GABA release in rat cortical slices is unable to cope with demand if the autoreceptor is blocked

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Abstract
Electrically stimulated release of neurotransmitters in brain slices normally displays frequency dependence because of progressive activation of autoreceptors by endogenously released transmitter, which is abolished by blockade of autoreceptors. In consequence, the maximal increase caused by an autoreceptor antagonist in percent of the corresponding controls should be greater at higher than at lower frequencies. In the case of γ-aminobutyric acid (GABA), we have previously found a marked deviation from this expectation. Among several explanations envisaged, computer simulation suggested only one to be compatible with the experimental data: the release mechanism may not be able to cope with high demand. This hypothesis was tested by investigating the frequency dependence of the release of3H-GABA in the presence and absence of a high concentration of the potent GABAB antagonist, CGP 55845, using extremely short stimulation periods. To this end, slices were stimulated with groups of 4 POPS (a POP — pseudo-one-pulse — consists of 4 pulses delivered at 100 Hz). The intervals between the POPs within a group were varied from 60-0.5 s, corresponding to frequencies within the POP group of 0.0167–2 Hz. Under such circumstances, the theoretically expected pattern was indeed observed: the GABAB antagonist abolished the frequency dependence. In a second series of experiments, fractional release per POP was determined when 4–32 POPs were delivered at 2 Hz, with and without CGP 55845. The increase of GABA release elicited by the GABAB antagonist gradually subsided with increasing number of POPS. It was about 50Q7o of that observed during the first 4 POPs in the 4 subsequent ones, and almost nil in the last 16 of a total of 32 POPs. The results of this study support the hypothesis generated with the help of computer simulation, that release may not be able to keep up with high demand. They further suggest that exhaustion of the releasable transmitter pool occurs surprisingly fast. It is not known whether this phenomenon is physiologically relevant or a consequence of metabolic stress to which the slices are subjected during preparation and superfusion, or of their exposure to transaminase and uptake inhibitors, but it provides an explanation for the anomalies observed in the studies of the effects of GABAB antagonists on3H-GABA release.

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