Effects of N6-(L-phenylisopropyl)adenosine, caffeine, theophylline and rolipram on the acquisition of conditioned responses in the rabbit

This study examined the effects of caffeine, theophylline and rolipram on the acquisition of conditioned responses in the rabbit and their ability to antagonize the retardant effects of the adenosine analog N6-(L-phenylisopropyl)adenosine (L-PIA) on acquisition. Pavlovian conditioning of nictitating membrane extension was accomplished by pairing the offset of a 800-msec tone- and light-conditioned stimulus with the onset of a 100-msec shock unconditioned stimulus to the skin just lateral to the outer canthus of the eye. L-PIA (5 mumol/kg) retarded the acquisition of conditioned responses to the tone- and light-conditioned stimuli, although theophylline (50-200 mumol/kg), caffeine (3-100 mumol/kg) and rolipram (0.03-3.0 mumol/kg) had no effect. The highest dose of caffeine used (300 mumol/kg) produced a small but significant enhancement of conditioned response acquisition in two of four experiments. The two adenosine antagonists theophylline (200 mumol/kg) and caffeine (300 mumol/kg) completely blocked the retardant effects of L-PIA on acquisition, although the phosphodiesterase inhibitor rolipram (3.0 mumol/kg) did not. In previously trained animals, L-PIA (5 mumol/kg) also increased the intensity threshold of a tone-conditioned stimulus for eliciting conditioned responses by more than 10 db. Theophylline (200 mumol/kg) and caffeine (300 mumol/kg) had no effect on the intensity threshold of the tone-conditioned stimulus but completely antagonized the effects of L-PIA. It was suggested that the depressant effects of the adenosine analog L-PIA on both the acquisition of conditioned responses and on the ability of a conditioned stimulus to elicit conditioned responses as soon as learning had occurred were mediated by adenosine receptors.