Acute PentyleneterazolInjection Reduces Rat GABA_A Receptor mRNA Levels and GABA Stimulation of Benzodiazepine Binding with NO Efect on Benzodiazepine Binding Site Density

摘要

The effects of a single convulsive dose of pentylenetetrazol (PTZ, 45 mg/kg i.p.) on rat brain 'Y-aminobutyric acid type A (GABAJ receptors were studied. Selected GABAA receptor subunit mRNAs were measured by Northern blot analysis (with {3-actin mRNA as a standard). Four hours after PTZ, the GABAA receptor 'Y2-mRNA was decreased in hippocampus, cerebral cortex, and cerebellum; a1-mRNA was decreased in cerebel- lum; and {32 subunit mRNA was decreased in cortex and cer- ebellum. The a5 subunit mRNA level was not altered. Those mRNAs that had been reduced were increased in some brain regions at the 24-h time point, and these changes reverted to control levels by 48 h. PTZ effect on GABAA receptors was also studied by autoradiographic binding assay with the benzodiaz- epine agonist [3Hjflunitrazepam (FNP), the GABAA agonist [3H]muscimol, and the benzodiazepine antagonist [3H]flumaze- nil. There was an overall decrease in rH]FNP binding 12 but not 24 h after PTZ treatment. In contrast, rH]muscimol binding was minimally affected, and [3H]flumazenil binding was unchanged after PTZ treatment. Additional binding studies were performed with well-washed cerebral cortical homogenates to minimize the amount of endogenous GABA. There was no PTZ effect on specific [3H]FNP binding. However, there was a significant re- duction in the stimulation of [3H]FNP binding by GABA. The results showed that an acute injection of PTZ caused transient changes in GABAA receptor mRNA levels without altering re- ceptor number but affected the coupling mechanism between the GABA and benzodiazepine sites of the GABAA receptor.