Delta(9)-Tetrahydrocannabinol-induced Desensitization of Cannabinoid-Mediated Inhibition of Synaptic Transmission Between Hippocampal Neurons in Culture

Neuropharmacology. 2005 Dec;49(8):1170-7. doi: 10.1016/j.neuropharm.2005.07.012. Epub 2005 Sep 12.


Prolonged exposure to cannabinoids results in desensitization of cannabinoid receptors. Here, we compared the desensitization produced by the partial agonist, Delta(9)-tetrahydrocannabinol (THC) to that produced by the full agonist Win55,212-2 on cannabinoid-mediated inhibition of glutamatergic synaptic transmission. Synaptic activity between rat hippocampal neurons was determined from network-driven increases in the intracellular Ca(2+) concentration ([Ca(2+)](i) spikes). To assess the effects of prolonged treatment, cultures were incubated with cannabinoids, washed in 0.5% fatty-acid-free bovine serum albumin to ensure the removal of the lipophilic drug and then tested for inhibition of [Ca(2+)](i) spiking by Win55,212-2. In control experiments, 0.1 microM Win55,212-2 inhibited [Ca(2+)](i) spiking by 93 +/- 5%. Win55,212-2 produced significantly less inhibition of [Ca(2+)](i) spiking following 18-24h treatment with 1 microM THC (48 +/- 5%) or treatment with 1 microM Win55,212-2 (29 +/- 6%). Thus, THC produced significantly less functional desensitization than Win55,212-2. The desensitization produced by THC was maximal at 0.3 microM, remained stable between 1 and 7 days of preincubation and shifted the EC(50) of acute inhibition by Win55,212-2 from 27 to 251 nM. Differences in the long-term effects of cannabinoid receptor agonists on synaptic transmission may prove important for evaluating their therapeutic and abuse potential.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzoxazines
  • Calcium / metabolism
  • Cannabinoids / antagonists & inhibitors*
  • Cannabinoids / pharmacology*
  • Cells, Cultured
  • Dronabinol / pharmacology*
  • Hallucinogens / pharmacology*
  • Hippocampus / cytology*
  • Hippocampus / drug effects
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Neurons / drug effects*
  • Rats
  • Receptor, Cannabinoid, CB1 / drug effects
  • Synaptic Transmission / drug effects*


  • Benzoxazines
  • Cannabinoids
  • Hallucinogens
  • Morpholines
  • Naphthalenes
  • Receptor, Cannabinoid, CB1
  • Win 55212-2
  • Dronabinol
  • Calcium