Retardation of associative learning in the rabbit by an adenosine analog as measured by classical conditioning of the nictitating membrane response.

A series of 5 experiments examined the effects of the adenosine agonist, N6-(L-phenylisopropyl) adenosine (L-PIA) and its isomer, D-PIA, on the acquisition of conditioned responses in the rabbit. Extension of the nictitating membrane was classically conditioned to a tone and light stimulus presented for 800 msec before delivery of a 100 msec shock--the unconditioned stimulus--to the skin over the paraorbital region of the head. L-PIA (5.0 mumol/kg) retarded the rate of acquisition of conditioned responses to both the tone- and light-conditioned stimuli, while D-PIA, at doses of 5.0 and 10.0 mumol/kg, had no significant effect. Control experiments employing the explicitly unpaired presentations of tone, light, and shock stimuli indicated that the retarded acquisition of conditioned responses produced by L-PIA was due to an action on associative learning. L-PIA had no effect on the threshold of the shock's eliciting of the unconditioned response nor on the amplitude of the elicited response, but produced a large and significant reduction in the ability of the tone-conditioned stimulus to evoke conditioned responses. It was concluded that L-PIA blocked the rate of associative learning by decreasing the excitatory properties of conditioned stimuli. These effects of L-PIA suggest that endogenous adenosine may act to modulate the rate of associative learning.