Application of MRS
It is well known that GABA is the major inhibitory neurotransmitter in the mammalian cerebral cortex and that the functional activity of the GABAergic system is disrupted in several neurological and psychiatric disorders. Furthermore, several classes of psychotropic drugs are known to specifically affect the GABAergic system. Thus MRS should be an ideal method for assessing changes in the glutamate–GABA system in both man and animals. The initial studies using MRS were performed in rats following the administration of the antiepileptic drug, and GABA transaminase inhibitor, vigabatrin and subsequently in epileptic patients being treated with the drug. In the MRS studies on epileptic patients, it was shown that vigabatrin failed to raise the GABA concentration at a dose that exceeded 3 g/day (an antiepileptic dose). This led to a detailed analysis of the mechanism regulating the GABA concentration in the brain. The enzyme synthesizing GABA from glutamate, glutamate decarboxylase (GAD), exists in two major isoforms (GAD 67 and 65) in the brain and these are products of separate genes, differentially distributed (GAD 67 in the cytoplasm and GAD 65 in synaptic terminals) and have different kinetic properties. Using MRS, it was found that GAD 67 activity was reduced in response to the elevated GABA concentration and that, in rats, vigabatrin selectively inhibited the GAD 67 isoform. Other studies using the MRS technique have shown that several antiepileptic drugs with no known action on the GABAergic system (for example, GABApentin, topiramate and lamotrigine) also increase theconcentration of GABA in vivo. MRS studies also showed that the regulation of GABA metabolism was closely integrated with GABAergic function. In epileptic patients, these studies showed that the GABA concentration was decreased and that it was the cytosolic GABA concentration which was important in the suppression of seizures by antiepileptic drugs. Chronic vigabatrin administration was shown to reduce the seizure frequency in parallel with the rise in cytosolic GABA. In addition to epilepsy, reduced GABA has been recorded in patients with unipolar depression, following alcohol withdrawal and in hepatic encephalopathy. The finding that the concentration of GABA is reduced in depression is unexpected as there is no evidence that the disorder is associated with an increased cortical excitability. One possibility is that the reduction in GABA is a reflection of a decreased availability in its excitatory amino acid precursor glutamate.
It is well known that GABA is the major inhibitory neurotransmitter in the mammalian cerebral cortex and that the functional activity of the GABAergic system is disrupted in several neurological and psychiatric disorders. Furthermore, several classes of psychotropic drugs are known to specifically affect the GABAergic system. Thus MRS should be an ideal method for assessing changes in the glutamate–GABA system in both man and animals. The initial studies using MRS were performed in rats following the administration of the antiepileptic drug, and GABA transaminase inhibitor, vigabatrin and subsequently in epileptic patients being treated with the drug. In the MRS studies on epileptic patients, it was shown that vigabatrin failed to raise the GABA concentration at a dose that exceeded 3 g/day (an antiepileptic dose). This led to a detailed analysis of the mechanism regulating the GABA concentration in the brain. The enzyme synthesizing GABA from glutamate, glutamate decarboxylase (GAD), exists in two major isoforms (GAD 67 and 65) in the brain and these are products of separate genes, differentially distributed (GAD 67 in the cytoplasm and GAD 65 in synaptic terminals) and have different kinetic properties. Using MRS, it was found that GAD 67 activity was reduced in response to the elevated GABA concentration and that, in rats, vigabatrin selectively inhibited the GAD 67 isoform. Other studies using the MRS technique have shown that several antiepileptic drugs with no known action on the GABAergic system (for example, GABApentin, topiramate and lamotrigine) also increase theconcentration of GABA in vivo. MRS studies also showed that the regulation of GABA metabolism was closely integrated with GABAergic function. In epileptic patients, these studies showed that the GABA concentration was decreased and that it was the cytosolic GABA concentration which was important in the suppression of seizures by antiepileptic drugs. Chronic vigabatrin administration was shown to reduce the seizure frequency in parallel with the rise in cytosolic GABA. In addition to epilepsy, reduced GABA has been recorded in patients with unipolar depression, following alcohol withdrawal and in hepatic encephalopathy. The finding that the concentration of GABA is reduced in depression is unexpected as there is no evidence that the disorder is associated with an increased cortical excitability. One possibility is that the reduction in GABA is a reflection of a decreased availability in its excitatory amino acid precursor glutamate.
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