Modulation of cannabinoid agonist binding by 5-HT in the rat cerebellum

J Neurochem. 2002 Mar;80(6):1095-102. doi: 10.1046/j.0022-3042.2002.00797.x.


Cross-talk between cannabinoid CB1 and serotonin 5-HT receptors in rat cerebellar membranes was investigated using radioligand binding. In competition against the CB1 antagonist, [3 H]SR141716A, the agonist, WIN 55,212-2 yielded a biphasic isotherm. The majority of binding was to a high-affinity state that was significantly reduced by the GTP analogue, Gpp(NH)p. Interestingly, 5-HT enhanced the high-affinity binding constant of WIN 55,212-2 while attenuating the proportion of high-affinity binding. 5-HT also significantly reduced the proportion of high-affinity binding of the cannabinoid agonist, HU 210, but had no effect on the agonist, CP 55,940. The effect of 5-HT on WIN 55,212-2 binding was inhibited by the 5-HT2 receptor antagonist ritanserin as well as Gpp(NH)p, suggesting a dependence on the 5-HT2 receptor and on G protein-receptor interactions, respectively. Subsequent [3 H]WIN 55,212-2 dissociation kinetic experiments revealed that 5-HT promoted a slower-dissociating species of radiolabelled agonist-receptor complex. Our findings support a membrane-delimited cross-talk between two G protein-coupled receptors that are co-localized in certain cells of the central nervous system. Intriguingly, the cannabinoid agonist dependence of the 5-HT modulatory effect suggests that agonist-specific conformations of the CB1 receptor may also be important in determining the extent of this cross-talk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazines
  • Binding, Competitive / drug effects
  • Cannabinoids / agonists*
  • Cannabinoids / metabolism*
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cerebellum / chemistry*
  • Cerebellum / metabolism*
  • Cyclohexanols / metabolism
  • Dronabinol / analogs & derivatives
  • Dronabinol / metabolism
  • GTP-Binding Proteins / metabolism
  • Male
  • Morpholines / metabolism
  • Naphthalenes / metabolism
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Cross-Talk / drug effects
  • Receptor Cross-Talk / physiology
  • Receptors, Cannabinoid
  • Receptors, Drug / chemistry
  • Receptors, Drug / metabolism
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism*
  • Serotonin / pharmacology


  • Benzoxazines
  • Cannabinoids
  • Cyclohexanols
  • Morpholines
  • Naphthalenes
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Receptors, Serotonin
  • Serotonin
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Dronabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • GTP-Binding Proteins
  • HU 211