Skip to main content
SpringerLink
Log in

Enhanced P2Y1 receptor expression in the brain after sensitisation with d-amphetamine

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

Abstract

Rationale and objectives

Many pathological and physiological processes are associated with the transcriptional induction of specific receptors. The aim of the present study was to examine whether the development of d-amphetamine (AMPH)-induced sensitisation is related to an altered P2Y1 receptor expression.

Methods

Rats, treated for 5 successive days with AMPH (1.5 mg/kg, i.p.), alone or after pre-treatment with the non-specific P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2,4-disulphonic acid (PPADS, 0.6 nmol, i.c.v.) and tested in an open field system with respect to locomotor response, were studied immunocytochemically 5 days after the last AMPH injection.

Results

In the behaviourally sensitised animals, astrogliosis, characterised by hypertrophy, increase in glial fibrillary acidic protein (GFAP) immunoreactivity (IR) and astrocytic proliferation in striatal areas and the nucleus accumbens were observed. Quantification of the P2Y1 receptor stained cells revealed an increase in the receptor expression after AMPH-induced sensitisation in the studied regions. Pre-treatment with PPADS prior to each AMPH administration prevented the development of sensitisation, astrogliosis and P2Y1 receptor up-regulation. PPADS failed to alter the number of P2Y1 receptor-labelled cells when given alone. Confocal laser scanning microscopy indicated the localisation of P2Y1 receptors on GFAP-labelled astrocytes as well as on tubulin (βIII)-labelled neurones, under control conditions and after AMPH administration.

Conclusion

The present results confirm the existence of P2Y1 receptors on astrocytes and neurones as possible targets of endogenous ATP and in addition show their up-regulation as a consequence of P2Y1 receptor-involvement in AMPH-induced sensitisation in vivo.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1. A
Fig. 2A–C.
Fig. 3A–O.

Similar content being viewed by others

References

  • Abbracchio MP, Burnstock G (1994) Purinoceptors: are there families of P2X and P2Y purinoceptors? Pharmacol Ther 64:445–475

    Google Scholar 

  • Abbracchio MP, Brambilla R, Ceruti S, Cattabeni F (1999) Signalling mechanisms involved in P2Y receptor-mediated reactive astrogliosis. Prog Brain Res 120:333–342

    CAS  PubMed  Google Scholar 

  • Afanas'ev I, Ferger B, Kuschinsky K (2000) The associative type of sensitisation to d-amphetamine is expressed as an NO-dependent dramatic increase in extracellular dopamine in the nucleus accumbens. Naunyn-Schmiedeberg's Arch Pharmacol 362:232–237

    CAS  Google Scholar 

  • Bolego C, Ceruti S, Brambilla R, Puglisi L, Cattabeni F, Burnstock G, Abbracchio MP (1997) Characterization of signalling pathways involved in ATP and basic fibroblast growth factor-induced astrogliosis. Br J Pharmacol 121:1692–1699

    CAS  PubMed  Google Scholar 

  • Bowyer JF, Clausing P, Gough B, Slikker W, Holson RR (1995) Nitric oxide regulation of methamphetamine-induced dopamine release in caudate/putamen. Brain Res 699:62–70

    Article  CAS  PubMed  Google Scholar 

  • Braun N, Zhu Y, Krieglstein J, Culmsee C, Zimmermann H (1998) Upregulation of the enzyme chain hydrolyzing extracellular ATP after transient forebrain ischemia in the rat. J Neurosci 18:4891–4900

    CAS  PubMed  Google Scholar 

  • Bredt DS, Glatt CE, Hwang PM, Fotuhi M, Dawson TM, Snyder SH (1991) Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 7:615–624

    CAS  PubMed  Google Scholar 

  • Burnstock G (2001) Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 22:182–188

    CAS  PubMed  Google Scholar 

  • Communi D, Gonzalez NS, Detheux M, Brezillon S, Lannoy V, Parmentier M, Boeynaems JM (2001) Identification of a novel human ADP receptor coupled to G(i). J Biol Chem 276:41479–41485

    Article  CAS  PubMed  Google Scholar 

  • Donaldson LF, Hanley MR, Villablanca AC (1997) Inducible receptors, Trends Pharmacol Sci 18:171–181

    Article  CAS  PubMed  Google Scholar 

  • Eclancher F, Kehrli P, Labourdette G, Sensenbrenner M (1996) Basic fibroblast growth factor (bFGF) injection activates the glial reaction in the injured adult rat brain. Brain Res 737:201–214

    Article  CAS  PubMed  Google Scholar 

  • Flores C, Steward J (2000) Changes in astrocytic basic fibroblast growth factor expression during and after prolonged exposure to escalating doses of amphetamine. Neuroscience 98:287–293

    Article  CAS  PubMed  Google Scholar 

  • Flores C, Rodaros D, Stewart J (1998) Long-lasting induction of astrocytic basic fibroblast growth factor by repeated injections of amphetamine: blockade by concurrent treatment with a glutamate antagonist. J Neurosci 18:9547–9555

    CAS  PubMed  Google Scholar 

  • Flores C, Samaha AN, Stewart J (2000) Requirement of endogenous basic growth factor for sensitization to amphetamine. J Neurosci 20:1–5

    PubMed  Google Scholar 

  • Franke H (1995) Influence of chronic alcohol treatment on the GFAP-immunoreactivity in astrocytes of the hippocampus in rats. Acta Histochem 97:263–271

    CAS  PubMed  Google Scholar 

  • Franke H, Krügel U, Illes P (1999) P2 receptor-mediated proliferative effects on astrocytes in vivo. Glia 28:190–200

    Article  CAS  PubMed  Google Scholar 

  • Franke H, Grosche J, Schädlich H, Krügel U, Allgaier C, Illes P (2001a) P2X receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience 108:421–429

    Article  CAS  PubMed  Google Scholar 

  • Franke H, Krügel U, Schmidt R, Grosche J, Reichenbach A, Illes P (2001b) P2 receptor-types involved in astrogliosis in vivo. Br J Pharmacol 134:1180–1189

    CAS  PubMed  Google Scholar 

  • Gordon L (1986) Extracellular ATP: effects, sources and fate. Biochem J 233:309–319

    CAS  PubMed  Google Scholar 

  • Hess A, Desidero C, McAuliffe WG (1990) Acute neuropathological changes in the caudate nucleus caused by MPTP and methamphetamine: immunohistochemical studies. J Neurocytol 19:338–342

    CAS  PubMed  Google Scholar 

  • Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden A, Julius D, Conley PB (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207

    Google Scholar 

  • Hu XT, Koeltzow TE, Cooper DC, Robertson GS, White FJ, Vezina P (2002) Repeated ventral tegmental area amphetamine administration alters dopamine D1 receptor signaling in the nucleus accumbens. Synapse 45:159–170

    Article  CAS  PubMed  Google Scholar 

  • Kálmán M, Hajós F (1989) Distribution of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the rat brain. Exp Brain Res 78:147–163

    PubMed  Google Scholar 

  • Kim JH, Perugini M, Austin JD, Vezina P (2001) Previous exposure to amphetamine enhances the subsequent locomotor response to a D1 dopamine receptor agonist when glutamate reuptake is inhibited. J Neurosci 21:1–6

    Google Scholar 

  • Kittner H, Krügel U, Illes P (2001) The purinergic P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid prevents both the acute locomotor effects of amphetamine and the behavioural sensitisation caused by repeated amphetamine injections in rats. Neuroscience 102:241–243

    Article  CAS  PubMed  Google Scholar 

  • Kittner H, Franke H, Fischer W, Schultheis N, Krügel U, Illes P (2003) Stimulation of P2Y1 receptors causes anxiolytic-like effects in the rat elevated plus-maze; implications for the involvement of P2Y1 receptor-mediated nitric oxide production. Neuropsychopharmacology (in press)

  • Krügel U, Kittner H, Illes P (1999) Adenosine 5'-triphosphate-induced dopamine release in the rat nucleus accumbens in vivo. Neurosci Lett 265:49–52

    PubMed  Google Scholar 

  • Krügel U, Kittner H, Franke H, Illes P (2001a) Stimulation of P2 receptors in the ventral tegmental area enhances dopaminergic mechanisms in vivo. Neuropharmacology 40:1084–1093

    Article  PubMed  Google Scholar 

  • Krügel U, Kittner H, Illes P (2001b) Mechanisms of adenosine 5'-triphosphate-induced dopamine release in the rat nucleus accumbens in vivo. Synapse 39:222–232

    Article  PubMed  Google Scholar 

  • Krügel U, Schraft T, Franke H, Kittner H, Illes P (2002) P2Y1 receptor stimulation facilitates dopamine release in the nucleus accumbens. Abstract 012.14, 3rd Forum of European Neuroscience, Paris, p 40, Abstract book

  • Lau JWS, Senok S, Stadlin A (2000) Methamphetamine-induced oxidative stress in cultured mouse astrocytes. Ann NY Acad Sci 914:146–56

    CAS  PubMed  Google Scholar 

  • Lenz G, Gootfried C, Luo Z, Avruch J, Rodnight R, Nie WJ, Kang Y, Neary JT (2000) P2Y purinoceptor subtypes recruit different Mek activators in astrocytes. Br J Pharmacol 129:927–936

    CAS  PubMed  Google Scholar 

  • Lin HC, Kang BH, Wong CS, Mao SP, Wan FJ (1999) Systemic administration of d-amphetamine induced a delayed production of nitric oxide in the striatum of rats. Neurosci Lett 276:141–144

    Article  CAS  PubMed  Google Scholar 

  • Mao L, Wang JQ (2001) Differentially altered mGluR1 and mGluR5 mRNA expression in rat caudate nucleus and nucleus accumbens in the development and expression of behavioural sensitization to repeated amphetamine administration. Synapse 41:230–240

    Article  CAS  PubMed  Google Scholar 

  • Moore D, Chambers J, Waldvogel H, Faull R, Emson P (2000a) Regional and cellular distribution of the P2Y1 purinergic receptor in the human brain: striking neuronal localisation. J Comp Neurol 421:374–384

    Article  CAS  PubMed  Google Scholar 

  • Moore D, Iritani S, Chambers J, Emson P (2000b) Immunohistochemical localization of the P2Y1 purinergic receptor in Alzheimer's disease. NeuroReport 11:3799–3803

    CAS  PubMed  Google Scholar 

  • Morán-Jiménez MJ, Matute C (2000) Immunohistochemical localization of the P2Y1 purinergic receptor in neurons and glial cells of the central nervous system. Mol Brain Res 78:50–58

    Article  PubMed  Google Scholar 

  • Neary JT, Zhu Q (1994) Signaling by ATP receptors in astrocytes. Neuroreport 5:1617–1620

    CAS  PubMed  Google Scholar 

  • Neary JT, Baker L, Jorgensen SL, Norenberg MD (1994a) Extracellular ATP induces stellation and increases glial fibrillary acidic protein content and DNA synthesis in primary astrocyte cultures. Acta Neuropathol 87:8–13

    Article  CAS  PubMed  Google Scholar 

  • Neary JT, Whittemore SR, Zhu Q, Norenberg MD (1994b) Synergistic activation of DNA synthesis in astrocytes by fibroblast growth factors and extracellular ATP. J Neurochem 63:490–494

    CAS  PubMed  Google Scholar 

  • Neary JT, Rathbone MP, Cattabeni F, Abbracchio MP, Burnstock G (1996) Trophic actions of extracellular nucleotides and nucleosides on glial and neuronal cells. Trends Neurosci 19:13–18

    Google Scholar 

  • Neary JT, McCarthy M, Cornell-Bel A, Kang Y (1999a) Trophic signaling pathways activated by purinergic receptors in rat and human astroglia. Prog Brain Res 120:323–332

    CAS  PubMed  Google Scholar 

  • Neary JT, Kang Y, Bu Y, Akong K, Peters CS (1999b) Mitogenic signaling by ATP/P2Y purinergic receptors in astrocytes: Involvement of a calcium-independent protein kinase C, extracellular signal-regulated protein kinase pathway distinct from the phosphatidyinositol-specific phospholipase C/calcium pathway. J Neurosci 19:4211–4220

    Google Scholar 

  • O'Callaghan JP, Miller DB (1994) Neurotoxicity of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther 270:741–751

    Google Scholar 

  • Pacchioni AM, Gionio G, Assis A, Cancela LM (2002) A single exposure to restraint stress induces behavioral and neurochemical sensitization to stimulating effects of amphetamine: involvement of NMDA receptors. Ann NY Acad Sci 965:233–246

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain stereotaxic coordinates, 4th edn. Academic Press, San Diego

  • Pintor J, Porras A, Mora F, Miras-Portugal MT (1995) Dopamine receptor blockade inhibits the amphetamine-induced release of diadenosine polyphosphates, diadenosine tetraphosphate and diadenosine pentaphosphate, from neostriatum of the conscious rat. J Neurochem 64:670–676

    CAS  PubMed  Google Scholar 

  • Pu C, Vorhees VC (1993) Developmental dissociation of methamphetamine-induced depletion of dopaminergic terminals and astrocyte reaction in rat striatum. Dev Brain Res 72:325–328

    CAS  Google Scholar 

  • Pu C, Vorhees CV (1995) Protective effects of MK-801 on methamphetamine-induced depletion of dopaminergic and serotonergic terminals and striatal astrocytic response: an immunocytochemical study. Synapse 19:97–104

    CAS  PubMed  Google Scholar 

  • Pu C, Fisher JE, Cappon GD, Vorhees CV (1994) The effects of amonelic acid, a dopamine uptake inhibitor, on methamphetamine-induced dopaminergic terminal degeneration and astrocytic response in rat striatum. Brain Res 649:217–224

    CAS  PubMed  Google Scholar 

  • Ralevic V, Burnstock G (1998) Receptor for purines and pyrimidines. Pharmacol Rev 50:413–492

    CAS  PubMed  Google Scholar 

  • Reiser G (1995) Ca2+- and nitric oxide-dependent stimulation of cyclic GMP synthesis in neuronal cell line induced by P2-purinergic/pyrimidinergic receptor. J Neurochem 64:61–68

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Robinson TE, Kolb B (1997) Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci 17:8491–8497

    CAS  PubMed  Google Scholar 

  • Sellers LA, Simon J, Lundahl TS, Cousens DJ, Humphrey PPA, Barnard EA (2001) Adenosine nucleotides acting at the human P2Y1 receptor stimulate mitogen-activated protein kinase and induce apoptosis. J Biol Chem 276:16379–16390

    Article  CAS  PubMed  Google Scholar 

  • Stadlin A, Lau JWS, Szeto YK (1998) A selective regional response of cultured astrocytes to methamphetamine. Ann NY Acad Sci 844:108–121

    CAS  PubMed  Google Scholar 

  • Vincent SR (1994) Nitric oxide: a radical neurotransmitter in the central nervous system. Prog Neurobiol 42:129–160

    CAS  PubMed  Google Scholar 

  • Von Kügelgen I, Wetter A (2000) Molecular pharmacology of P2Y-receptors. Naunyn-Schmiedeberg's Arch Pharmacol 362:310–323

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. D. Moore (Department of Neurobiology, The Babraham Institute, Cambridge and SmithKline Beecham Pharmaceuticals, UK) for the P2Y1 receptor antibody. The authors are grateful to M. Henschke, M. Noack and K. Krause for technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (KI 677/2-1) and by the "Interdisciplinary Center for Clinical Research" at the University of Leipzig (01KS9504, Project Z10).

Author information

Authors and Affiliations

  1. Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstrasse 16-18, 04107, Leipzig, Germany

    Heike Franke, Holger Kittner & Peter Illes

  2. Department of Neurophysiology, Paul-Flechsig-Institute of Brain Research, University of Leipzig, Jahnallee 59, 04109, Leipzig, Germany

    Jens Grosche

Authors
  1. Heike Franke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Holger Kittner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jens Grosche
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Illes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heike Franke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Franke, H., Kittner, H., Grosche, J. et al. Enhanced P2Y1 receptor expression in the brain after sensitisation with d-amphetamine. Psychopharmacology 167, 187–194 (2003). https://doi.org/10.1007/s00213-002-1386-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-002-1386-6

Keywords

Search

Navigation