexyl-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalen-1-yl)-n-propyl]piperazine; 1 and 10 mg/kg), a putative sigma2 receptor agonist. The BMY 14802 action on METH-induced stereotypy was mimicked by BD 1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine; 10 mg/kg), a putative sigma1 receptor antagonist, but not by SM-21 ((±)-tropanyl 2-(4-chlorophenoxy)butanoate; 1 mg/kg), a putative sigma2 receptor antagonist. The BD 1047 effect on METH-induced stereotypy was also abolished completely by (+)-SKF 10,047 and partially by PB 28. The overall frequency of METH-induced stereotypical behavior was unchanged with these sigma receptor ligands, despite the alteration in particular behavioral patterns. The BMY 14802 action on METH-induced stereotypy was unaffected by pretreatment with centrally acting histamine H1 receptor antagonists (pyrilamine or ketotifen, 10 mg/kg), suggesting that these effects are independent of histamine H1 receptor signaling systems.


In summary, modulation of central sigma1 receptors alters the pattern of METH-induced stereotypy, producing a shift from stereotypical biting to stereotypical sniffing, without affecting the overall frequency of stereotypical behavior.


Methamphetamine Stereotypy Sniffing Biting BMY 14802 Sigma ligand Sigma receptor 


  1. Aman MG (1982) Stimulant drug effects in developmental disorders and hyperactivity—toward a resolution of disparate findings. J Autism Dev Disord 12:385–398CrossRefPubMedGoogle Scholar
  2. Azzariti A, Colabufo NA, Berardi F, Porcelli L, Niso M, Simone GM, Perrone R, Paradiso A (2006) Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer. Mol Cancer Ther 5:1807–1816CrossRefPubMedGoogle Scholar
  3. Berridge CW (2006) Neural substrates of psychostimulant-induced arousal. Neuropsychopharmacology 31:2332–2340CrossRefPubMedGoogle Scholar
  4. Blanchard RJ, Hebert M, Dulloog L, Markham C, Figueira R, Nishimura O, Newsham K, Kaawaloa JN, Blanchard DC (2000) Cocaine-induced sniffing stereotypy changes in response to threat. Pharmacol Biochem Behav 66:249–256CrossRefPubMedGoogle Scholar
  5. Braestrup C (1977) Changes in drug-induced stereotyped behavior after 6-OHDA lesions in noradrenaline neurons. Psychopharmacology (Berl) 51:199–204CrossRefGoogle Scholar
  6. Budygin EA (2007) Dopamine uptake inhibition is positively correlated with cocaine-induced stereotyped behavior. Neurosci Lett 429:55–58PubMedGoogle Scholar
  7. Costall B, Naylor RJ, Neumeyer JL (1975) Differences in the nature of the stereotyped behaviour induced by aporphine derivatives in the rat and in their actions in extrapyramidal and mesolimbic brain areas. Eur J Pharmacol 31:1–16CrossRefPubMedGoogle Scholar
  8. Costall B, Marsden CD, Naylor RJ, Pycock CJ (1977) Stereotyped behaviour patterns and hyperactivity induced by amphetamine and apomorphine after discrete 6-hydroxydopamine lesions of extrapyramidal and mesolimbic nuclei. Brain Res 123:89–111CrossRefGoogle Scholar
  9. Delfs JM, Kelley AE (1990) The role of D1 and D2 dopamine receptors in oral stereotypy induced by dopaminergic stimulation of the ventrolateral striatum. Neuroscience 39:59–67CrossRefPubMedGoogle Scholar
  10. Derbez AE, Mody RM, Werling LL (2002) Sigma2-receptor regulation of dopamine transporter via activation of protein kinase C. J Pharmacol Exp Ther 301:306–314CrossRefPubMedGoogle Scholar
  11. Dickson PR, Lang CG, Hinton SC, Kelley AE (1994) Oral stereotypy induced by amphetamine microinjection into striatum: an anatomical mapping study. Neuroscience 61:81–91CrossRefPubMedGoogle Scholar
  12. Eichler AJ, Antelman SM, Black CA (1980) Amphetamine stereotypy is not a homogenous phenomenon: sniffing and licking show distinct profiles of sensitization and tolerance. Psychopharmacology (Berl) 68:287–290CrossRefGoogle Scholar
  13. Goldstein SR, Matsumoto RR, Thompson TL, Patrick RL, Bowen WD, Walker JM (1989) Motor effects of two σ ligands mediated by nigrostriatal neurons. Synapse 4:254–258CrossRefPubMedGoogle Scholar
  14. Groves PM, Rebec GV (1976) Biochemistry and behavior: some central actions of amphetamine and antipsychotic drugs. Annu Rev Psychol 27:91–127CrossRefPubMedGoogle Scholar
  15. Gudelsky GA (1999) Biphasic effect of sigma receptor ligands on the extracellular concentration of dopamine in the striatum of the rat. J Neural Transm 106:849–856CrossRefPubMedGoogle Scholar
  16. Guitart X, Codony X, Monroy X (2004) Sigma receptors: biology and therapeutic potential. Psychopharmacology (Berl) 174:301–319CrossRefGoogle Scholar
  17. Hamamura T, Akiyama K, Akimoto K, Kashihara K, Okumura K, Ujike H, Otsuki S (1991) Co-administration of either a selective D1 or D2 dopamine antagonist with methamphetamine prevents methamphetamine-induced behavioral sensitization and neurochemical change, studied by in vivo intracerebral dialysis. Brain Res 546:40–46CrossRefPubMedGoogle Scholar
  18. Hayashi T, Su T-P (2004) Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18:269–284CrossRefPubMedGoogle Scholar
  19. Iversen SD (1977) Neural substrates mediating amphetamine response. In: Ellinwood EH, Kilbey MM (eds) Cocaine and other stimulants. Plenum, New York, pp 31–45Google Scholar
  20. Izenwasser S, Thompson-Montgomery D, Deben SE, Chowdhury IN, Werling LL (1998) Modulation of amphetamine-stimulated (transporter mediated) dopamine release in vitro by σ2 receptor agonists and antagonists. Eur J Pharmacol 346:189–196CrossRefPubMedGoogle Scholar
  21. Kalivas PW (1982) Histamine-induced arousal in the conscious and pentobarbital-pretreated rat. J Pharmacol Exp Ther 222:37–42PubMedGoogle Scholar
  22. Kamei H, Kameyama T, Nabeshima T (1994) SKF-10,047 reverses stress-induced motor suppression: interaction with dopaminergic system. Eur J Pharmacol 260:39–46CrossRefPubMedGoogle Scholar
  23. Kamei H, Kameyama T, Nabeshima T (1996) (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated sigma1 sites. Eur J Pharmacol 309:149–158CrossRefPubMedGoogle Scholar
  24. Kassiou M, Dannals RF, Liu X, Wong DF, Ravert HT, Scheffel UA (2005) Synthesis and in vivo evaluation of a new PET radioligand for studying sigma-2 receptors. Bioorg Med Chem 13:3623–3626CrossRefPubMedGoogle Scholar
  25. Kelley AE, Lang CG, Gauthier AM (1988) Induction of oral stereotypy following amphetamine microinjection into a discrete subregion of the striatum. Psychopharmacology (Berl) 95:556–559CrossRefGoogle Scholar
  26. Kelly PH, Iversen SD (1976) Selective 6-OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 40:45–56CrossRefPubMedGoogle Scholar
  27. Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94:507–522CrossRefPubMedGoogle Scholar
  28. Kita T, Matsunari Y, Saraya T, Shimada K, O’Hara K, Kubo K, Wagner GC, Nakashima T (2000) Methamphetamine-induced striatal dopamine release, behavior changes and neurotoxicity in BALB/c mice. Int J Dev Neurosci 18:521–530CrossRefPubMedGoogle Scholar
  29. Kitanaka N, Kitanaka J, Takemura M (2003) Behavioral sensitization and alteration in monoamine metabolism in mice after single versus repeated methamphetamine administration. Eur J Pharmacol 474:63–70CrossRefPubMedGoogle Scholar
  30. Kitanaka J, Kitanaka N, Tatsuta T, Takemura M (2005) 2-Phenylethylamine in combination with l-deprenyl lowers the striatal level of dopamine and prolongs the duration of the stereotypy in mice. Pharmacol Biochem Behav 82:488–494CrossRefPubMedGoogle Scholar
  31. Kitanaka J, Kitanaka N, Tatsuta T, Morita Y, Takemura M (2007) Blockade of brain histamine metabolism alters methamphetamine-induced expression pattern of stereotypy in mice via histamine H1 receptors. Neuroscience 147:765–777CrossRefPubMedGoogle Scholar
  32. Kitanaka J, Kitanaka N, Tatsuta T, Morita Y, Takemura M (2008) Toxicity of an alkaloid extracted from the plant Lobelia inflata: association with methamphetamine-induced behavioral abnormalities. Chudoku Kenkyu (Jpn J Toxicol) 21:189–191 (in Japanese)Google Scholar
  33. Kramer JC, Fischman VS, Littlefield DC (1967) Amphetamine abuse: pattern and effects of high doses taken intravenously. JAMA 201:305–309CrossRefPubMedGoogle Scholar
  34. Largent BL, Gundlach AL, Snyder SH (1986) Pharmacological and autoradiographic discrimination of sigma and phencyclidine receptor binding sites in brain with (+)-[3H]SKF 10,047, (+)-[3H]-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine and [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine. J Pharmacol Exp Ther 238:739–748PubMedGoogle Scholar
  35. Lieberman JA, Kinon BJ, Loebel AD (1990) Dopaminergic mechanisms in idiopathic and drug-induced psychoses. Schizophrenia Bull 16:97–110Google Scholar
  36. Markham CM, Yang M, Blanchard RJ, Blanchard DC (2006) Effects of d-amphetamine on defensive behaviors related to fear and anxiety. Pharmacol Biochem Behav 83:490–499CrossRefPubMedGoogle Scholar
  37. Matson JL, Lovullo SV (2008) A review of behavioral treatments for self-injurious behaviors of persons with autism spectrum disorders. Behav Modif 32:61–76CrossRefPubMedGoogle Scholar
  38. Matsumoto RR, Mack AL (2001) (±)-SM-21 attenuates the convulsive and locomotor stimulatory effects of cocaine in mice. Eur J Pharmacol 417:R1–R2CrossRefPubMedGoogle Scholar
  39. Matsumoto RR, Pouw B, Mack AL, Daniels A, Coop A (2007) Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice. Pharmacol Biochem Behav 86:86–91CrossRefPubMedGoogle Scholar
  40. McCann DJ, Weissman AD, Su TP (1994) Sigma-1 and sigma-2 sites in rat brain: comparison of regional, ontogenetic, and subcellular patterns. Synapse 17:182–189CrossRefPubMedGoogle Scholar
  41. McCracken KA, Bowen WD, de Costa BR, Matsumoto RR (1999) Two novel sigma receptor ligands, BD1047 and LR172, attenuate cocaine-induced toxicity and locomotor activity. Eur J Pharmacol 370:225–232CrossRefPubMedGoogle Scholar
  42. Moison D, De Deurwaerdère P, Cagnotto A, Marrazzo A, Prezzavento O, Ronsisvalle G, Mennini T, Spampinato U (2003) Intrastriatal administration of sigma ligands inhibits basal dopamine release in vivo. Neuropharmacology 45:945–953CrossRefPubMedGoogle Scholar
  43. Mori T, Ito S, Kita T, Sawaguchi T (2004) Effects of dopamine- and serotonin-related compounds on methamphetamine-induced self-injurious behavior in mice. J Pharmacol Sci 96:459–464CrossRefPubMedGoogle Scholar
  44. Moy SS, Nadler JJ, Poe MD, Nonneman RJ, Young NB, Koller BH, Crawley JN, Duncan GE, Bodfish JM (2008) Development of a mouse test for repetitive, restricted behaviors: relevance to autism. Behav Brain Res 188:178–194CrossRefPubMedGoogle Scholar
  45. Mueller K, Saboda S, Palmour R, Nyhan WL (1982) Self-injurious behavior produced in rats by daily caffeine and continuous amphetamine. Pharmacol Biochem Behav 17:613–617CrossRefPubMedGoogle Scholar
  46. Nguyen EC, McCracken KA, Liu Y, Pouw B, Matsumoto RR (2005) Involvement of sigma (σ) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies. Neuropharmacology 49:638–645PubMedGoogle Scholar
  47. Okuyama S, Kawashima N, Chaki S, Yoshikawa R, Funakoshi T, Ogawa SI, Suzuki Y, Ikeda Y, Kumagai T, Nakazato A, Nagamine M, Tomisawa K (1999) A selective dopamine D4 receptor antagonist, NRA0160: a preclinical neuropharmacological profile. Life Sci 65:2109–2125CrossRefPubMedGoogle Scholar
  48. Randrup A, Munkvad I (1967) Stereotyped activities produced by amphetamine in several animal species and man. Psychopharmacologia (Berl) 11:300–310CrossRefGoogle Scholar
  49. Rebec GV, Bashore TR (1984) Critical issues in assessing the behavioral effects of amphetamine. Neurosci Biobehav Rev 8:153–159CrossRefPubMedGoogle Scholar
  50. Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 11:157–198CrossRefGoogle Scholar
  51. Schulz EM, Wright JW, Harding JW (1981) Distinctions between stereotyped sniffing and licking in rats with methamphetamine and apomorphine. Pharmacol Biochem Behav 15:521–523CrossRefPubMedGoogle Scholar
  52. Segal DS, Kuczenski R (1997) An escalating dose “binge” model of amphetamine psychosis: behavioral and neurochemical characteristics. J Neurosci 17:2551–2566PubMedGoogle Scholar
  53. Skuza G, Rogóz Z (2006) Effect of BD 1047, a sigma1 receptor antagonist, in the animal models predictive of antipsychotic activity. Pharmacol Rep 58:626–635PubMedGoogle Scholar
  54. Takahashi S, Miwa T, Horikomi K (2000) Involvement of σ1 receptors in methamphetamine-induced behavioral sensitization in rats. Neurosci Lett 289:21–24CrossRefPubMedGoogle Scholar
  55. Tatsuta T, Kitanaka N, Kitanaka J, Morita Y, Takemura M (2005) Effects of monoamine oxidase inhibitors on methamphetamine-induced stereotypy in mice and rats. Neurochem Res 30:1377–1385CrossRefPubMedGoogle Scholar
  56. Tatsuta T, Kitanaka N, Kitanaka J, Morita Y, Takemura M (2006) Lobeline attenuates methamphetamine-induced atereotypy in adolescent mice. Neurochem Res 31:1359–1369CrossRefPubMedGoogle Scholar
  57. Tatsuta T, Kitanaka N, Kitanaka J, Morita Y, Takemura M (2007) Lack of effect of anticonvulsant topiramate on methamphetamine-induced stereotypy and rewarding property in mice. Pharmacol Biochem Behav 87:48–55CrossRefPubMedGoogle Scholar
  58. Terleckyj I, Sonsalla PK (1994) The sigma receptor ligand (±)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors. J Pharmacol Exp Ther 269:44–50PubMedGoogle Scholar
  59. Ujike H, Kanzaki A, Okumura K, Akiyama K, Otsuki S (1992) Sigma (σ) antagonist BMY 14802 prevents methamphetamine-induced sensitization. Life Sci 50:PL29–PL34Google Scholar
  60. Ujike H, Kuroda S, Otsuki S (1996) σ Receptor antagonists block the development of sensitization to cocaine. Eur J Pharmacol 296:123–128CrossRefPubMedGoogle Scholar
  61. Walker JM, Bowen WD, Walker FO, Matsumoto RR, De Costa B, Rice KC (1990) Sigma receptors: biology and function. Pharmacol Rev 42:355–402PubMedGoogle Scholar
  62. Weatherspoon JK, Werling LL (1999) Modulation of amphetamine-stimulated [3H]dopamine release from rat pheochromocytoma (PC12) cells by sigma type 2 receptors. J Pharmacol Exp Ther 289:278–284PubMedGoogle Scholar
  63. Winchel RM, Stanley M (1991) Self-injurious behavior: a review of the behavior and biology of self-mutilation. Am J Psychiatry 148:306–317PubMedGoogle Scholar
  64. Woods-Kettelberger A, Kongsamut S, Smith CP, Winslow JT, Corbett R (1997) Animal models with potential applications for screening compounds for the treatment of obsessive–compulsive disorder. Expert Opin Invest Drugs 6:1369–1381CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • J. Kitanaka
    • 1
  • N. Kitanaka
    • 1
  • T. Tatsuta
    • 2
  • F. S. Hall
    • 3
  • G. R. Uhl
    • 3
  • K. Tanaka
    • 4
  • N. Nishiyama
    • 4
  • Y. Morita
    • 2
  • M. Takemura
    • 1
  1. 1.Department of PharmacologyHyogo College of MedicineNishinomiyaJapan
  2. 2.Department of NeuropsychiatryHyogo College of MedicineNishinomiyaJapan
  3. 3.Molecular Neurobiology BranchNational Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, U.S. Department of Health and Human ServicesBaltimoreUSA
  4. 4.Division of Pharmacology, Department of Pharmacy, School of PharmacyHyogo University of Health SciencesKobeJapan

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