Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Chronic haloperidol treatment leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum


Stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) in rat striatal membrane preparations, produces a decrease in both the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G protein. This intramembrane A2-D2 interaction might be responsible for the behavioural depressant effects of adenosine agonists and for the behavioural stimulant effects of adenosine antagonists such as caffeine and theophylline. Dopamine denervation induces an increase in the intramembrane A2-D2 interaction, which may underlie the observed higher sensitivity to the behavioural effects induced by adenosine antagonists found in these animals. The present study was designed to examine if chronic treatment with haloperidol, which also produces dopamine receptor supersensitivity, is also associated with an increase in the intramembrane A2-D2 interaction in the neostriatum and with a higher sensitivity to the behavioural effects induced by adenosine antagonists. The data showed that: (i) haloperidol pretreatment causes a higher binding of the D2 antagonist [3H] raclopride in striatal membrane preparations due to an increase in the number of D2 receptors without changes in their affinity for the antagonist (increase in Bmax without changes in kd); (ii) GCS 21680 decreases the affinity of dopamine for the D2 receptor, by increasing the equilibrium dissociation constants of high (Kh) and low affinity (K1) dopamine D2 binding sites and increases the proportion of high affinity binding sites (Rh); (iii) a low dose of CGS 21680 (3 nM), which is ineffective in membrane preparations from neostriatum of nontreated animals, is effective in membranes from the striatum of haloperidol-pretreated animals; (iv) the nonselective adenosine antagonist theophylline (20 mg/kg SC) causes a higher motor activation in rats pretreated with haloperidol. The possible relevance of these results for the pathophysiology and treatment of tardive dyskinesias is discussed.

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


  1. Burt DR, Creese I, Snyder SH (1977) Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196:326–328

  2. Creese I, Snyder SH (1979) Nigrostriatal lesions enhance striatal [3H] apomorphine and [3H] spiroperidol binding. Eur J Pharmacol 56:277–281

  3. Creese I, Burt DR, Snyder SH (1977) Dopamine receptor binding enhancement accompanies lesion-induced behavioural super-sensitivity. Science 197:596–598

  4. Dunwiddie TV (1985) The physiological role of adenosine in the central nervous system. Int Rev Neurobiol 27:63–139

  5. Ferré S, Fuxe K (1992) Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum. Brain Res 594:124–130

  6. Ferré S, Herrera-Marschitz M, Grabowska-Andén M, Ungerstedt U, Casas M, Andén N-E (1991a) Postsynaptic dopamine/adenosine interaction: I. Adenosine analogues inhibit a D-2 mediated behaviour in short-term reserpinized mice. Eur J Pharmacol 192:30–35

  7. Ferré S, Herrera-Marschitz M, Grabowska-Andén M, Ungerstedt U, Casas M, Andén N-E (1991b) Postsynaptic dopamine/adenosine interaction: II. Postsynaptic dopamine agonism and adenosine antagonism of methylxanthines in short-term reserpinized mice. Eur J Pharmacol 192:36–42

  8. Ferré S, Rubio A, Fuxe K (1991c) Stimulation of adenosine A2 receptors induces catalepsy. Neurosci Lett 130:162–164

  9. Ferré S, von Euler G, Johansson B, Fredholm B, Fuxe K (1991d) Stimulation of high affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci USA 88:7238–7241

  10. Ferré S, Fuxe K, von Euler G, Johansson B, Fredholm BB (1992) Adenosine-dopamine interactions in the brain. Neuroscience 51:501–512

  11. Ferré S, Snaprud P, Fuxe K (1993) Opposing actions of an adenosine A2 receptor agonist and a GTP analogue on the regulation of dopamine D2 receptors in rat neostriatal membranes. Eur J Pharmacol 244:311–315

  12. Fink JS, Weaver DR, Rivkees SA, Peterfreund RA, Pollack AE, Adler EM, Reppert SM (1992) Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Mol Brain Res 14:186–195

  13. Fredholm BB, Hedqvist P (1979) Modulation of neurotransmission by purine nucleotides and nucleosides. Biochem Pharmacol 29:1635–1643

  14. Fredholm BB, Dunér-Engström M. Fastbom J, Jonzon B, Lindgren E, Nordstedt C (1988) Formation and actions of adenosine in the rat hippocampus, with special reference to the interactions with classical transmitters. In: Avoli M, Reader TA, Dykes RW, Gloor P (eds) From molecules to mind: neurotransmitters and cortical function. Plenum Press, New York, pp 437–451

  15. Fuxe K, Ungerstedt U (1974) Action of caffeine and theophyllamine on supersensitive dopamine receptors: considerable enhancement of receptor response to treatment withl-dopa and dopamine agonists. Med Biol 52:48–54

  16. Fuxe K, Ferré S, Snaprud P, Von Euler G, Johansson B, Fredholm (1993) Antagonistic A2a/D2 receptor interactions in the striatum as a basis for adenosine/dopamine interactions in the central nervous system. Drug Dev Res 28:374–380

  17. Gingrich JA, Caron MG (1993) Recent advances in the molecular biology of dopamine receptors. Annu Rev Neurosci 16:299–321

  18. Herrera-Marschitz M, Casas M, Ungerstedt U (1988) Caffeine produces contralateral rotation in rats with unilateral dopamine denervation: comparisons with apomorphine-induced responses. Psychopharmacology 94:38–45

  19. Hutchison GJ, Webb RI, Oei HH, Ghai GR, Zimmerman MB, Williams M (1989) CGS 21680C, an A2 selective adenosine receptor agonist with preferential hypotensive activity. J Pharmacol Exp Ther 251:47–55

  20. Jarvis MF, Williams M (1989) Direct autoradiographic localization of adenosine A2 receptors in the rat brain. Eur J Pharmacol 168:243–246

  21. Jarvis MF, Schulz R, Hutchison AJ, Do UH, Sills A, Williams M (1989)3H] CGS 21680, a selective A2 adenosine agonist directly labels A2 receptors in rat brain. J Pharmacol Exp Ther 251:888–893

  22. Klawans H, Rubovits R (1972) An experimental model of tardive dyskinesia. J Neural Tansm 33:235–138

  23. Köhler C, Hall H, Ögren S-O, Gawell L (1985) Specific in vitro and in vivo binding of [3H] raclopride. A potent substituted benzamide drug with high affinity for dopamine D2 receptors in rat brain. Biochem Pharmacol 34:2251–2259

  24. LaHoste GH, Marshall JF (1992) Dopamine supersensitivity and D1/D2 syngergism are unrelated to changes in striatal receptor density. Synapse 12:14–26

  25. Libert F, Passage E, Parmentier M, Simons M-J, Vassart G, Mattei M-G (1991) Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of sertonin receptor. Genomics 11:225–227

  26. Linden J, Tucker AL, Lynch KR (1991) Molecular cloning of adenosine A1 and A2 receptors. Trends Pharmacol 12:326–328

  27. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

  28. Lupica CR, Cass WA, Zahniser NR, Dunwiddie V (1990) Effects of the selective adenosine A2 receptor agonist CGS 21680 on in vitro electrophysiology, cAMP formation and dopamine release in rat hippocampus and striatum. J Pharmacol Exp Ther 252:1134–1141

  29. Maenhaut C, Van Sande J, Libert F, Abramowicz M, Parmentier M, Vanderhaeghen J-J, Dumont JE, Vassart G, Schiffmann SN (1990) RDC8 codes for an adenosine A2 receptor with physiological constitutive activity. Biochem Biophys Res Commun 173:1169–1178

  30. Martinez-Mir MI, Probst A, Palacios JM (1991) Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease. Neuroscience 42:697–706

  31. Munson PJ, Rodbard D (1980) LIGAND: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107:220–239

  32. Neve KA, Altar CA, Wong CA, Marshall JF (1984) Quantitative analysis of [3H] spiroperidol binding to rat forebrain sections: plasticity of neostriatal dopamine receptors after nigrostriatal injury. Brain Res 302:9–18

  33. Örgen SO, Köhler C, Fuxe K, Ängeby K (1979) Behavioural effects of ergot drugs. In: Fuxe K, Calne DB (eds) Dopamine ergot derivatives and motor function. Pergamon Press, Oxford, pp 187–205

  34. Parkinson FE, Fredholm BB (1990) Autoradiographic evidence for G-protein coupled A2-receptors in rat neostriatum using [3H]-CGS 21680 as a ligand. Naunyn Schmiedeberg's Arch Pharmacol 342:85–89

  35. Pierce KD, Furlong TJ, Selbie LA, Shine J (1992) Molecular cloning and expression of an adenosine A2b receptor from human brain. Biochem Biophys Res Commun 187:86–89

  36. Rupniak NMJ, Hall MD, Mann S, Fleminger S, Kilpatrick G, Jenner P, Marsden CD (1985) Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat. Biochem Pharmacol 34:2755–2763

  37. Savasta M, Dubois A, Feuerstein C, Manier M, Scatton B (1987) Denervation supersensitivity of striatal D2 dopamine receptors is restricted to the ventro- and dorsolateral regions of the striatum. Neurosci Lett 74:180–186

  38. Snyder SH (1985) Adenosine as a neuromodulator. Annu Rev Neurosci 8:103–124

  39. Schiffmann SN, Jacobs O, Vanderhaeghen J-J (1991) Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J Neurochem 57:1062–1067

  40. Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system in the rat brain. Acta Physiol Scand 82 [suppl. 367]:69–93

  41. Winn HR, Welsh JE, Rubio R, Berne RM (1980) Brain adenosine production in rat during sustained alteration in systemic blood pressure. Am J Physiol 239:H636-H641

  42. Winn HR, Rubio R, Berne RM (1981) Brain adenosine concentration during hypoxia in rats. Am J Physiol 241:H235-H242

  43. Zetterström T, Vernet L, Ungerstedt U, Tossman U, Jonzon B, Fredholm BB (1982) Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre. Neurosci Lett. 29:111–115

  44. Zhou QY, Li C, Olah ME, Johnson RA, Stiles GL, Civelli O (1992) Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc Natl Acad Sci USA 89:7432–7436

Download references

Author information

Correspondence to Sergi Ferré.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ferré, S., Schwarcz, R., Li, X.M. et al. Chronic haloperidol treatment leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum. Psychopharmacology 116, 279–284 (1994).

Download citation

Key words

  • Adenosine A2 receptor
  • Dopamine D2 receptor
  • Methylxanthine
  • Tardive dyskinesias
  • Receptor-receptor interaction
  • Rat