CPP impairs contextual learning at concentrations below those that block pyramidal neuron NMDARs and LTP in the CA1...

Drugs that block N-methyl-d-aspartate receptors (NMDARs) suppress hippocampus-dependent memory formation; they also block long-term potentiation (LTP), a cellular model of learning and memory. However, the fractional block that is required to achieve these effects is unknown. Here, we measured the dose-dependent suppression of contextual memory in vivo by systemic administration of the competitive antagonist (R,S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP); in parallel, we measured the concentration-dependent block by CPP of NMDAR-mediated synapses and LTP of excitatory synapses in hippocampal brain slices in vitro. We found that the dose of CPP that suppresses contextual memory in vivo (EC50 = 2.3 mg/kg) corresponds to a free concentration of 53 nM. Surprisingly, applying this concentration of CPP to hippocampal brain slices had no effect on the NMDAR component of evoked field excitatory postsynaptic potentials (fEPSP_NMDA), or on LTP. Rather, the IC50 for blocking the fEPSP_NMDA was 434 nM, and for blocking LTP was 361 nM - both nearly an order of magnitude higher. We conclude that memory impairment produced by systemically administered CPP is not due primarily to its blockade of NMDARs on hippocampal pyramidal neurons. Rather, systemic CPP suppresses memory formation by actions elsewhere in the memory-encoding circuitry.