Skip to main content
SpringerLink
Log in

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

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

Abstract

Objective

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.

Results

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.

Conclusion

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.

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.

Institutional subscriptions

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

Similar content being viewed by others

References

  • Aman MG (1982) Stimulant drug effects in developmental disorders and hyperactivity—toward a resolution of disparate findings. J Autism Dev Disord 12:385–398

    Article  CAS  PubMed  Google Scholar 

  • 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 5:1807–1816

    Article  CAS  PubMed  Google Scholar 

  • Berridge CW (2006) Neural substrates of psychostimulant-induced arousal. Neuropsychopharmacology 31:2332–2340

    Article  CAS  PubMed  Google Scholar 

  • 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 66:249–256

    Article  CAS  PubMed  Google Scholar 

  • Braestrup C (1977) Changes in drug-induced stereotyped behavior after 6-OHDA lesions in noradrenaline neurons. Psychopharmacology (Berl) 51:199–204

    Article  CAS  Google Scholar 

  • Budygin EA (2007) Dopamine uptake inhibition is positively correlated with cocaine-induced stereotyped behavior. Neurosci Lett 429:55–58

    CAS  PubMed  Google Scholar 

  • 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 31:1–16

    Article  CAS  PubMed  Google Scholar 

  • 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 123:89–111

    Article  CAS  Google Scholar 

  • 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 39:59–67

    Article  CAS  PubMed  Google Scholar 

  • Derbez AE, Mody RM, Werling LL (2002) Sigma2-receptor regulation of dopamine transporter via activation of protein kinase C. J Pharmacol Exp Ther 301:306–314

    Article  CAS  PubMed  Google Scholar 

  • Dickson PR, Lang CG, Hinton SC, Kelley AE (1994) Oral stereotypy induced by amphetamine microinjection into striatum: an anatomical mapping study. Neuroscience 61:81–91

    Article  CAS  PubMed  Google Scholar 

  • 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) 68:287–290

    Article  CAS  Google Scholar 

  • Goldstein SR, Matsumoto RR, Thompson TL, Patrick RL, Bowen WD, Walker JM (1989) Motor effects of two σ ligands mediated by nigrostriatal neurons. Synapse 4:254–258

    Article  CAS  PubMed  Google Scholar 

  • Groves PM, Rebec GV (1976) Biochemistry and behavior: some central actions of amphetamine and antipsychotic drugs. Annu Rev Psychol 27:91–127

    Article  CAS  PubMed  Google Scholar 

  • Gudelsky GA (1999) Biphasic effect of sigma receptor ligands on the extracellular concentration of dopamine in the striatum of the rat. J Neural Transm 106:849–856

    Article  CAS  PubMed  Google Scholar 

  • Guitart X, Codony X, Monroy X (2004) Sigma receptors: biology and therapeutic potential. Psychopharmacology (Berl) 174:301–319

    Article  CAS  Google Scholar 

  • 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 546:40–46

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T, Su T-P (2004) Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18:269–284

    Article  CAS  PubMed  Google Scholar 

  • Iversen SD (1977) Neural substrates mediating amphetamine response. In: Ellinwood EH, Kilbey MM (eds) Cocaine and other stimulants. Plenum, New York, pp 31–45

    Google Scholar 

  • 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 346:189–196

    Article  CAS  PubMed  Google Scholar 

  • Kalivas PW (1982) Histamine-induced arousal in the conscious and pentobarbital-pretreated rat. J Pharmacol Exp Ther 222:37–42

    CAS  PubMed  Google Scholar 

  • Kamei H, Kameyama T, Nabeshima T (1994) SKF-10,047 reverses stress-induced motor suppression: interaction with dopaminergic system. Eur J Pharmacol 260:39–46

    Article  CAS  PubMed  Google Scholar 

  • 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 309:149–158

    Article  CAS  PubMed  Google Scholar 

  • 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 13:3623–3626

    Article  CAS  PubMed  Google Scholar 

  • Kelley AE, Lang CG, Gauthier AM (1988) Induction of oral stereotypy following amphetamine microinjection into a discrete subregion of the striatum. Psychopharmacology (Berl) 95:556–559

    Article  CAS  Google Scholar 

  • 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 40:45–56

    Article  CAS  PubMed  Google Scholar 

  • 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 94:507–522

    Article  CAS  PubMed  Google Scholar 

  • 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 18:521–530

    Article  CAS  PubMed  Google Scholar 

  • 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 474:63–70

    Article  CAS  PubMed  Google Scholar 

  • 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 82:488–494

    Article  CAS  PubMed  Google Scholar 

  • 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 147:765–777

    Article  CAS  PubMed  Google Scholar 

  • 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)

    CAS  Google Scholar 

  • Kramer JC, Fischman VS, Littlefield DC (1967) Amphetamine abuse: pattern and effects of high doses taken intravenously. JAMA 201:305–309

    Article  CAS  PubMed  Google Scholar 

  • 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 238:739–748

    CAS  PubMed  Google Scholar 

  • Lieberman JA, Kinon BJ, Loebel AD (1990) Dopaminergic mechanisms in idiopathic and drug-induced psychoses. Schizophrenia Bull 16:97–110

    CAS  Google Scholar 

  • Markham CM, Yang M, Blanchard RJ, Blanchard DC (2006) Effects of d-amphetamine on defensive behaviors related to fear and anxiety. Pharmacol Biochem Behav 83:490–499

    Article  CAS  PubMed  Google Scholar 

  • Matson JL, Lovullo SV (2008) A review of behavioral treatments for self-injurious behaviors of persons with autism spectrum disorders. Behav Modif 32:61–76

    Article  PubMed  Google Scholar 

  • Matsumoto RR, Mack AL (2001) (±)-SM-21 attenuates the convulsive and locomotor stimulatory effects of cocaine in mice. Eur J Pharmacol 417:R1–R2

    Article  CAS  PubMed  Google Scholar 

  • 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 86:86–91

    Article  CAS  PubMed  Google Scholar 

  • McCann DJ, Weissman AD, Su TP (1994) Sigma-1 and sigma-2 sites in rat brain: comparison of regional, ontogenetic, and subcellular patterns. Synapse 17:182–189

    Article  CAS  PubMed  Google Scholar 

  • 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 370:225–232

    Article  CAS  PubMed  Google Scholar 

  • 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 45:945–953

    Article  CAS  PubMed  Google Scholar 

  • 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 96:459–464

    Article  CAS  PubMed  Google Scholar 

  • 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 188:178–194

    Article  CAS  PubMed  Google Scholar 

  • Mueller K, Saboda S, Palmour R, Nyhan WL (1982) Self-injurious behavior produced in rats by daily caffeine and continuous amphetamine. Pharmacol Biochem Behav 17:613–617

    Article  CAS  PubMed  Google Scholar 

  • 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 49:638–645

    CAS  PubMed  Google Scholar 

  • 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 65:2109–2125

    Article  CAS  PubMed  Google Scholar 

  • Randrup A, Munkvad I (1967) Stereotyped activities produced by amphetamine in several animal species and man. Psychopharmacologia (Berl) 11:300–310

    Article  CAS  Google Scholar 

  • Rebec GV, Bashore TR (1984) Critical issues in assessing the behavioral effects of amphetamine. Neurosci Biobehav Rev 8:153–159

    Article  CAS  PubMed  Google Scholar 

  • 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 11:157–198

    Article  CAS  Google Scholar 

  • Schulz EM, Wright JW, Harding JW (1981) Distinctions between stereotyped sniffing and licking in rats with methamphetamine and apomorphine. Pharmacol Biochem Behav 15:521–523

    Article  CAS  PubMed  Google Scholar 

  • Segal DS, Kuczenski R (1997) An escalating dose “binge” model of amphetamine psychosis: behavioral and neurochemical characteristics. J Neurosci 17:2551–2566

    CAS  PubMed  Google Scholar 

  • Skuza G, Rogóz Z (2006) Effect of BD 1047, a sigma1 receptor antagonist, in the animal models predictive of antipsychotic activity. Pharmacol Rep 58:626–635

    CAS  PubMed  Google Scholar 

  • Takahashi S, Miwa T, Horikomi K (2000) Involvement of σ1 receptors in methamphetamine-induced behavioral sensitization in rats. Neurosci Lett 289:21–24

    Article  CAS  PubMed  Google Scholar 

  • 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 30:1377–1385

    Article  CAS  PubMed  Google Scholar 

  • Tatsuta T, Kitanaka N, Kitanaka J, Morita Y, Takemura M (2006) Lobeline attenuates methamphetamine-induced atereotypy in adolescent mice. Neurochem Res 31:1359–1369

    Article  CAS  PubMed  Google Scholar 

  • 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 87:48–55

    Article  CAS  PubMed  Google Scholar 

  • 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 269:44–50

    CAS  PubMed  Google Scholar 

  • Ujike H, Kanzaki A, Okumura K, Akiyama K, Otsuki S (1992) Sigma (σ) antagonist BMY 14802 prevents methamphetamine-induced sensitization. Life Sci 50:PL29–PL34

    Google Scholar 

  • Ujike H, Kuroda S, Otsuki S (1996) σ Receptor antagonists block the development of sensitization to cocaine. Eur J Pharmacol 296:123–128

    Article  CAS  PubMed  Google Scholar 

  • Walker JM, Bowen WD, Walker FO, Matsumoto RR, De Costa B, Rice KC (1990) Sigma receptors: biology and function. Pharmacol Rev 42:355–402

    CAS  PubMed  Google Scholar 

  • 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 289:278–284

    CAS  PubMed  Google Scholar 

  • Winchel RM, Stanley M (1991) Self-injurious behavior: a review of the behavior and biology of self-mutilation. Am J Psychiatry 148:306–317

    CAS  PubMed  Google Scholar 

  • 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 6:1369–1381

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Dr. Morio Yamada of the Department of Chemistry, Hyogo College of Medicine, for valuable comments on the manuscript. We also thank Dr. Tsung-Ping Su of the National Institute on Drug Abuse-IRP (USA) and Dr. Nicola A. Colabufo of Dipartimento Farmaco-Chimico, Università di Bari, Italy, for their advice on the sigma receptor ligand properties. This research was supported, in part, by Grants-in-Aid for Researchers, Hyogo College of Medicine (2005 to NK, 2007 to JK) and intramural funding from the National Institute on Drug Abuse (NIH/DHHS, USA, GRU, FSH).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    J. Kitanaka, N. Kitanaka & M. Takemura

  2. Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    T. Tatsuta & Y. Morita

  3. Molecular Neurobiology Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, U.S. Department of Health and Human Services, Baltimore, MD, 21224, USA

    F. S. Hall & G. R. Uhl

  4. Division of Pharmacology, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 650-8530, Japan

    K. Tanaka & N. Nishiyama

Authors
  1. J. Kitanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Kitanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Tatsuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. S. Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. R. Uhl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N. Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y. Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Takemura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Kitanaka.

Additional information

J. Kitanaka and N. Kitanaka contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kitanaka, J., Kitanaka, N., Tatsuta, T. et al. Sigma1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice. Psychopharmacology 203, 781–792 (2009). https://doi.org/10.1007/s00213-008-1425-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1425-z

Keywords

Search

Navigation