Compounds from both the
beta-carboline (BC) and
xanthine groups have been suggested to be the natural
ligands for
benzodiazepine (BZ) receptors. In this study we examined the effects of several BC's and
caffeine,
1,3,7-trimethylxanthine, on the binding of 3H-flunitrazepam (3H-FZ) and beta-3H-carboline-3-carboxylic
acid ethyl
ester (3H-BCCE) to the BZ receptors of rat and mouse brain. In mice, convulsion-producing doses of
caffeine (120 mg/kg intravenously) and
harmane (30 mg/kg intravenously) lowered the specific binding of 3H-FZ in vivo by 12-31%. A tremorogenic dose of
harmaline (30 mg/kg intravenously) increased binding by 31%.
Caffeine and
harmane also slightly decreased the in vivo binding of 3H-BCCE, a compound that binds preferentially to the cerebellar type of BZ receptors.
Harmaline stimulated the binding of 3H-BCCE only in the forebrain. Both
harmaline and
harmane increased by 41-111% the amount of 3H-BCCE that was distributed to the brain. In vitro BC's and
caffeine displaced 3H-FZ from receptors in the rat brain with various Ki values (4.7 to 206.9 microM). The antagonism for BZ binding was competitive and in Scatchard analysis produced linear plots. Exceptions were
harmaline and
caffeine in the forebrain: both exhibited curvilinear plots for 3H-FZ binding.
Harmaline increased the binding, and
caffeine decreased it by altering the affinity of a subgroup of BZ receptors. In the hindbrain both
harmaline and
caffeine inhibited binding and produced linear plots. BC-induced
tremor and convulsions unveil a large number of spare receptors in the brain, and these seem to be of the cerebellar type of BZ receptors. In addition, our results show that tremorogenic and convulsive BC's act differently on BZ receptors: during
harmaline-induced
tremor the affinity of some BZ receptors is increased, while
harmane-induced convulsions are connected to direct occupation of BZ receptors.