Advantages of an antagonist: bicuculline and other GABA antagonists

AbstractGABA 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 μM, 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 μM, 8 μM, and 94.6 μM, 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.

Download Full-text

Role of GABAergic Inhibition in the Coding of Interaural Time Differences of Low-Frequency Sounds in the Inferior Colliculus

Journal of Neurophysiology ◽

10.1152/jn.00956.2004 ◽

2005 ◽

Vol 93 (6) ◽

pp. 3390-3400 ◽

Cited By ~ 17

Author(s):

W. R. D’Angelo ◽

S. J. Sterbing ◽

E.-M. Ostapoff ◽

S. Kuwada

Keyword(s):

Inferior Colliculus ◽

Signal To Noise Ratio ◽

Interaural Time Difference ◽

Low Frequency ◽

Gabaergic Inhibition ◽

Interaural Time Differences ◽

Gaba Antagonists ◽

Inhibitory Transmitter ◽

Almost All

A major cue for the localization of sound in space is the interaural time difference (ITD). We examined the role of inhibition in the shaping of ITD responses in the inferior colliculus (IC) by iontophoretically ejecting γ-aminobutyric acid (GABA) antagonists and GABA itself using a multibarrel pipette. The GABA antagonists block inhibition, whereas the applied GABA provides a constant level of inhibition. The effects on ITD responses were evaluated before, during and after the application of the drugs. If GABA-mediated inhibition is involved in shaping ITD tuning in IC neurons, then applying additional amounts of this inhibitory transmitter should alter ITD tuning. Indeed, for almost all neurons tested, applying GABA reduced the firing rate and consequently sharpened ITD tuning. Conversely, blocking GABA-mediated inhibition increased the activity of IC neurons, often reduced the signal-to-noise ratio and often broadened ITD tuning. Blocking GABA could also alter the shape of the ITD function and shift its peak suggesting that the role of inhibition is multifaceted. These effects indicate that GABAergic inhibition at the level of the IC is important for ITD coding.

Download Full-text

EFFECTS OF GABA ANTAGONISTS AND HABITUATION TO NOVELTY ON ETHANOL-INDUCED LOCOMOTOR ACTIVITY IN MICE

Alcohol and Alcoholism ◽

10.1093/oxfordjournals.alcalc.a045117 ◽

1991 ◽

Vol 26 (3) ◽

pp. 315-322 ◽

Cited By ~ 11

Author(s):

ULRIKE M. KOECHLING ◽

BRIAN R. SMITH ◽

ZALMAN AMIT

Keyword(s):

Locomotor Activity ◽

Gaba Antagonists

Download Full-text

Neurotransmitter receptors mediating excitatory input to cells in the cat lateral geniculate nucleus. I. Lagged cells

Journal of Neurophysiology ◽

10.1152/jn.1990.63.6.1347 ◽

1990 ◽

Vol 63 (6) ◽

pp. 1347-1360 ◽

Cited By ~ 73

Author(s):

P. Heggelund ◽

E. Hartveit

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Receptor Antagonist ◽

Lateral Geniculate Nucleus ◽

Transient Response ◽

Visual Response ◽

Response Component ◽

Gaba Antagonists ◽

Gaba A ◽

Lagged Cells

1. Synaptic mechanisms that might explain the functional properties of the recently discovered class of lagged cells in the dorsal lateral geniculate nucleus (LGN) were analyzed with electrophysiological and pharmacologic techniques. To study the type of excitatory amino acid (EAA) receptor that mediates visual responses of lagged cells, we recorded the response of single cells to a stationary flashing light spot before, during, and after microiontophoretic application of antagonists and agonists to EAA receptors. 2. The visual response of the lagged cells could be almost completely blocked by an antagonist to the N-methyl-D-aspartate (NMDA) receptor. The degree of suppression was dose dependent, and the average maximum degree of suppression for all the cells was 94%. NMDA enhanced the response, and this enhancement was antagonized by NMDA antagonists. A quisqualate/kainate receptor antagonist had no significant effect on the lagged cells. 3. These findings indicate that the visual response in lagged cells is dependent upon activation of NMDA receptors, which may directly result from activation of retinal inputs. 4. No pharmacologic difference was seen between lagged X- and Y-cells, or between lagged ON- and OFF-center cells. 5. gamma-Aminobutyric acid-A (GABA-A) receptor antagonists were used to study whether the characteristic lag of the visual response and the suppression of the initial transient response component of the lagged cells are dependent on geniculate inhibition. Beside enhancement of the visual response, the GABA antagonists strongly reduced the lag of the visual response, and an initial transient response component occurred instead of the initial suppression. The lag remained slightly longer than for nonlagged cells, and the peak firing rate of the transient was below values typical for nonlagged cells, indicating that the lagged cell properties are dependent on other factors beside GABA-A receptor-mediated inhibition. 6. The enhanced visual response during iontophoresis of GABA antagonists could be completely blocked by simultaneous iontophoresis of an NMDA-receptor antagonist. This gives further support to the hypothesis that the retinal input to these cells is mediated by NMDA receptors. 7. The NMDA-receptor/ionophore complex mediates excitatory postsynaptic potentials (EPSPs) characterized by slow rise and decay times and long duration. The ionophore is characterized by a voltage-dependent blockade that makes these receptors particularly sensitive to inhibitory input. The temporal interplay between the slow NMDA receptor-mediated EPSPs and the fast GABA receptor-mediated inhibitory postsynaptic potentials (IPSPs) may explain the characteristic response properties of the lagged cells.

Download Full-text