Relationship of plasma and brain concentrations of caffeine and metabolites to benzodiazepine receptor binding and locomotor activity.

CD-1 mice were treated with caffeine-sodium benzoate solution (caffeine doses: 0, 5, 15 or 30 mg/kg i.p.) to determine plasma and brain concentrations, effects on benzodiazepine receptor binding based on specific uptake of a high affinity ligand, and locomotor activity. There was a linear relationship between caffeine dose and mean brain or plasma concentrations, but concentrations varied considerably at any given dose. There were also linear relationships between plasma and brain concentrations of caffeine and each metabolite, with caffeine itself having the greatest brain:plasma uptake ratio. Benzodiazepine receptor binding was determined based on uptake of the benzodiazepine receptor ligand [3H]Ro15-1788, 3 microCi i.v. given 40 min after caffeine (30 mg/kg). Nonspecific binding was measured in animals pretreated with saturating doses of clonazepam. Specific uptake (measured by subtracting nonspecific from total [3H] Ro15-1788 uptake) increased significantly with caffeine as opposed to vehicle treatment in the cortex, hippocampus and hypothalamus. Brain caffeine concentrations associated with enhanced uptake were between 11 to 17 micrograms/g. Total locomotor activity and activity at 60 min, measured by an infrared sensor system, increased progressively with brain caffeine concentrations when comparing the following groups: 0, 2 to 9 micrograms/g of brain and 9 to 20 micrograms/g. Animals with brain concentrations exceeding 20 micrograms/g showed a decline in both measures but activity was significantly greater than placebo. In conclusion, brain caffeine concentrations between 9 to 20 micrograms/g are associated with increases in specific ligand uptake and motor activity.