GABA and neuropsychiatric disorders.

Because GABA appears to be an important, if not the primary, inhibitory neurotransmitter in brain, it is not surprising to find biochemical, physiological and behavioral data indicating that activation of the GABAergic system may be efficacious in the treatment of epilepsy (Meldrum, 1975). In addition, a significant loss of GABA neurons has been noted around the seizure foci in monkey cortex after application of alumina gel (Ribek et al, 1979) and the GABA content of brain biopsy specimens from humans with focal epilepsy is reportedly reduced (Van Gelder et al, 1972). Furthermore, a significant reduction in cerebrospinal fluid GABA content has been found associated with myoclonic epilepsy (Enna et al, 1979). Probably the strongest evidence linking GABA to neuropsychiatric diseases has been obtained from studies on extrapyramidal disorders. Thus, with regard to Huntington's disease, numerous laboratories have reported finding a decrease in GABA containing neurons in the basal ganglia and substantia nigra of the Huntington brain (Perry et al, 1973: Enna et al, 1976b). In addition GABA receptor binding is also altered in postmortem brain samples obtained from Huntington patients, being increased in some regions (substantia nigra and cerebellum) (Enna et al, 1976a; Lloyd and Davidson, 1979) and possibly decreased in the corpus striatum (Enna et al, 1976 a & b; Lloyd et al, 1977b). Furthermore, cerebrospinal fluid analysis has revealed a decrease in the GABA content of this fluid (Enna et al, 1977). In addition, a recent report suggests that administration of GABAmimetics may be of benefit in treating the symptoms of this disease (Bartholini et al, 1979). GABA has also been implicated in Parkinson's disease since extrapyramidal glutamic acid decarboxylase (GAD) activity, and GABA content, are significantly reduced in untreated patients (Hornykiewicz et al, 1976; Laaksonen et al, 1978). In addition, while GABA receptor binding is unaltered in most regions of the Parkinson brain, there is a significant decrease in this receptor in the substantia nigra, probably as a result of the loss of dopamine cells in this brain region (Lloyd et al, 1977a; Reisine et al, 1977). To date, however, attempts to treat this disorder by increasing brain GABA activity have proven unsuccessful (Barbeau, 1973). Another neurological disorder that has been investigated is Alzheimer's disease, the most common form of presenile dementia. The results of this study indicate that there are regionally selective decreases in the number of GABA receptors in postmortem brain samples (Reisine et al, 1978). Specifically, both the cerebral cortex and corpus striatum had fewer GABA receptors than age-matched controls, whereas the hippocampal GABA receptors appear intact. This apparent loss of GABA receptors is undoubtedly related to the characteristic neuronal degeneration found in this disorder. However, it is impossible to predict which, if any, of the symptoms of Alzheimer's disease are primarily related to this apparent loss of GABA receptor sites.