Studies of the pharmacokinetics, cellular actions and motor stimulant effects of caffeine in horses

In view of the wide use of caffeine (CA) as a central nervous system stimulant and its potential to improve athletic performance in animals, the motor stimulant effects of CA and its central mechanisms of action were studied in the horse. An in vivo microdialysis procedure for free-moving horses was developed and used in conjunction with measurements of locomotor activity to monitor the concentrations of CA and CA metabolites in venous blood, splenius muscle and cerebral spinal fluid (CSF). After intravenous administration of 3 mg/kg CA, pharmacokinetic and statistical analyses indicated that microdialysis and venipuncture provide equivalent measures of drug levels in the blood. Free CA levels in muscle were significantly higher and eliminated more rapidly than CA in venous blood. Caffeine and theophylline (TP) crossed the blood brain barrier at different efficiencies while theobromine (TB) was not detected in CSF. These results suggested the suitable use of microdialysis for simultaneous measurement of drug and metabolite concentrations and underscored the importance of direct measurements of drug levels within target tissue. Caffeine dose-dependently (0.5 to 3 mg/kg) increased motor activity for 2 to 4 hours; the motor stimulation correlated well with free CA levels in venous blood but not to CA or TP levels in CSF.;While high-affinity and high-density adenosine A1 receptor binding sites were identified in both equine cortex and striatum, adenosine A2a binding sites were found predominantly in striatum. Caffeine, TP and paraxanthine (XN) bound non-selectively at adenosine A1 and A2a receptors with micromolar affinities and exhibited rank order potency of TP > XN > CA at both receptor subtypes. The exchange of [35S]-guanosine-5'-(gamma-thio)-triphosphate binding studies illustrated the antagonistic nature of CA and metabolites at adenosine receptors.;The studies have demonstrated that after a therapeutic dose of CA, the locomotor activities significantly increased in the horse and levels of CA and TP reached in CSF were sufficient to partially block equine adenosine A1 and A2a receptors in vitro. It is likely that adenosine receptor antagonism is involved in the motor stimulant effects of CA in the horse. The developed microdialysis model is expected to be of value for pharmacokinetic, pharmacodynamic and drug residue studies in large animals.