Gender differences in brain peripheral benzodiazepine receptor (PBR) expression and seizures produced by heptachlor...

Heptachlor has been widely used as an insecticide. It is a GABA-A antagonist and causes seizures. It also increases peripheral benzodiazepine receptors (PBRs) in brain. PBRs are found on the outer mitochondrial membrane in glia, rather than in neurons, and are necessary for steroidogenesis in brain. We compared the effects of acute oral administration of heptachlor (60 mg/ml oil/kg body wt) at 10 ages from postnatal day (PND) 0 to 60 on brain PBR expression and seizure severity in both male and female rats at 1 and 2 hr after administration. From PND 10 through 60, brain PBR expression was increased about 175-225% of controls at both 1 and 2 hr after heptachlor in females. In males however, PBRs were only increased at 30-60 days at 1 hr but not at any age at 2 hr. At 2 hr after heptachlor at 30-60 days in males, PBRs were significantly lower than at 1 hr and even tended to be lower than control levels. By contrast, seizure intensity was greater in males than in females from 10 through 20 days of age at 1 hr and was even greater at 2 hr from 16 through 30 days of age, reflecting the lower PBR levels at 2 hr than at 1 hr in males. Thus, the gender difference in PBR expression was the opposite of the gender difference in seizure intensity. PBRs in brain synthesize several neurosteroids, including allopregnanolone, which is a potent anticonvulsant agent. We hypothesize that the gender differences in seizure intensity after heptachlor were due to the action of heptachlor in greatly increasing PBR expression in females but not in males. Thus the greater expression of PBRs in females would result in more synthesis of allopregnanolone than in males. Therefore, because of allopregnanolone's anticonvulsant effects, seizure intensity was less in females than in males. By comparison, maximal electroshock (MES) caused seizures and increased PBRs in brain in both male and female developing rats with no gender differences at 10-20 days of age.