Caffeine-induced behavioural stimulation is dose- and concentration-dependent.

1. The relationship between plasma and brain caffeine and metabolite concentrations and behavioural stimulation was investigated over a 4 h time course. 2. CD-1 mice receiving single intraperitoneal doses of caffeine-sodium benzoate solution (caffeine doses: 0, 20, and 40 mg kg-1) were evaluated in an activity monitor, and their plasma and brain caffeine and metabolite concentrations were determined by high performance liquid chromatography (h.p.l.c.). 3. Kinetic variables for caffeine at low and high caffeine doses were: volume of distribution (Vd), 1.16 and 0.88 l kg-1; plasma elimination half-life (t1/2), 1.25 and 1.62 h; brain t1/2, 0.93 and 1.30 h; clearance, 0.64 and 0.38 l h-1 kg-1, respectively, with Vd and brain t1/2 differing significantly between the two caffeine doses. 4. Low-dose caffeine stimulated vertical behaviours significantly more than high-dose, during the first 150 min post-dosage; both doses stimulated vertical behaviours significantly more than vehicle treatment. 5. Low-dose and high-dose caffeine stimulated horizontal and stereotypic behaviours equivalently, during the first 150 min post-dosage; both doses stimulated these behaviours significantly more than vehicle. 6. Only later, 150 min post-dosage, did high-dose caffeine stimulate all behaviours significantly more than both low-dose and vehicle treatment; this occurred when caffeine concentrations had fallen to approximately 10 micrograms g-1 in the high-dose group. 7. The maximal stimulant effects of caffeine occurred in an intermediate concentration range, between 10-20 micrograms g-1, while lower and higher concentrations produced either no additional stimulation or decrements in activity.