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GABA_A receptor -subunit may confer benzodiazepine insensitivity to the caudal aspect of the nucleus tractus solitarii of the rat

Sergey Kasparov, Katy A. Davies *, Umesh A. Patel *, Pedro Boscan, Maurice Garret † and Julian F. R. Paton

1. Benzodiazepines (BZ) and barbiturates both potentiate chloride currents through GABA_A receptors to enhance inhibition. However, unlike barbiturates BZ do not impair autonomic control of heart rate. We hypothesised that BZ might not significantly potentiate GABAergic transmission in the caudal nucleus of the solitary tract (cNTS), which is critically important for mediating the baroreceptor reflex.
2. In rat brain slices the BZ agonists chlordiazepoxide and midazolam (2 and 50 µM) did not significantly enhance currents evoked by GABA in voltage-clamped cNTS neurones. Chlordiazepoxide (50 µM) reversibly increased electrically evoked IPSPs in 5/10 rostral NTS (rNTS) neurones but only in 2/10 cNTS neurones. Pentobarbitone (50-100 µM) was effective in enhancing GABA_A-mediated responses in all NTS neurones. An inverse BZ agonist, methyl 6,7-dimethoxy-4-ethyl--carboline-3-carboxylate (DMCM; 1 or 10 µM), failed to depress GABA-induced currents in the cNTS.
3. Microinjections of midazolam (10 and 100 µM solutions) into the cNTS did not affect the baroreceptor reflex (P > 0.2) while pentobarbitone (100 µM) significantly and reversibly depressed it (gain decrease to 53 ± 11 % of control, P < 0.01).
4. Reverse transcriptase polymerase chain reaction revealed the presence of ₁, ₂, ₂, ₃ and ₂ GABA_A receptor subunit mRNA in the cNTS. No alternatively spliced variants of the ₁- and ₂-subunits were revealed. Moreover, GABA_A -subunit mRNA was found in both the cNTS and rNTS as two alternatively spliced transcripts.
5. Immunocytochemical analysis revealed numerous GABA_A -subunit-positive neurones within the cNTS with significantly fewer -subunit-positive cells in the rNTS.
6. As incorporation of the -subunit in recombinant GABA_A receptors may confer BZ insensitivity we propose that the paucity of BZ actions in the cNTS is due to a high level of -subunit expression. This is the first demonstration of a possible physiological impact of the -subunit on native GABA_A receptors.

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