GABA(A) receptor changes in acute allopregnanolone tolerance

• To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.

Keyword

Anesthetics/administration & dosage/blood/pharmacokinetics

Animals

Brain/*drug effects/metabolism

Brain Chemistry/drug effects

Dentate Gyrus/chemistry/drug effects/metabolism

Dose-Response Relationship; Drug

Drug Tolerance

Gene Expression/drug effects

Immunohistochemistry

In Situ Hybridization

Infusions; Intravenous

Male

Pregnanolone/*administration & dosage/blood/pharmacokinetics

Protein Subunits/analysis/genetics

RNA; Messenger/genetics/metabolism

Rats

Rats; Sprague-Dawley

Receptors; GABA-A/analysis/*genetics

Receptors; GABA-B/analysis/genetics

Ventral Thalamic Nuclei/chemistry/drug effects/metabolism

Publication and Content Type

ref (subject category)

art (subject category)