Adenosine analogs have been suggested as virtually non-toxic hypnotics or anticonvulsants. However, chronic caffeine exposure may induce supersensitivity to adenosine analogs and thereby enhance their potency and influence their safety. The proposed study is aimed at characterizing the pharmacological and behavioral specificity of adenosine supersensitivity. Preliminary data show that rats consuming caffeine (0.5 mg/ml) in their drinking water from 30 to about 150 days of age become supersensitive to hypnotic effects of the adenosine agonist 1-PIA when compared to rats drinking only tap water. Theses groups did not differ on 1-PIA's effect on caffeine or water consumption or on muscle strength as measured by the ability to hang from a rod. This observation provides functional support for in-vitro observations of upregulation of adenosine receptors following chronic caffeine. The proposed studies are designed to replicate the observation of supersensitivity and extend it to operant behavior. Rats will be trained on a multiple schedule in which one component is a conventional fixed- interval schedule of reinforcement selected to enable direct comparisons with the extant literature showing behavioral effects of methylxanthines, adenosine analogs, and sedative/hypnotic drugs. In the other component the rat must hold down the lever for a specified duration. This task was selected for sensitivity and because it has been shown to be detect to motor effects of chemical exposure. To characterize pharmacological specificity, drugs from other pharmacological classes, including psychomotor stimulants and adrenergic agonists, will also be examined. Such data will enable quantitative comparisons how chronic caffeine use influence the behavioral actions of drugs. The provisional hypothesis is that chronic exposure to caffeine induces supersensitivity that is specific to adenosine agonists and tolerance that is specific to methylxanthines.
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