Barbiturates are allosteric modulators of the CNS GABAA receptor, increasing [3H]-GABA binding to its receptor sites. In the present work we have studied the modulatory effect of the barbiturate pentobarbital on low-affinity GABA binding sites during ontogenetic development of the chick optic lobe. Our results indicate that [3H]-GABA binding enhancement by pentobarbital shows a differential profile during development, following a two-component enhancement model at early stages of development and a single-component enhancement model in the adult stage. Kinetic analysis performed at different stages of development showed that barbiturate enhancement was invariably due to an increase in [3H]-GABA binding affinity, while maximal binding capacity remained unchanged. Using GABA antagonists, picrotoxinin and bicuculline, convulsant sensitivity of high-affinity barbiturate modulatory sites was found at early stages. These data suggest that barbiturate action displays receptor heterogeneity during development, with high- and low-affinity modulatory sites only at early stages, while the high-affinity sites disappear between hatching and adulthood. Kinetic data indicate that both barbiturate modulatory sites are coupled to the GABAA receptor at early stages. The presence of high-affinity modulatory sites at early stages and at hatching suggests a major role during visual pathway maturation.
In the present report we studied the GABA-stimulated 36Cl- uptake during chick optic lobe development in order to establish the ontogenetic profile of the functional GABAA receptor complex. A concentration-dependent stimulation of 36Cl- influx by GABA was demonstrated, starting at developmental stages as early as 10 days of incubation. The maximal GABA-induced 36Cl- uptake changed significantly during ontogeny with highest values near hatching. However, GABA potency to stimulate ion influx remained unchanged. We also examined the effect of two neurosteroids, allopregnanolone and epipregnanolone, on GABA-stimulated 36Cl- influx at three developmental stages (embryonic day 14, post-hatching day 1 and adult stage). Both steroids enhanced ion uptake in a concentration-dependent manner, exerting greater stimulatory effects at early developmental stages. Allopregnanolone displayed EC50 values lower than epipregnanolone at all three time points and was also more potent at post-hatching stages. Analysis of the GABA concentration-effect curve disclosed that both steroid decreased EC50 values for GABA stimulation while Emax levels were unaffected. In conclusion, our results showed an early appearance of the GABA-associated chloride channel together with the ability of neurosteroids to modulate GABA-gating of such channel.
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