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.

Separate and combined effects of caffeine and alprazolam on motor activity and benzodiazepine receptor binding in vivo.

CD-1 mice received single intraperitoneal (IP) doses of caffeine-sodium benzoate (caffeine doses: 0, 20 and 40 mg/kg) followed by injections of alprazolampropylene glycol (0, 0.05, and 2 mg/kg, IP) to determine brain concentrations, effects on in vivo receptor binding of a specific high-affinity benzodiazepine receptor ligand [3H]Ro15-1788, and effects on motor activity over a 1-h period. A behavioral monitoring device, using infrared sensors, measured horizontal and ambulatory activity. Caffeine produced significant increases in all motor activity measures as compared to vehicle treatment, with low dose caffeine (with brain concentrations of 13 micrograms/g) stimulating activity to a greater degree than the high dose (with brain concentrations of 30 micrograms/g). The overall effect of caffeine on benzodiazepine receptor binding was not significant. Alprazolam significantly diminished motor activity and altered benzodiazepine receptor binding. Low dose alprazolam increased binding, while the high dose diminished it. Caffeine and alprazolam antagonized each other's behavioral effects in this study, but did not alter each other's uptake into brain. Alprazolam's antagonism of caffeine-induced motor stimulation was associated with decreases in receptor binding, whereas caffeine's reversal of alprazolam-induced motor depression was not associated with any changes in binding. The lack of a clear association between drug effects on benzodiazepine binding and on motor activity suggests that behavioral effects of caffeine and alprazolam may be mediated by other sites in addition to the benzodiazepine receptor.

Kinetic and dynamic study of intravenous lorazepam: comparison with intravenous diazepam.

Six healthy volunteers received a single i.v. dose of 'low dose' lorazepam (0.0225 mg/kg), 'high dose' lorazepam (0.045 mg/kg) and placebo by 1-min infusion in a double-blind three-way crossover study. Plasma concentrations were measured 24 hr after dosage, and the EEG power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13-30-Hz range. Low and high dose lorazepam did not differ significantly in distribution volume (1.89 versus 1.81 l/kg) or elimination half-life (11.5 versus 12.2 hr); clearance was slightly although significantly reduced at the higher dose (2.08 versus 1.88 ml/min/kg, P less than .005). EEG effects were of relatively slow onset, reaching their maximum change over baseline 30 min after infusion. The duration of action was prolonged, with the fraction of EEG activity in the 13-30-Hz range still significantly above baseline 8 hr after the 0.045 mg/kg dose. Five of these subjects received 0.15 mg/kg of i.v. diazepam in a companion study of identical design. EEG effects of diazepam were shorter than those of lorazepam, probably because of the more rapid and extensive decline in plasma diazepam concentrations in the postinfusion distribution phase. In addition, the onset of diazepam's effect was immediate. In male CD-1 mice that received i.v. diazepam (8.3 mg/kg) or lorazepam (3.3 mg/kg), the brain:plasma concentration ratio was maximal 2.5 min after dosage for diazepam, but equilibration was delayed at least 30 min after dosage for lorazepam. Thus the slow onset of action of lorazepam is probably attributable to slow entry into brain.