PROGRESSIVE DECREASE IN EXTRACELLULAR GABA CONCENTRATIONS IN THE POSTISCHEMIC PERIOD IN THE STRIATUM - A MICRODIALYSIS STUDY

Repetitive cerebral ischemia in gerbils produces delayed neuronal dama ge in the substantia nigra reticulata (SNr). This damage begins 4 to 5 days after the insult and is severe by day 7. The damage can be atten uated by GABA agonists. There is a prominent GABAergic striatal pathwa y to the SNr. Damage to this pathway leads to progressive loss of SNr neurons. This loss can be prevented by GABA agonists. We postulate tha t, ischemia-induced lack of GABAergic inhibitory input from the striat um to the SNr, may be responsible for this delayed neuronal damage. In the present experiment, we have measured striatal extracellular GABA concentrations with or without nipecotic acid, a GABA-reuptake inhibit or, in gerbils exposed to repetitive ischemia. GABA levels were measur ed on days 1, 3, 5, and 7 after the ischemic insult. Five control anim als and a similar number of ischemic animals were monitored on each da y. Extracellular fluid was collected using in vivo microdialysis and G ABA levels were measured by electrochemical detection with HPLC. The e xtracellular striatal GABA levels were very low in the initial three s pecimens collected, both in the control and in the ischemic animals. H owever, addition of nipecotic acid resulted in an immediate increase o f GABA in measurable range. In comparison to the controls, the increas e in GABA on day 1 and 3 were significantly higher in animals with rep etitive ischemia (two-way ANOVA with repeated measures). Subsequent me asurements showed a gradual decrease in GABA levels when compared to c ontrols. The increase in GABA with nipecotic acid was significantly lo wer on day 7 after the ischemic insults when compared to the controls. The increased GABA responsiveness immediately after the ischemic insu lts may reflect a protective effect against excitotoxicity. The subseq uent decline in GABA levels after the insult may be secondary to progr essive loss of striatal GABAergic neurons. This may contribute to the production of delayed neural damage in the SNr by a decrease in the in hibitory striatal input.