Skip to main content

Advertisement

SpringerLink
Log in

Effect of methamphetamine self-administration on tyrosine hydroxylase and dopamine transporter levels in mesolimbic and nigrostriatal dopamine pathways of the rat

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

Abstract

Rationale and objectives

Many studies have examined the effect of experimenter-delivered methamphetamine on the mesolimbic and nigrostriatal dopamine pathways. In contrast, little is known about the effect of methamphetamine self-administration on these neuronal pathways. We studied the effect of methamphetamine self-administration on two key regulators of dopamine transmission, tyrosine hydroxylase (TH), and dopamine transporter (DAT), in components of the mesolimbic and nigrostriatal dopamine pathways.

Methods

Rats self-administered methamphetamine (0.1 mg/kg per infusion, fixed-ratio-1 reinforcement schedule) or saline (control condition) for 9 h/day over 10 days. The brains of these rats were collected after 1 or 30 days of forced abstinence and the expression levels of TH and DAT were assayed by in situ, hybridization and western blot.

Results

TH mRNA and protein levels were increased in the ventral tegmental area (VTA, the cell body region of the mesolimbic dopamine system) and the substantia nigra pars compacta (SNC, the cell body region of the nigrostriatal dopamine system) after 1 day, but not 30 days, of forced abstinence from methamphetamine. In contrast, methamphetamine self-administration had no effect on TH protein levels in dopaminergic terminals located in the nucleus accumbens and caudate–putamen. In addition, methamphetamine self-administration had no effect on DAT mRNA levels in the VTA.

Conclusions

Results suggest that extended daily access to self-administered methamphetamine results in a transient, short-lasting effect on mesolimbic and nigrostriatal dopamine neurons of the rat brain.

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

  • Beitner-Johnson D, Nestler EJ (1991) Morphine and cocaine exert common chronic actions on tyrosine hydroxylase in dopaminergic brain reward regions. J Neurochem 57:344–347

    PubMed  Google Scholar 

  • Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a) Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse 23:28–38

    Article  PubMed  Google Scholar 

  • Bremner JD, Krystal JH, Southwick SM, Charney DS (1996b) Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 23:39–51

    Article  PubMed  Google Scholar 

  • Broening HW, Pu C, Vorhees CV (1997) Methamphetamine selectively damages dopaminergic innervation to the nucleus accumbens core while sparing the shell. Synapse 27:153–160

    Article  PubMed  Google Scholar 

  • Brown JM, Yamamoto BK (2003) Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress. Pharmacol Ther 99:45–53

    Google Scholar 

  • Cadet JL, Jayanthi S, Deng X (2003) Speed kills: cellular and molecular bases of methamphetamine-induced nerve terminal degeneration and neuronal apoptosis. FASEB J 17:1775–1788

    Article  PubMed  Google Scholar 

  • Cappon GD, Pu C, Vorhees CV (2000) Time-course of methamphetamine-induced neurotoxicity in rat caudate–putamen after single-dose treatment. Brain Res 863:106–111

    Article  PubMed  Google Scholar 

  • Crespo JA, Manzanares J, Oliva JM, Corchero J, Palomo T, Ambrosio E (2001) Extinction of cocaine self-administration produces a differential time- related regulation of proenkephalin gene expression in rat brain. Neuropsychopharmacology 25:185–194

    Article  PubMed  Google Scholar 

  • Davidson C, Gow AJ, Lee TH, Ellinwood EH (2001) Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev 36:1–22

    PubMed  Google Scholar 

  • Deroche-Gamonet V, Piat F, Le Moal M, Piazza PV (2002) Influence of cue-conditioning on acquisition, maintenance and relapse of cocaine intravenous self-administration. Eur J Neurosci 15:1363–1370

    Google Scholar 

  • Dworkin SI, Mirkis S, Smith JE (1995) Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug. Psychopharmacology 117:262–266

    Google Scholar 

  • Fallon JH, Moore RY (1978) Catecholamine innervation of the basal forebrain. IV. Topography of the dopamine projection to the basal forebrain and neostriatum. J Comp Neurol 180:545–580

    Article  PubMed  Google Scholar 

  • Fukumura M, Cappon GD, Pu C, Broening HW, Vorhees CV (1998) A single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein. Brain Res 806:1–7

    Article  PubMed  Google Scholar 

  • Ghitza UE, Gray SM, Epstein DH, Rice KC, Shaham Y (2006) The anxiogenic drug yohimbine reinstates palatable food seeking in a rat relapse model: a role of CRF(1) receptors. Neuropsychopharmacology (in press)

  • Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Incubation of cocaine craving after withdrawal. Nature 412:141–142

    Article  PubMed  Google Scholar 

  • Grimm JW, Shaham Y, Hope BT (2002) Effect of the cocaine and sucrose withdrawal period on extinction behavior, cue-induced reinstatement and protein levels of the dopamine transporter and tyrosine hydroxylase in limbic and cortical areas in rats. Behav Pharmacol 13:379–388

    Google Scholar 

  • Gudelsky GA, Yamamoto BK (2003) Neuropharmacology and neurotoxicity of 3,4-methylenedioxymethamphetamine. Methods Mol Med 79:55–73

    PubMed  Google Scholar 

  • Hanson GR, Rau KS, Fleckenstein AE (2004) The methamphetamine experience: a NIDA partnership. Neuropharmacology 47(Suppl 1):92–100

    Article  Google Scholar 

  • Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT (2001) Lobeline attenuates d-methamphetamine self-administration in rats. J Pharmacol Exp Ther 298:172–179

    Google Scholar 

  • Hemby SE, Co C, Koves TR, Smith JE, Dworkin SI (1997) Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat. Psychopharmacology 133:7–16

    Google Scholar 

  • Highfield D, Clements A, Shalev U, McDonald RJ, Featherstone R, Stewart J, Shaham Y (2000) Involvement of the medial septum in stress-induced relapse to heroin seeking in rats. Eur J Neurosci 12:1705–1713

    Google Scholar 

  • Kiyatkin EA (2005) Brain hyperthermia as physiological and pathological phenomena. Brain Res Brain Res Rev (in press)

  • Kiyatkin EA, Brown PL (2003) Fluctuations in neural activity during cocaine self-administration: clues provided by brain thermorecording. Neuroscience 116:525–538

    Article  PubMed  Google Scholar 

  • Le AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology 179:366–373

    Article  Google Scholar 

  • Lu L, Grimm JW, Shaham Y, Hope BT (2003) Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats. J Neurochem 85:1604–1613

    Google Scholar 

  • Lu L, Grimm JW, Dempsey J, Shaham Y (2004a) Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months. Psychopharmacology 176:101–108

    Google Scholar 

  • Lu L, Grimm JW, Hope BT, Shaham Y (2004b) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47(Suppl 1):214–226

    Article  PubMed  Google Scholar 

  • Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8:212–219

    Article  PubMed  Google Scholar 

  • Masserano JM, Baker I, Natsukari N, Wyatt RJ (1996) Chronic cocaine administration increases tyrosine hydroxylase activity in the ventral tegmental area through glutaminergic- and dopaminergic D2-receptor mechanisms. Neurosci Lett 217:73–76

    Article  PubMed  Google Scholar 

  • McCann UD, Ricaurte GA (2004) Amphetamine neurotoxicity: accomplishments and remaining challenges. Neurosci Biobehav Rev 27:821–826

    Article  PubMed  Google Scholar 

  • McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA (1998) Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci 18:8417–8422

    Google Scholar 

  • Morales M, Bloom FE (1997) The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon. J Neurosci 17:3157–3167

    PubMed  Google Scholar 

  • Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LT, Palmer A, Marshall JF (2000) Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. J Neurosci 20:798–805

    Google Scholar 

  • Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128

    Article  PubMed  Google Scholar 

  • Palkovits M, Browstein MJ (1988) Maps and guide to microdissection of the rat brain. Elsevier, New York

    Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5 edn. Elsevier, New York

    Google Scholar 

  • Preston KL, Wagner GC, Schuster CR, Seiden LS (1985) Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain. Brain Res 338:243–248

    Article  PubMed  Google Scholar 

  • Ranaldi R, Poeggel K (2002) Baclofen decreases methamphetamine self-administration in rats. Neuroreport 13:1107–1110

    Article  PubMed  Google Scholar 

  • Seiden LS (1985) Methamphetamine: toxicity to dopaminergic neurons. NIDA Res Monogr 62:100–116

    PubMed  Google Scholar 

  • Seiden LS, Fischman MW, Schuster CR (1976) Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeys. Drug Alcohol Depend 1:215–219

    Article  PubMed  Google Scholar 

  • Shalev U, Morales M, Hope B, Yap J, Shaham Y (2001) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology 156:98–107

    Google Scholar 

  • Shalev U, Robarts P, Shaham Y, Morales M (2003) Selective induction of c-Fos immunoreactivity in the prelimbic cortex during reinstatement of heroin seeking induced by acute food deprivation in rats. Behav Brain Res 145:79–88

    Article  PubMed  Google Scholar 

  • Shepard JD, Bossert JM, Liu SY, Shaham Y (2004) The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psychiatry 55:1082–1089

    Article  PubMed  Google Scholar 

  • Sorg BA, Chen SY, Kalivas PW (1993) Time course of tyrosine hydroxylase expression after behavioral sensitization to cocaine. J Pharmacol Exp Ther 266:424–430

    PubMed  Google Scholar 

  • Sorge RE, Stewart J (2005) The contribution of drug history and time since termination of drug taking to footshock stress-induced cocaine seeking in rats. Psychopharmacology 183:210–217

    Google Scholar 

  • Stefanski R, Ladenheim B, Lee SH, Cadet JL, Goldberg SR (1999) Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine. Eur J Pharmacol 371:123–135

    Article  PubMed  Google Scholar 

  • Stefanski R, Lee SH, Yasar S, Cadet JL, Goldberg SR (2002) Lack of persistent changes in the dopaminergic system of rats withdrawn from methamphetamine self-administration. Eur J Pharmacol 439:59–68

    Article  PubMed  Google Scholar 

  • Stefanski R, Justinova Z, Hayashi T, Takebayashi M, Goldberg SR, Su TP (2004) Sigma1 receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls. Psychopharmacology 175:68–75

    Google Scholar 

  • Ungerstedt U (1971) Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand 367:1–48 (Suppl)

    Google Scholar 

  • Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler M, Gatley SJ, Miller E, Hitzemann R, Ding YS, Logan J (2001a) Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci 21:9414–9418

    Google Scholar 

  • Volkow ND, Chang L, Wang GJ, Fowler JS, Leonido-Yee M, Franceschi D, Sedler MJ, Gatley SJ, Hitzemann R, Ding YS, Logan J, Wong C, Miller EN (2001b) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377–382

    Article  PubMed  Google Scholar 

  • Vrana SL, Vrana KE, Koves TR, Smith JE, Dworkin SI (1993) Chronic cocaine administration increases CNS tyrosine hydroxylase enzyme activity and mRNA levels and tryptophan hydroxylase enzyme activity levels. J Neurochem 61:2262–2268

    Google Scholar 

  • Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ (1996) Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2:699–703

    Article  PubMed  Google Scholar 

  • Yokel RA, Pickens R (1973) Self-administration of optical isomers of amphetamine and methylamphetamine by rats. J Pharmacol Exp Ther 187:27–33

    PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Program of the NIH, and the National Institute on Drug Abuse.

Author information

Author notes

  1. Jack D. Shepard

    Present address: Department of Biological Sciences, Towson University, 8000 York Road, Towson, MD, 21252, USA

Authors and Affiliations

  1. Cellular Neurobiology Research Branch, IRP/NIDA/NIH, 5500 Nathan Shock Drive, Baltimore, MD, 21224, USA

    Jack D. Shepard & Marisela Morales

  2. Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD, USA

    David T. Chuang & Yavin Shaham

Authors
  1. Jack D. Shepard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David T. Chuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yavin Shaham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marisela Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marisela Morales.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shepard, J.D., Chuang, D.T., Shaham, Y. et al. Effect of methamphetamine self-administration on tyrosine hydroxylase and dopamine transporter levels in mesolimbic and nigrostriatal dopamine pathways of the rat. Psychopharmacology 185, 505–513 (2006). https://doi.org/10.1007/s00213-006-0316-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-006-0316-4

Keywords

Search

Navigation