IDENTIFICATION OF CENTRAL NEUROTRANSMITTERS
Because drug selectivity is based on the fact that different pathways use different transmitters, a primary goal of neuropharmacologists is to identify the transmitters in CNS pathways. Establishing that a chemical substance is a transmitter has been far more difficult for central synapses than for peripheral synapses. The following criteria have been established for transmitter identification.
Approaches that have been used to prove that a suspected trans-mitter resides in the presynaptic terminal of the pathway under study include biochemical analysis of regional concentrations of suspected transmitters and immunocytochemical techniques for enzymes and peptides.
To determine whether the substance is released from a particular region, local collection (in vivo) of the extracellular fluid can sometimes be accomplished. In addition, slices of brain tissue can be electrically or chemically stimulated in vitro and the released substances measured. To determine whether the release is relevant to synaptic transmission, it is important to establish that the release is calcium-dependent.
Finally, application of the suspected substance should produce a response that mimics the action of the transmitter released by nerve stimulation. Furthermore, application of a selective antagonist should block the response. Micro-iontophoresis, which permits highly local-ized drug administration, has been a valuable technique in assessing the action of suspected transmitters. Because of the complexity of the CNS, specific pharmacologic antagonism of a synaptic response pro-vides a particularly powerful technique for transmitter identification.