Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes

J Pharmacol Exp Ther. 1975 Jul;194(1):74-81.


We have examined the effect of Delta1-tetrahydrocannabinol (delat1-THC) and 12 of its derivatives on the uptake of 3H-labeled norepinephrine (NE), dopamine (DA), serotonin (5-HT) gamma-aminobutyric acid (GABA) into synaptosomes in homogenates of various regions of rat brain. Delta1-THC inhibits the accumulation of NE and 5-HT into hypothalamic preparations and DA into the corpus striatum with Ki values of about 12 to 25 muM while GABA uptake into cerebral cortical preparations is inhibited less (Ki = 140 muM). The affinities of delta6-THC, 7-hydroxy-delta1-THC, 7-hydroxy-delta6-THC and cannabidiol for 5-HT, NE and GABA transports are similar to values for delta1-THC, while cannabigerol, cannabinol and delta6-THC-7-oic acid have substantially less affinity. Thus, hydroxylation of C-7 in delta6-THC does not alter inhibitory potency, but its oxidation to an acid and aromatization of ring A greatly reduce affinity. The hydroxyl at C-3(1) of ring C is critical for inhibition of NE, 5-HT and GABA uptake, since its acetylation or methylation abolishes activity. Inhibition of NE, DA, 5-HT and GABA uptake by all cannabinoids examined is noncompetitive. Only about 1% of delta1-THC and delta6-THC and 5% of cannabidiol are fully soluble under our experimental conditions.

Publication types

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

MeSH terms

  • Acetylation
  • Animals
  • Brain / metabolism*
  • Cannabis / pharmacology*
  • Cerebral Cortex / analysis
  • Corpus Striatum / analysis
  • Dopamine / metabolism
  • Dronabinol / analogs & derivatives
  • Dronabinol / pharmacology*
  • Hypothalamus / analysis
  • In Vitro Techniques
  • Kinetics
  • Male
  • Methylation
  • Norepinephrine / metabolism
  • Rats
  • Serotonin / metabolism
  • Structure-Activity Relationship
  • Synaptic Transmission / drug effects*
  • Synaptosomes / metabolism*
  • Tritium
  • gamma-Aminobutyric Acid / metabolism


  • Tritium
  • Serotonin
  • gamma-Aminobutyric Acid
  • Dronabinol
  • Dopamine
  • Norepinephrine