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

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).

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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).

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Correspondence to Jesús A. García-Sevilla.

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Moranta, D., Esteban, S. & García-Sevilla, J.A. 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. Naunyn-Schmiedeberg's Arch Pharmacol 369, 516–524 (2004). https://doi.org/10.1007/s00210-004-0921-x

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Keywords

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