Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5

Abstract

Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA)¹ and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization^2,3. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation^4–6. We now report that chronic intraventricular infusion of D, L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage⁷, without affecting visual discrimination learning, which is not⁸. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis^9–11 that LTP is involved in some, but not all, forms of learning.