Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Dopamine activation of endogenous cannabinoid signaling in dorsal striatum

Abstract

We measured endogenous cannabinoid release in dorsal striatum of freely moving rats by microdialysis and gas chromatography/mass spectrometry. Neural activity stimulated the release of anandamide, but not of other endogenous cannabinoids such as 2-arachidonylglycerol. Moreover, anandamide release was increased eightfold over baseline after local administration of the D2-like (D2, D3, D4) dopamine receptor agonist quinpirole, a response that was prevented by the D2-like receptor antagonist raclopride. Administration of the D1-like (D1, D5) receptor agonist SKF38393 had no such effect. These results suggest that functional interactions between endocannabinoid and dopaminergic systems may contribute to striatal signaling. In agreement with this hypothesis, pretreatment with the cannabinoid antagonist SR141716A enhanced the stimulation of motor behavior elicited by systemic administration of quinpirole. The endocannabinoid system therefore may act as an inhibitory feedback mechanism countering dopamine-induced facilitation of motor activity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Microdialysis of endogenous cannabinoids in rat brain.
Figure 2: Local application of a high KCl concentration (60 mM) stimulates anandamide release in dorsal striatum of freely moving rats.
Figure 3: K+-stimulated anandamide release requires membrane depolarization and external Ca2+.
Figure 4: D2-like dopamine receptor activation evokes anandamide release in striatum.
Figure 5: The cannabinoid antagonist SR141716A potentiates quinpirole-evoked hyperactivity.

Similar content being viewed by others

References

  1. Gerfen, C. R. The neostriatal mosaic: multiple levels of compartmental organization. Annu. Rev. Neurosci. 15, 285–320 (1992).

    Article  CAS  Google Scholar 

  2. Graybiel, A. M., Aosaki, T., Flaherty, A. W. & Kimura, M. The basal ganglia and adaptive motor control. Science 265, 1826–1831 (1994).

    Article  CAS  Google Scholar 

  3. Chase, T. N., Engber, T. M. & Mouradian, M. M. Contribution of dopaminergic and glutamatergic mechanisms to the pathogenesis of motor response complications in Parkinson's disease. Adv. Neurol. 69, 497–501 (1996).

    CAS  PubMed  Google Scholar 

  4. Wolf, S. S. et al. Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding. Science 273, 1225–1227 (1996).

    Article  CAS  Google Scholar 

  5. Eidelberg, D. et al. The metabolic anatomy of Tourette's syndrome. Neurology 48, 927–934 (1997).

    Article  CAS  Google Scholar 

  6. Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA 87, 1932–1936 (1990).

    Article  CAS  Google Scholar 

  7. Matsuda, L. A., Lolait, S. J., Brownstein, M., Young, A. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).

    Article  CAS  Google Scholar 

  8. Herkenham, M. et al. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci. 11, 563–583 (1991).

    Article  CAS  Google Scholar 

  9. Sim, L. J., Selley, D. E., Xiao, R. & Childers, S. R. Differences in G-protein activation by μ- and δ-opioid, and cannabinoid receptors in rat striatum. Eur. J. Pharmacol. 307, 97–105 (1996).

    Article  CAS  Google Scholar 

  10. Szabo, B., Dörner, L., Pfreundtner, C., Nörenberg, W. & Starke, K. Inhibition of GABAergic inhibitory postsynaptic currents by cannabinoids in rat corpus striatum. Neuroscience 85, 395–403 (1998).

    Article  CAS  Google Scholar 

  11. Sañudo-Peña, M. C., Patrick, S. L., Patrick, R. L. & Walker, J. M. Effects of intranigral cannabinoids on rotational behavior in rats: interactions with the dopaminergic system. Neurosci. Lett. 206, 21–24 (1996).

    Article  Google Scholar 

  12. Hemming, M. & Yellowlees, P. M. Effective treatment of Tourette's syndrome with marijuana. J. Psychopharmacol. 7, 389–391 (1993).

    Article  CAS  Google Scholar 

  13. Müller-Vahl, K. R., Schneider, U., Kolbe, H. & Emrich, H. M. Treatment of Tourette-syndrome with delta-9-tetrahydrocannabinol. Am. J. Psychiatry (in press).

  14. Devane, W. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    Article  CAS  Google Scholar 

  15. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686– 691 (1994).

    Article  CAS  Google Scholar 

  16. Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).

    Article  CAS  Google Scholar 

  17. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).

    Article  CAS  Google Scholar 

  18. Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773– 778 (1997).

    Article  CAS  Google Scholar 

  19. Cadas, H., di Tomaso, E. & Piomelli, D. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. 17, 1226–1242 (1997).

    Article  CAS  Google Scholar 

  20. Sugiura, T. et al. Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Eur. J. Biochem. 240, 53–62 (1996).

    Article  CAS  Google Scholar 

  21. Sugiura, T. et al. Enzymatic synthesis of anandamide, an endogenous cannabinoid receptor ligand, through N-acylphosphatidylethanolamine pathway in testis: involvement of Ca2+-dependent transacylase and phosphodiesterase activities. Biochem. Biophys. Res. Commun. 218, 113–117 (1996).

    Article  CAS  Google Scholar 

  22. Giuffrida, A. & Piomelli, D. Isotope dilution GC/MS determination of anandamide and other fatty acylethanolamides in rat blood plasma. FEBS Lett. 422, 373–376 (1998).

    Article  CAS  Google Scholar 

  23. Facci, L. et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc. Natl. Acad. Sci. USA 92, 3376– 3380 (1995).

    Article  CAS  Google Scholar 

  24. Calignano, A., La Rana, G., Giuffrida, A. & Piomelli, D. Control of pain initiation by endogenous cannabinoids. Nature 394, 277–281 (1998).

    Article  CAS  Google Scholar 

  25. Schmid, H. H. O., Schmid, P. C. & Natarajan, V. The N-acylation-phosphodiesterase pathway and cell signalling. Chem. Phys. Lipids 80, 133–142 (1996).

    Article  CAS  Google Scholar 

  26. Desarnaud, F., Cadas, H. & Piomelli, D. Anandamide amidohydrolase activity in rat brain microsomes: identification and partial characterization. J. Biol. Chem. 270, 6030–6035 (1995).

    Article  CAS  Google Scholar 

  27. Ueda, N., Kurahashi, Y., Yamamoto, S. & Tokunaga, T. Partial purification and characterization of the porcine brain enzyme hydrolyzing and synthesizing anandamide. J. Biol. Chem. 270, 23823–23827 (1995).

    Article  CAS  Google Scholar 

  28. Hillard, C. J., Wilkison, D. M., Edgemont, W. S. & Campbell, W. B. Characterization of the kinetics and distribution of N-arachidonylethanolamine (anandamide) hydrolysis by rat brain. Biochim. Biophys. Acta 1257, 249–256 (1995).

    Article  Google Scholar 

  29. Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996).

    Article  CAS  Google Scholar 

  30. Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094–1097 (1997).

    Article  CAS  Google Scholar 

  31. Civelli, O. in Psychopharmacology: The Fourth Generation of Progress (eds. Bloom, F. E. & Kupfer, D. J.) 155–161 (Raven, New York, 1995).

    Google Scholar 

  32. Surmeier, D. J., Yan, Z. & Song, W. J. Coordinated expression of dopamine receptors in neostriatal medium spin neurons. Adv. Pharmacol. 42, 1020–1023 (1998).

    Article  Google Scholar 

  33. Rinaldi-Carmona, M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 350, 240–244 (1994).

    Article  CAS  Google Scholar 

  34. Eilam, D. & Szechtman, H. Biphasic effect of D-2 agonist quinpirole on locomotion and movements. Eur. J. Pharmacol. 161, 151–157 (1989).

    Article  CAS  Google Scholar 

  35. Thorn, L., Ashmeade, T. E., Storey, V. J., Routledge, C. & Reavill, C. Evidence to suggest that agonist modulation of hyperlocomotion is via post-synaptic dopamine D2 or D3 receptors. Neuropharmacology 36, 787– 792 (1997).

    Article  CAS  Google Scholar 

  36. Compton, D. R., Aceto, M. D., Lowe, J. & Martin, B. R. In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of Δ9-tetrahydrocannabinol-induced responses and apparent agonist activity. J. Pharmacol. Exp. Ther. 277, 586–594 (1996).

    CAS  PubMed  Google Scholar 

  37. Gough, A. L. & Olley, J. E. Catalepsy induced by intrastriatal injections of Δ9-THC and 11-OH-Δ9-THC in the rat. Neuropharmacology 17, 137– 144 (1978).

    Article  CAS  Google Scholar 

  38. Souilhac, J., Poncelet, M., Rinaldi-Carmona, M., Le Fur, G. & Soubrié, P. Intrastriatal injection of cannabinoid receptor agonist induced turning behavior in mice. Pharmacol. Biochem. Behav. 51, 3–7 (1995).

    Article  CAS  Google Scholar 

  39. Navarro, M. et al. Motor disturbances induced by an acute dose of Δ9-tetrahydrocannabinol: possible involvement of nigrostriatal dopaminergic alterations. Pharmacol. Biochem. Behav. 45, 291–298 (1993).

    Article  CAS  Google Scholar 

  40. Kondo, S. et al. 2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and independent mechanisms. FEBS Lett. 429, 152–156 (1998).

    Article  CAS  Google Scholar 

  41. Showalter, V. M., Compton, D. R., Martin, B. R. & Abood, M. E. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J. Pharmacol. Exp. Ther. 278, 989– 999 (1996).

    CAS  PubMed  Google Scholar 

  42. Matsuda, L. A. Molecular aspects of cannabinoid receptors. Crit. Rev. Neurobiol. 11, 143–166 (1997).

    Article  CAS  Google Scholar 

  43. Cadas, H., Gaillet, S., Beltramo, M., Venance, L. & Piomelli, D. Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J. Neurosci. 16, 3934–3942 (1996).

    Article  CAS  Google Scholar 

  44. Piomelli, D. in Psychopharmacology: The Fourth Generation of Progress (eds. Bloom, F. E. & Kupfer, D. J.) 595–607 (Raven, New York, 1995).

    Google Scholar 

  45. Landsman, R. S., Burkey, T. H., Consroe, P., Roeske, W. R. & Yamamura, H. I. SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur. J. Pharmacol. 334, R1–2 (1997).

    Article  CAS  Google Scholar 

  46. Waddington, J. L., Molloy, A. G., O'Boyle, K. M. & Pugh, M. T. in Neurobiology of Stereotyped Behaviour (eds. Cooper, S. J. & Dourish, C. T.) 64–90 (Clarendon, Oxford, 1990).

    Google Scholar 

  47. Fride, E. & Mechoulam, R. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur. J. Pharmacol. 231, 313–314 (1993).

    Article  CAS  Google Scholar 

  48. Pryor, G. T., Larsen, F. F., Husain, S. & Braude, M. C. Interactions of delta9-tetrahydrocannabinol with d-amphetamine, cocaine, and nicotine in rats. Pharmacol. Biochem. Behav. 8, 295–318 (1978).

    Article  CAS  Google Scholar 

  49. Parsons, L. H. & Justice, J. B. J. Quantitative approaches to in vivo brain microdialysis. Crit. Rev. Neurobiol. 8, 189–220 (1994).

    CAS  PubMed  Google Scholar 

  50. Parsons, L. H. et al. Neurochemical evidence that postsynaptic nucleus accumbens D3 receptor stimulation enhances cocaine reinforcement. J. Neurochem. 67, 1078–1089 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Sañudo-Peña, N. Stella and M.J. Walker for comments and discussion. Part of this work was conducted at the Neurosciences Institute and was supported by Neurosciences Research Foundation, which receives major support from Novartis. Additional support was from the National Institute of Drug Abuse (DA12447 and DA12413, to D.P.), CICYT and Plan Nacional sobre Drogas (F.R.F., M.N.). F.R.F. is a research Fellow of the Jaime del Amo Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D. Piomelli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Giuffrida, A., Parsons, L., Kerr, T. et al. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum . Nat Neurosci 2, 358–363 (1999). https://doi.org/10.1038/7268

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/7268

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing