Differential effects of acute cannabinoid drug treatment, mediated by CB1 receptors, on the in vivo activity of tyrosine and tryptophan hydroxylase in the rat brain

  • David Moranta
  • Susana Esteban
  • Jesús A. García-Sevilla
Original Article

Abstract

The acute effects of cannabinoid drugs on the synthesis of noradrenaline, dopamine, and serotonin (5-HT) were assessed, simultaneously, using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Treatment (1 h, i.p.) with Δ9-tetrahydrocannabinol (THC, 5, 10, and 20 mg/kg) and the cannabinoid receptor agonist WIN 55,212–2 (WIN, 2 and 4 mg/kg) increased dopa/noradrenaline synthesis (40–70%) in various brain regions enriched in this neurotransmitter (e.g., cerebral cortex, hippocampus, hypothalamus). In most brain regions, the content of noradrenaline was reduced by cannabinoid drugs (27–66%). For the effects of WIN (2 and 4 mg/kg), an inverse correlation (r=−0.61, P=0.036) was obtained between the accumulation of dopa and the content of noradrenaline in the hypothalamus. The stimulatory effect on dopa accumulation induced by THC was antagonized by the selective CB1 receptor antagonists SR141716A and AM 281 (10 mg/kg). In contrast, THC and WIN decreased the synthesis of dopa/dopamine in the corpus striatum (16–37%) and that of 5-HTP/5-HT (20–35%) in brain regions enriched in 5-HT (e.g., cerebral cortex and hippocampus). These inhibitory effects of THC and WIN were also antagonized by AM 281 and/or SR141716A. THC did not alter the content of 5-HT or dopamine in the brain. The effects may be related to the activation of presynaptic inhibitory cannabinoid CB1 receptors located on the neurones themselves (serotonin) and on facilitatory (dopamine) and inhibitory interneurones (noradrenaline).

Keywords

Δ9-THC WIN 55,212–2 CB1 receptors Dopa/noradrenaline synthesis Dopa/dopamine synthesis 5-HTP/5-HT synthesis Rat brain 

Notes

Acknowledgements

This study was supported by grants BFI2000–0306 and SAF2004–03685 from the Ministerio de Ciencia y Tecnología (MCT, Madrid, Spain). D.M. was supported by a predoctoral fellowship from MCT (Madrid, Spain). The authors wish to thank Sanofi-Synthelabo for the gift of SR141716A generously supplied for this study. J.A. García-Sevilla is a member of the Institut d’Estudis Catalans (Barcelona, Spain).

References

  1. Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58:315–348PubMedGoogle Scholar
  2. Cadogan AK, Alexander SP, Boyd EA, Kendall DA (1997) Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum. J Neurochem 69:1131–1137PubMedGoogle Scholar
  3. Carlsson A, Lindqvist M (1973) In-vivo measurements of tryptophan and tyrosine hydroxylase activities in mouse brain. J Neural Transm 34:79–91PubMedGoogle Scholar
  4. Castaneda E, Moss DE, Oddie SD, Whishaw IQ (1991) THC does not affect striatal dopamine release: microdialysis in freely moving rats. Pharmacol Biochem Behav 40:587–591Google Scholar
  5. Cheer JF, Marsden CA, Kendall DA, Mason R (2000) Lack of response suppression follows repeated ventral tegmental cannabinoid administration: an in vitro electrophysiological study. Neuroscience 99:661–667CrossRefPubMedGoogle Scholar
  6. Cheer JF, Kendall DA, Mason R, Marsden CA (2003) Differential cannabinoid-induced electrophysiological effects in rat ventral tegmentum. Neuropharmacology 44:633–641CrossRefPubMedGoogle Scholar
  7. Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL (1990) Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berl) 102:156–162Google Scholar
  8. Egashira N, Mishima K, Katsurabayashi S, Yoshitake T, Matsumoto Y, Ishida J, Yamaguchi M, Iwasaki K, Fujiwara M (2002) Involvement of 5-hydroxytryptamine neuronal system in delta9-tetrahydrocannabinol-induced impairment of spatial memory. Eur J Pharmacol 445:221–229CrossRefPubMedGoogle Scholar
  9. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le-Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61PubMedGoogle Scholar
  10. Gerdeman G, Lovinger DM (2001) CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol 85:468–471PubMedGoogle Scholar
  11. Gifford AN, Samiian L, Gatley SJ, Ashby CR (1997) Examination of the effect of the cannabinoid receptor agonist, CP 55,940, on electrically evoked transmitter release from rat brain slices. Eur J Pharmacol 324:187–192PubMedGoogle Scholar
  12. Hajos N, Katona I, Naiem SS, MacKie K, Ledent C, Mody I, Freund TF (2000) Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci 12:3239–3249CrossRefPubMedGoogle Scholar
  13. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de-Costa BR, Rice KC (1991a) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  14. Herkenham M, Lynn AB, de-Costa BR, Richfield EK (1991b) Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res 547:267–274PubMedGoogle Scholar
  15. Hohmann AG, Herkenham M (2000) Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. Synapse 37:71–80CrossRefPubMedGoogle Scholar
  16. Jentsch JD, Andrusiak E, Tran A, Bowers MB, Roth RH (1997) Delta 9-tetrahydrocannabinol increases prefrontal cortical catecholaminergic utilization and impairs spatial working memory in the rat: blockade of dopaminergic effects with HA966. Neuropsychopharmacology 16:426–432Google Scholar
  17. Kataoka Y, Ohta H, Fujiwara M, Oishi R, Ueki S (1987) Noradrenergic involvement in catalepsy induced by delta 9-tetrahydrocannabinol. Neuropharmacology 26:55–60CrossRefPubMedGoogle Scholar
  18. Kathmann M, Bauer U, Schlicker E, Gothert M (1999) Cannabinoid CB1 receptor-mediated inhibition of NMDA- and kainate-stimulated noradrenaline and dopamine release in the brain. Naunyn-Schmiedebergs Arch Pharmacol 359:466–470Google Scholar
  19. Katona I, Sperlagh B, Sik A, Kafalvi A, Vizi ES, Mackie K, Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558PubMedGoogle Scholar
  20. Kawahara Y, Kawahara H, Westerink BH (1999) Tonic regulation of the activity of noradrenergic neurons in the locus coeruleus of the conscious rat studied by dual-probe microdialysis. Brain Res 823:42–48CrossRefPubMedGoogle Scholar
  21. Levenes C, Daniel H, Soubrie P, Crepel F (1998) Cannabinoids decrease excitatory synaptic transmission and impair long-term depression in rat cerebellar Purkinje cells. J Physiol 510:867–879PubMedGoogle Scholar
  22. Maldonado R, Rodriguez-de-Fonseca F (2002) Cannabinoid addiction: behavioral models and neural correlates. J Neurosci 22:3326–3331PubMedGoogle Scholar
  23. Malone DT, Taylor DA (1999) Modulation by fluoxetine of striatal dopamine release following delta 9-tetrahydrocannabinol: a microdialysis study in conscious rats. Br J Pharmacol 128:21–26PubMedGoogle Scholar
  24. Manzoni OJ, Bockaert J (2001) Cannabinoids inhibit GABAergic synaptic transmission in mice nucleus accumbens. Eur J Pharmacol 412:R3–5CrossRefPubMedGoogle Scholar
  25. Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225CrossRefPubMedGoogle Scholar
  26. Melis M, Gessa GL, Diana M (2000) Different mechanisms for dopaminergic excitation induced by opiates and cannabinoids in the rat midbrain. Prog Neuropsychopharmacol Biol Psychiatry 24:993–1006CrossRefPubMedGoogle Scholar
  27. Moranta M, Esteban S, García-Sevilla JA (2003) Differential effects of cannabinoid drugs on the synthesis of monoamines in the rat brain in vivo. Methods Find Exp Clin Pharmacol 25 [Suppl A]:134Google Scholar
  28. Nakazi M, Bauer U, Nickel T, Kathmann M, Schlicker E (2000) Inhibition of serotonin release in the mouse brain via presynaptic cannabinoid CB1 receptors. Naunyn-Schmiedebergs Arch Pharmacol 361:19–24Google Scholar
  29. National Institutes of Health (1985) Principles of laboratory animal care, NIH publication No. 85–23, revised edn. National Institutes of Health, Bethesda, MDGoogle Scholar
  30. Patel S, Hillard CJ (2003) Cannabinoid-induced Fos expression within A10 dopaminergic neurons. Brain Res 963:15–25CrossRefPubMedGoogle Scholar
  31. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedGoogle Scholar
  32. Pi F, García-Sevilla JA (1992) α2-Autoreceptor-mediated modulation of tyrosine hydroxylase activity in noradrenergic regions of the rat brain in vivo. Naunyn-Schmiedebergs Arch Pharmacol 345:653–660Google Scholar
  33. Sastre-Coll A, Esteban S, Garcia-Sevilla JA (1999) Effects of imidazoline receptor ligands on monoamine synthesis in the rat brain in vivo. Naunyn-Schmiedebergs Arch Pharmacol 360:50–62Google Scholar
  34. Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572PubMedGoogle Scholar
  35. Schlicker E, Timm J, Zentner J, Gothert M (1997) Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the human and guinea-pig hippocampus. Naunyn-Schmiedebergs Arch Pharmacol 356:583–589Google Scholar
  36. Shen M, Piser TM, Seybold VS, Thayer SA (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 16:4322–4334PubMedGoogle Scholar
  37. Szabo B, Dorner L, Pfreundtner C, Norenberg W, Starke K (1998) Inhibition of GABAergic inhibitory postsynaptic currents by cannabinoids in rat corpus striatum. Neuroscience 85:395–403CrossRefPubMedGoogle Scholar
  38. Szabo B, Muller T, Koch H (1999) Effects of cannabinoids on dopamine release in the corpus striatum and the nucleus accumbens in vitro. J Neurochem 73:1084–1089CrossRefPubMedGoogle Scholar
  39. Szabo B, Siemes S, Wallmichrath I (2002) Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur J Neurosci 15:2057–2061CrossRefPubMedGoogle Scholar
  40. Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276:2048–22050PubMedGoogle Scholar
  41. Trendelenburg AU, Cox SL, Schelb V, Klebroff W, Khairallah L, Starke K (2000) Modulation of (3H)-noradrenaline release by presynaptic opioid, cannabinoid and bradykinin receptors and beta-adrenoceptors in mouse tissues. Br J Pharmacol 130:321–330PubMedGoogle Scholar
  42. Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83:393–411CrossRefPubMedGoogle Scholar
  43. Tsou K, Mackie K, Sanudo-Pena MC, Walker JM (1999) Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation. Neuroscience 93:969–975CrossRefPubMedGoogle Scholar
  44. Tzavara ET, Perry KW, Rodriguez DE, Bymaster FP, Nomikos GG (2001) The cannabinoid CB(1) receptor antagonist SR141716A increases norepinephrine outflow in the rat anterior hypothalamus. Eur J Pharmacol 426:R3–4CrossRefPubMedGoogle Scholar
  45. Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Witkin JM, Nomikos GG (2003) The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J Pharmacol 138:544–553CrossRefPubMedGoogle Scholar
  46. Vaughan CW, Connor M, Bagley EE, Christie MJ (2000) Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol Pharmacol 57:288–295Google Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • David Moranta
    • 1
  • Susana Esteban
    • 1
  • Jesús A. García-Sevilla
    • 1
  1. 1.Laboratory of Neuropharmacology, Department of BiologyUniversity of the Balearic IslandsPalma de MallorcaSpain

Personalised recommendations