Changes of GABA receptor binding and subunit mRNA level in rat

In the present study, we have investigated the effects of prolonged inhibition of NMDA receptor by infusion of subtoxic dose of MK-801 to examine the modulation of GABA receptor binding and GABA receptor subunit mRNA level in rat brain. It has been A A reported that NMDA-selective glutamate receptor stimulation alters GABA receptor pharmacology in cerebellar granule neurons in vitro A by altering the levels of selective subunit. However, we have investigated the effect of NMDA antagonist, MK-801, on GABA receptor A binding characteristics in discrete brain regions by using autoradiographic and in situ hybridization techniques. The GABA receptor A 3 3 35 bindings were analyzed by quantitative autoradiography using [ H]muscimol, [ H]flunitrazepam, and [ S]TBPS in rat brain slices. Rats were infused with MK-801 (1 pmol /10 ml per h, i.c.v.) for 7 days, through pre-implanted cannula by osmotic minipumps (Alzet, model 3 2ML). The levels of [ H]muscimol binding were highly elevated in almost all of brain regions including cortex, caudate putamen, 3 35 thalamus, hippocampus, and cerebellum. However, the [ H]flunitrazepam binding and [ S]TBPS binding were increased only in specific regions; the former level was increased in parts of the cortex, thalamus, and hippocampus, while the latter binding sites were only slightly elevated in parts of thalamus. The levels of b2-subunit were elevated in the frontal cortex, thalamus, hippocampus, brainstem, and cerebellar granule layers while the levels of b3-subunit were significantly decreased in the cortex, hippocampus, and cerebellar granule layers in MK-801-infused rats. The levels of a6and d-subunits, which are highly localized in the cerebellum, were increased in the cerebellar granule layer after MK-801 treatment. These results show that the prolonged suppression of NMDA receptor function by 3 3 35 MK-801-infusion strongly elevates [ H]muscimol binding throughout the brain, increases regional [ H]flunitrazepam and [ S]TBPS binding, and alters GABA receptor subunit mRNA levels in different directions. The chronic MK-801 treatment has differential effect on A various GABA receptor subunits, which suggests involvement of differential regulatory mechanisms in interaction of NMDA receptor A with the GABA receptors.  2000 Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: GABA receptors