Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists

Adenosine A(2A) antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A(1) antagonists (DPCPX and CPT), and two adenosine A(2A) antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A(2A) antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A(1) antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. These results suggest that adenosine A(2A) antagonists enhance operant response rates, but A(1) antagonists do not. The involvement of adenosine A(2A) receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.