GABA is a major inhibitory
neurotransmitter in the mammalian retina and it acts at many different sites via a variety of postsynaptic receptors. These include GABAA receptors and
bicuculline-resistant
GABAC receptors. The release of
acetylcholine (ACh) is inhibited by
GABA and strongly potentiated by
GABA antagonists. In addition,
GABA appears to mediate the null inhibition which is responsible for the mechanism of directional selectivity in certain
ganglion cells. We have used these two well-known examples of
GABA inhibition to compare three
GABA antagonists and assess the contributions of GABAA and
GABAC receptors. All three
GABA antagonists stimulated ACh release by as much as ten-fold. By this measure, the ED50s for
SR-95531,
bicuculline, and
picrotoxin were 0.8, 7.0, and 14 microM, respectively.
Muscimol, a potent GABAA agonist, blocked the effects of
SR-95531 and
bicuculline, but not
picrotoxin. This indicates that
SR-95531 and
bicuculline are competitive antagonists at the GABAA receptor, while
picrotoxin blocks GABAA responses by acting at a different, nonreceptor site such as the
chloride channel. In the presence of a saturating dose of
SR-95531 to completely block GABAA receptors,
picrotoxin caused a further increase in the release of ACh. This indicates that
picrotoxin potentiates ACh release by a mechanism in addition to the block of GABAA responses, possibly by also blocking
GABAC receptors, which have been associated with bipolar cells. All three
GABA antagonists abolished directionally selective responses from ON/OFF directional-selective (DS)
ganglion cells. In this system, the ED50S for
SR-95531,
bicuculline, and
picrotoxin were 0.7 microM, 8 microM, and 94.6 microM, respectively. The results with
SR-95531 and
bicuculline indicate that GABAA receptors mediate the inhibition responsible for directional selectivity. The addition of
picrotoxin to a high dose of
SR-95531 caused no further increase in firing rate. The comparatively high dose required for
picrotoxin also suggests that
GABAC receptors do not contribute to directional selectivity. This in turn suggests that feedforward GABAA inhibition, as opposed to feedback at bipolar terminals, is responsible for the null inhibition underlying directional selectivity.