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

Abstract

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.

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

“…Thus, basal and MK-801-induced elevation of 5-HT were both completely dependent on nerve impulse. However, basal dialysate glutamate in the mPFC was not blocked by TTX, in good agreement with prior work (Moghaddam, 1993;Timmerman et al, 1999), which pointed out that only a minor portion of basal extracellular glutamate is indeed exocytotically released (Timmerman and Westerink, 1997). Nevertheless, the present study evidenced that MK-801-stimulated glutamate efflux is largely TTX dependent, that is released from neurons in an impulse-dependent manner.…”

The 5‐HT1A receptor agonist 8‐OH‐DPAT prevents prefrontocortical glutamate and serotonin release in response to blockade of cortical NMDA receptors

“…The lack of effect of 8-OH-DPAT on basal extracellular GLU is consistent with previous findings (Dijk et al 1995;Matsuyama et al 1996). This is not surprising as the inhibition of neurotransmission with tetrodotoxin does not affect basal GLU, probably reflecting the lack of relationship between basal GLU and neuronal activity in microdialysis studies (Timmerman and Westerink 1997;Melendez et al 2005). Interestingly, in vivo studies showed that 8-OH-DPAT potently inhibited the K + -evoked release of GLU in cerebellar synaptosomes (Maura et al 1988) but did not affect veratridine-evoked release of GLU in the rat mPFC (Golembiowska and Dziubina 2002).…”

Excitotoxicity in neurological disorders — the glutamate paradox

“…In contrast to our data outlined above, and those of Fillenz et al [25] and Westerink et al [54], electrical stimulation of the prefrontal cortex was found in several studies to increase extracellular glutamate in brain regions receiving projections from this area, and some of these changes have been linked to enhanced release of vesicular glutamate because they were inhibited by the Na + -channel blocker tetrodotoxin (TTX) [20,44,59]. However, when a compound has both transmitter and metabolic functions (e.g.…”