Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors

The purpose of this study was to determine the mechanism by which caffeine increases anxiety. Rats were tested in the social interaction test of anxiety after administration of caffeine (20 or 40 mg/kg) alone or in combination with various compounds. In order to investigate the role of adenosine receptors, caffeine was given in combination with 2-chloroadenosine (0.1 and 1 mg/kg). To investigate the role of benzodiazepine receptors, chlordiazepoxide (5 mg/kg), a benzodiazepine antagonist, flumazenil (RO 15-1788, 1 and 10 mg/kg) and a triazolobenzodiazepine U-43,465 (32 mg/kg) were used. Finally, an alpha 2-receptor agonist, clonidine (0.1 and 0.025 mg/kg) and a beta-adrenoceptor antagonist, DL-propranolol (5 mg/kg), were used to study the role of noradrenergic systems in the effects of caffeine. Caffeine (20 and 40 mg/kg) reduced the time spent in social interaction and this effect was antagonized by chlordiazepoxide, U-43,465 and DL-propranolol, but not by flumazenil, 2-chloroadenosine or clonidine. It was therefore concluded that the anxiogenic effect of caffeine was unlikely to be due to its effects at adenosine or benzodiazepine receptors. It is suggested that the reversal of caffeine's effects by chordiazepoxide may have been "functional," i.e., merely a cancellation of two opposite effects. It is discussed whether the reversal of caffeine's effects by propranolol and U-43,465 are functional, or reflect a noradrenergic site of action.