Cocaine inhibits hippocampal long-term potentiation

Long-term potentiation (LTP) is a form of synaptic plasticity that may underlie learning and memory. The experiments reported here demonstrate that cocaine blocks the induction of LTP at the excitatory synapses in the CA1 region of the hippocampus, but does not appear to do so by blocking NMDA receptors or channels. Once LTP had been established, however, cocaine had no effect on the potentiated response. Cocaine was also able to block LTP initiated by superfusing slices with 25 mM TEA. The ability to block LTP was shared by the local anesthetics lidocaine and procaine, but not by tetrodotoxin, suggesting that the blockade of sodium channels alone did not disrupt LTP. Biochemical experiments demonstrated that cocaine can inhibit phosphorylation of purified Synapsin I by Ca2+/calmodulin-dependent protein kinase II. This effect, presumably mediated by effects on calmodulin, is a previously unreported action of cocaine, and suggests that cocaine at high dose levels might disrupt types of learning that are mediated by an LTP-like mechanism.