Skip to main content

Advertisement

SpringerLink
Log in

Neuronal development genes are key elements mediating the reinforcing effects of methamphetamine, amphetamine, and methylphenidate

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

Abstract

Rationale

The molecular mechanisms underlying susceptibility to psychostimulant addiction remain unclear. Searching for commonalities in the effects of addictive drugs on brain gene expression is a prolific approach to determine transcriptional signatures influencing drug abuse.

Objective

We explored the common transcriptional responses to the reinforcing effects of psychostimulants methamphetamine, amphetamine, and methylphenidate. We also aimed to identify transcriptional changes that may subserve abuse of these drugs.

Methods

Genome-wide transcriptome profiling analyses were performed to identify common prefrontal cortical (PFC) and striatal gene expression profiles in drug-naïve (cohort 1) and stimulant-pretreated (cohort 2) rats, which showed a conditioned place preference to and self-administration of methamphetamine, amphetamine, and methylphenidate.

Results

In behavioral studies, stimulant-pretreated rats showed behavioral sensitization characterized by enhanced behavioral response to the rewarding or reinforcing effects of psychostimulants. Inflammation-associated genes (e.g., Alas1, S100a8 and S100a9) were identified as the primary differentially expressed genes (DEGs) in both the PFC and the striatum of cohort 1 rats, while neuronal plasticity (Sgk1)- and brain development (e.g., Bhlhe22, Neurod1, Nr4a2, and Msx1)-associated genes comprised the major upregulated DEGs in the striatum of cohort 2 rats. Furthermore, a meta-analysis of the common striatal DEGs in this study along with morphine-regulated striatal transcriptomes in mice (National Center for Biotechnology Information-Gene Expression Omnibus Database Accession Code GSE7762) suggested similar expression profiles of genes involved in neuronal development (e.g., Bhlhe22, Nr4a2).

Conclusion

This study provides evidence that brain development-associated genes mediate the reinforcing effects of methamphetamine, amphetamine, and methylphenidate and that these transcripts may underlie susceptibility to psychostimulant addiction.

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

Similar content being viewed by others

References

  • Adler MW, Rogers TJ (2005) Are chemokines the third major system in the brain? J Leukoc Biol 78(6):1204–1209

    Article  PubMed  CAS  Google Scholar 

  • Albertson TE, Derlet RW, Van Hoozen BE (1999) Methamphetamine and the expanding complications of amphetamines. West J Med 170:214–219

    PubMed  CAS  Google Scholar 

  • Ang SL (2006) Transcriptional control of midbrain dopaminergic neuron development. Development 133:3499–3506

    Article  PubMed  CAS  Google Scholar 

  • Baldwin HA, Colado MI, Murray TK, De Souza RJ, Green AR (1993) Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine. Br J Pharmacol 108:590–596

    Article  PubMed  CAS  Google Scholar 

  • Beckman DA, Schneider M, Youreneff M, Tse FF (2008) Juvenile toxicity assessment of d,l-methylphenidate in rats. Birth Defects Res B Dev Reprod Toxicol 83(1):48–67

    Article  PubMed  CAS  Google Scholar 

  • Berman SM, Kuczenski R, McCracken JT, London ED (2009) Potential adverse effects of amphetamine treatment on brain and behavior: a review. Mol Psychiatry 14(2):123–142

    Article  PubMed  CAS  Google Scholar 

  • Cadet JL (2009) Amphetamine recapitulates developmental programs in the zebrafish. Genome Biol 10:231

    Article  PubMed  Google Scholar 

  • Childress AR, McElgin W, Mozley PD, O'Brien CP (1999) Limbic activation during cue-induced craving for cocaine and for natural rewards. Biol Psychiatry 45:170

    Google Scholar 

  • Clark KH, Wiley CA, Bradberry CW (2013) Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. Neurotox Res 23(2):174–188

    Article  PubMed  CAS  Google Scholar 

  • Compton WM, Volkow ND (2006) Abuse of prescription drugs and the risk of addiction. Drug Alcohol Depend 83(Suppl 1):S4–S7

    Article  PubMed  CAS  Google Scholar 

  • dela Peña I, Lee JC, Lee HL, Woo TS, Lee HC, Sohn AR, Cheong JH (2012a) Differential behavioral responses of the spontaneously hypertensive rat to methylphenidate and methamphetamine: lack of a rewarding effect of repeated methylphenidate treatment. Neurosci Lett 514(2):189–193

    Article  Google Scholar 

  • dela Peña I, Yoon SY, Lee JC, dela Peña JB, Sohn AR, Ryu JH, Shin CY, Cheong JH (2012b) Methylphenidate treatment in the spontaneously hypertensive rat: influence on methylphenidate self-administration and reinstatement in comparison with Wistar rats. Psychopharmacology (Berlin) 221(2):217–226

    Article  Google Scholar 

  • Filloux F, Townsend JJ (1993) Pre- and postsynaptic neurotoxic effects of dopamine demonstrated by intrastriatal injection. Exp Neurol 119:79–88

    Article  PubMed  CAS  Google Scholar 

  • Flames N, Hobert O (2011) Transcriptional control of the terminal fate of monoaminergic neurons. Annual Rev Neurosci 34:153–184

    Article  CAS  Google Scholar 

  • Folds Mathes W, Nehrenberg DL, Gordon R, Hua K, Garland J, Pomp D (2010) Dopaminergic dysregulation in mice selectively bred for excessive exercise of obesity. Behav Brain Res 210(2):155–163

    Article  Google Scholar 

  • Freeman WM, Lull ME, Patel KM, Brucklacher RM, Morgan D et al (2010) Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration. BMC Neurosci 11:29

    Article  PubMed  Google Scholar 

  • Gerdeman GL, Partridge JG, Lupica CR, Lovinger DM (2003) It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci 26:184–192

    Article  PubMed  CAS  Google Scholar 

  • Greco D, Volpicelli F, Di Lieto A, Leo D, Perrone-Capano C (2009) Comparison of gene expression profile in embryonic mesencephalon and neuronal primary cultures. PLoSOne 4(3):e4977

    Article  Google Scholar 

  • Jacobs EH, Smit AB, de Vries TJ, Schoffelmeer AN (2003) Neuroadaptive effects of active versus passive drug administration in addiction research. Trends Pharmacol Sci 24(11):566–573

    Article  PubMed  CAS  Google Scholar 

  • Jones JR, Caul WF (1992) Effects of amphetamine on food intake and weight: timing of injections and food access. Physiol Behav 52(3):515–520

    Article  PubMed  CAS  Google Scholar 

  • Joshi PS, Molyneaux BJ, Feng L, Xie X, Macklis JD, Gan L (2008) Bhlhb5 regulates the postmitotic acquisition of area identities in layers II–V of the developing neocortex. Neuron 60(2):258–272

    Article  PubMed  CAS  Google Scholar 

  • Kadkhodaei B, Ito T, Joodmardi E, Mattson B, Rouillard C et al (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29:15923–15932

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW (2005) How do we determine which drug-induced neuroplastic changes are important? Nat Neurosci 8(11):1440–1441

    Article  PubMed  CAS  Google Scholar 

  • Kelley AE (2004) Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44:161–179

    Article  PubMed  CAS  Google Scholar 

  • Kest B, Palmese CA, Hopkins E, Adler M, Juni A, Mogil JS (2002) Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: evidence for common genetic mechanisms in acute and chronic morphine physical dependence. Neuroscience 115:463–469

    Article  PubMed  CAS  Google Scholar 

  • Koob GF (2008) A role for brain stress systems in addiction. Neuron 59(1):11–34

    Article  PubMed  CAS  Google Scholar 

  • Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238

    Article  PubMed  Google Scholar 

  • Korostynski M, Piechota M, Kaminska D, Solecki W, Przewlocki R (2007) Morphine effects on striatal transcriptome in mice. Genome Biol 8:R128

    Article  PubMed  Google Scholar 

  • Krasnova IN, Li SM, Wood WH, McCoy MT, Prabhu VV, Becker KG, Katz JL, Cadet JL (2008) Transcriptional responses to reinforcing effects of cocaine in the rat hippocampus and cortex. Genes Brain Behav 7(2):193–202

    Article  PubMed  CAS  Google Scholar 

  • Krasnova IN, Justinova Z, Ladenheim B, Jayanthi S, McCoy MT et al (2010) Methamphetamine self-administration is associated with persistent biochemical alterations in striatal and cortical dopaminergic terminals in the rat. PLoS One 5:e8790

    Article  PubMed  Google Scholar 

  • Krasnova IN, Ladenheim B, Hodges AB, Volkow ND, Cadet JL (2011) Chronic methamphetamine administration causes differential regulation of transcription factors in the rat midbrain. PloS One 6(4):e19179

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25(4):402–408

    Article  PubMed  CAS  Google Scholar 

  • Loftis J (2011) Methamphetamine causes persistent immune dysregulation: a cross-species, translational report. Neurotox Res 20(1):59–68

    Article  PubMed  CAS  Google Scholar 

  • Lull ME, Freeman WM, Vrana KE, Mash DC (2008) Correlating human and animal studies of cocaine abuse and gene expression. Ann N Y Acad Sci 1141:58–75

    Article  PubMed  CAS  Google Scholar 

  • Mariotti KC, Rossato LG, Froehlich PE, Limberger RP (2013) Amphetamine-type medicines: a review of pharmacokinetics, pharmacodynamics and toxicological aspects. Curr Clin Pharmacol (in press)

  • Martinat C, Bacci JJ, Leete T, Kim J, Vanti WB et al (2006) Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc Natl Acad Sci USA 103:2874–2879

    Article  PubMed  CAS  Google Scholar 

  • Muñoz EM, Bailey MJ, Rath MF, Shi Q, Morin F, Coon SL, Møller M, Klein DC (2007) NeuroD1: developmental expression and regulated genes in the rodent pineal gland. J Neurochem 102(3):887–899

    Article  PubMed  Google Scholar 

  • Nacken W, Roth J, Sorg C, Kerkhoff C (2003) S100A9/S100A8: myeloid representatives of the S100 protein family as prominent players in innate immunity. Microsc Res Tech 60(6):569–580

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1996) The rat brain in stereotaxic coordinates. Academic, New York

    Google Scholar 

  • Piechota M, Korostynski M, Solecki W, Gieryk A, Slezak M, Bilecki W, Ziolkowska B et al (2010) The dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum. Genome Biol 11:R48

    Article  PubMed  Google Scholar 

  • Piechota M, Korostynski M, Sikora M, Golda S, Dzbek J (2012) Common transcriptional effects in the mouse sttiatum following chronic treatment with heroin and methamphetamine. Genes Brain Behav 11:404–414

    Article  PubMed  CAS  Google Scholar 

  • Renthal W, Kumar A, Xiao G, Wilkinson M, Covington HE 3rd, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ, Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ (2009) Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins. Neuron 62:335–348

    Article  PubMed  CAS  Google Scholar 

  • Rhodes JS, Crabbe JC (2005) Gene expression induced by drugs of abuse. Curr Opin Pharmacol 5(1):26–33

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291

    Article  PubMed  CAS  Google Scholar 

  • Robison AJ, Nestler EJ (2011) Transcriptional and epigenetic mechanisms of addiction. Nat Rev 12:623–637

    CAS  Google Scholar 

  • Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ (2012) Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. Plos One 7(3):333693

    Article  Google Scholar 

  • Sagvolden T (2000) Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD). Neurosci Biobehav Rev 24:31–39

    Article  PubMed  CAS  Google Scholar 

  • Tande D, Hoglinger G, Debeir T, Freundlieb N, Hirsch E, Francois C (2006) New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis. Brain 129:1194–1200

    Article  PubMed  Google Scholar 

  • Thomas DM, Walker PD, Benjamins JA, Geddes TJ, Kuhn DM (2004) Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther 311(1):1–7

    Article  PubMed  CAS  Google Scholar 

  • Todd RD (1992) Neural development is regulated by classical neurotransmitters: dopamine D2 receptor stimulation enhances neurite outgrowth. Biol Psychiatry 31:794–807

    Article  PubMed  CAS  Google Scholar 

  • Tripodi M, Filosa A, Armentano M, Studer M (2004) The COUP-TF nuclear receptors regulate cell migration in the mammalian basal forebrain. Development 131(24):6119–6129

    Article  PubMed  CAS  Google Scholar 

  • Valjent E, Pages C, Herve D, Girault JA, Caboche J (2004) Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 19:1826–1836

    Article  PubMed  Google Scholar 

  • Volkow ND, Swanson JM (2003) Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry 160(11):1909–1918

    Article  PubMed  Google Scholar 

  • Webb K, Norton W, Trümbach D, Meijer AH, Ninkovic J, Topp S, Heck H et al (2009) Zebrafish reward mutants reveal novel transcripts mediating the behavioral effects of amphetamine. Genome Biol 10(7):R81

    Article  PubMed  Google Scholar 

  • Werme M, Hermanson E, Carmine A, Buervenich S, Zetterstrom RH, Thoren P, Ogren SO, Olson L, Perlmann T, Brene S (2003) Decreased ethanol preference and wheel running in Nurr1-deficient mice. Eur J Neurosci 17:2418–2424

    Article  PubMed  Google Scholar 

  • Whitney NP, Eidem TM, Peng H, Huang YL, Zheng JC (2009) Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injusry and neurodegenerative disorders. J Neurochem 108(6):1343–1359

    Article  PubMed  CAS  Google Scholar 

  • Wise RA (2002) Brain reward circuitry: insights from unsensed incentives. Neuron 36:229–240

    Article  PubMed  CAS  Google Scholar 

  • Yuferov V, Nielsen D, Butelman E, Kreek MJ (2005) Microarray studies of psychostimulant-induced changes in gene expression. Addict Biol 10(1):101–118

    Article  PubMed  CAS  Google Scholar 

  • Yui S, Nakatani Y Mikami (2003) Calprotectin (S100a8/S100a9), an inflammatory protein complex from neutrophils with a broad apoptosis-inducing activity. Biol Pharm Bull 26(6):753–760

  • Zhang F, Shen G, Liu XL, Wang F, Zhao HL, Yu J, Zhang JW (2011) Hypoxic induction of human erythroid-specific δ-aminolevulinate synthase mediated by hypoxia-inducible factor 1. Biochemistry 50(7):1194–1202

    Article  PubMed  CAS  Google Scholar 

  • Zhou FC, Zhao Q, Liu Y, Goodlett CR, Liang T, McClintick JN, Edenberg HJ, Li L (2011) Alteration of gene expression by alcohol exposure at early neurulation. BMC Genomics 12:124

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Korean Food and Drug Administration (grant number 11182 Ui An Yu 602) and the Korea Healthcare Technology Research and Development Project, Ministry for Health and Welfare Affairs, Republic of Korea (grant number A120013).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Uimyung Research Institute for Neuroscience, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815, Nowon-gu, Seoul, 139-742, South Korea

    Ike dela Peña & Jae Hoon Cheong

  2. College of Pharmacy, Ajou University, Suwon, Gyeounggi-do, 443-749, South Korea

    Eunyoung Lee & Minsoo Noh

  3. Department of Neuroscience, School of Medicine, Konkuk University, Seoul, 143-701, South Korea

    Se Jin Jeon & Chan Young Shin

  4. Department of Oriental Pharmaceutical Science, Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, 472-864, Korea

    Jong Hoon Ryu

Authors
  1. Ike dela Peña
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Se Jin Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eunyoung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jong Hoon Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chan Young Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Minsoo Noh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jae Hoon Cheong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Minsoo Noh or Jae Hoon Cheong.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(JPEG 72 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

dela Peña, I., Jeon, S.J., Lee, E. et al. Neuronal development genes are key elements mediating the reinforcing effects of methamphetamine, amphetamine, and methylphenidate. Psychopharmacology 230, 399–413 (2013). https://doi.org/10.1007/s00213-013-3168-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3168-8

Keywords

Search

Navigation