Is GABA involved in the development of caffeine tolerance?

Caffeine (10 or 20 mg/kg per day, po)-induced stimulation of locomotor activity (LA) reached its peak following 4 consecutive days of caffeine administration. Caffeine-induced stimulation of LA was restored to the control values following caffeine tolerance after 16 or 12 consecutive days of caffeine treatment at a dose of 10 or 20 mg/kg per day, po. Biochemical studies showed that caffeine in the nontolerant condition reduced GABAergic activity in cerebral cortex, corpus striatum, cerebellum, hypothalamus and pons-medulla; but tolerance to caffeine (10 or 20 mg/kg per day, po) pushed up the GABAergic activity to the control value in all these regions of brain. Further, it was found that muscimol reduced the LA while bicuculline stimulated LA in the caffeine tolerant condition. Thus, from the present study it may be concluded that: (a) caffeine-induced stimulation of LA is dependent on dose and duration of caffeine treatment, (b) development of tolerance to caffeine is dependent on the dosage of caffeine, and (c) the reduction of central GABAergic activity in the caffeine-nontolerant condition pushed up and restored the LA to the control level on the development of tolerance to caffeine.