Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes.
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.
D000107:Acetylation; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002188:Cannabis / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000032:analysis; D003342:Corpus Striatum / Q000032:analysis; D004298:Dopamine / Q000378:metabolism; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology*; D007031:Hypothalamus / Q000032:analysis; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008745:Methylation; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects*; D013574:Synaptosomes / Q000378:metabolism*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D014316:Tritium; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D013759:Dronabinol; D004298:Dopamine; D009638:Norepinephrine