Presynaptic receptors for virtually all transmitters have been identified throughout the nervous system. Recent studies in the hippocampus provide new insights into the mechanisms by which the activation of these receptors leads to presynaptic inhibition of transmitter release, and characterize the second messengers involved in coupling presynaptic receptors to their effectors. Presynaptic receptors also provide a tractable route via which the amount of transmitter release may be selectively regulated in therapeutically useful ways.

Transmitter release is elicited by the influx of Ca 2+ through voltage-dependent channels that are activated when an action potential invades the axon terminal. Elevated intraterminal Ca e+ concentrations then increase the probability that transmitter-containing vesicles will fuse with the presynaptic membrane and release their contents into the synaptic cleft. Transmitter release at a given synapse is not constant, but rather is subject to a variety of modulatory influences that can either increase or decrease the probability of release. More than 35 years ago, Frank and Fuortes 1 presented the first evidence for presynaptic inhibition of synaptic transmission at Ia afferents to spinal motoneurons. We now know that there are receptors for neurotransmitters, at or near the presynaptic terminals of many synapses, whose activation can change the likelihood that a presynaptic action potential will successfully result in transmitter release. Surprisingly, all transmitters examined to date produce presynapfic inhibition in the hippocampus, and there are, to our knowledge, no examples of transmitters that produce presynaptic facilitation in