Brain microdialysis of GABA and glutamate: what does it signify?

Microdialysis has become a frequently used method to study extracellular levels of GABA and glutamate in the central nervous system. However, the fact that the major part of GABA and glutamate as measured by microdialysis does not fulfill the classical criteria for exocytotic release questions the vesicular origin of the amino acids in dialysates. Glial metabolism or reversal of the (re)uptake sites has been suggested to be responsible for the pool of nonexocytotically released amino-acid transmitters that seem to predominate over the neuronal exocytotic pool. The origin of extracellular GABA and glutamate levels and, as a consequence, the implications of changes in these levels upon manipulations are therefore obscure. This review critically analyzes what microdialysis data signify, i.e., whether amino-acid neurotransmitters sampled by microdialysis represent synaptic release, carrier-mediated release, or glial metabolism. The basal levels of GABA and glutamate are virtually tetrodotoxin- and calcium-independent. Given the fact that evidence for nonexocytotic release mediated by reversal of the uptake sites as a release mechanism relevant for normal neurotransmission is so far limited to conditions of "excessive stimulation," basal levels most likely reflect a nonneuronal pool of amino acids. Extracellular GABA and glutamate concentrations can be enhanced by a wide variety of pharmacological and physiological manipulations. However, it is presently impossible to ascertain that the stimulated GABA and glutamate in dialysates are of neuronal origin. On the other hand, under certain stimulatory conditions, increases in amino-acid transmitters can be obtained in the presence of tetrodotoxin, again suggesting that aspecific factors not directly related to neurotransmission underlie these changes in extracellular levels. It is concluded that synaptic transmission of GABA and glutamate is strictly compartmentalized and as a result, these amino acids can hardly leak out of the synaptic cleft and reach the extracellular space where the dialysis probe samples.