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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.

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