Effect of Ischemia on the In Vivo Release of Striatal Dopamine, Glutamate, and γ‐Aminobutyric Acid Studied by Intracerebral Microdialysis

Abstract

We have previously described a marked attenuation of postischemic striatal neuronal death by prior substantia nigra (SN) lesioning. The present study was carried out to evaluate whether the protective effect of the lesion involves changes in the degree of local cerebral blood flow (ICBF) reduction, energy metabolite depletion, or alterations in the extracellular release of striatal dopamine (DA), glutamate (Glu), or gamma-aminobutyric acid (GABA). Control and SN-lesioned rats were subjected to 20 min of forebrain ischemia by four-vessel occlusion combined with systemic hypotension. Levels of ICBF, as measured by the autoradiographic method, and energy metabolites were uniformly reduced in both the ipsi- and contralateral striata at the end of the ischemic period, a finding implying that the lesion did not affect the severity of the ischemic insult itself. Extracellular neurotransmitter levels were measured by microdialysis; the perfusate was collected before, during, and after ischemia. An approximately 500-fold increase in DA content, a 7-fold increase in Glu content, and a 5-fold increase in GABA content were observed during ischemia in nonlesioned animals. These levels gradually returned to baseline by 30 min of reperfusion. In SN-lesioned rats, the release of DA was completely prevented, the release of GABA was not affected, and the release of Glu was partially attenuated. However, excessive extracellular Glu concentrations were still attained, which are potentially toxic. This, taken together with the previous neuropathological findings, suggests that excessive release of DA is important for the development of ischemic cell damage in the striatum.

Protective Role of Kv7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

“…2 Thus, modulation of K + channel activity has been acknowledged as a possible target for neuroprotection. Among the different neurotransmitters, dopamine release has been shown to reach very high levels soon after an ischemic insult in the caudate, and also to contribute to neuronal damage; 5 indeed, depletion of dopaminergic nigro-striatal projections has been shown to reduce ischemic damage. 19 Dopamine and related compound such as L-3,4-dihydroxyphenylalanine and 6-OH-DOPA are considered as potent excitotoxic agents, possibly contributing to neurodegeneration in Parkinson's and Huntington's disease.…”

“…4 Although glutamate release has been viewed as a main cause of neuronal damage, massive release of monoamines, such as dopamine, also occurring immediately after the onset of ischemia, can be neurotoxic and thus contribute to cell death. 5 Moreover, it has been shown that chronic methamphetamine administration as well as striatal injection of dopamine caused a marked presynaptic and postsynaptic neuronal death in rodents. 6 Dopamine release during ischemia is supposed to be a consequence of different mechanisms, such as cell depolarization, reversal of dopamine transporters, and ATP shortage.…”

The relationship between excitotoxicity and oxidative stress in the central nervous system

“…This index was first used to describe the imbalance between excitatory and inhibitory processes at the neuronal level, where brain concentrations of glutamate and glycine, and the inhibitory amino acid gamma-aminobutyrate (GABA) were measured in rats subjected to transient global ischemia. 10 This index is intended to provide an overall assessment regarding the state of excitotoxicity and is thus a measure of neural imbalance. Under basal conditions the index would display homeostasis between excitatory and inhibitory processes.…”

Ischemia-Induced Release of Amino Acids in the Hippocampus of Aged Hypertensive Rats

“…The age related difference in increase in taurine might be based on regional nature because the magnitude of the increase in SHR during ischemia was smaller (-lO-fold) in the striatum of both adult and aged SHR compared with that in the hippocampus (16-to 26-fold). The vulnerability of the hippocampus to ischemia is likely to be more closely related to ex citotoxicity than that of the striatum (Globus et al , 1988;Benveniste et al , 1990) as is that of the cere bral cortex (Park et al , 1988). As for the other amino acids in this study, viz., glutamine, alanine, glycine plus threonine, and GABA, there were no differences in the changes in extracellular concentrations between the groups.…”