Garcia Eric F, Woolley Dorothy E
Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, CA, USA.
Proc West Pharmacol Soc. 2008;51:18-22.
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.
七氯曾被广泛用作杀虫剂。它是一种γ-氨基丁酸A受体拮抗剂，可引发癫痫发作。它还会增加大脑中的外周苯二氮䓬受体（PBRs）。PBRs存在于神经胶质细胞的线粒体外膜上，而非神经元中，并且是大脑中类固醇生成所必需的。我们比较了在出生后第0天至60天的10个年龄段，对雄性和雌性大鼠急性口服七氯（60毫克/毫升油/千克体重）后1小时和2小时时，大脑PBR表达和癫痫发作严重程度的影响。从出生后第10天到60天，雌性大鼠在口服七氯后1小时和2小时时，大脑PBR表达比对照组增加了约175 - 225%。然而，在雄性大鼠中，PBRs仅在30 - 60日龄时1小时增加，但在2小时时任何年龄段均未增加。在30 - 60日龄的雄性大鼠口服七氯后2小时，PBRs显著低于1小时时，甚至有低于对照水平的趋势。相比之下，在1小时时，10至20日龄的雄性大鼠癫痫发作强度大于雌性，在16至30日龄的2小时时更是如此，这反映出雄性大鼠2小时时的PBR水平低于1小时时。因此，PBR表达的性别差异与癫痫发作强度的性别差异相反。大脑中的PBRs合成多种神经甾体，包括别孕烯醇酮，它是一种有效的抗惊厥剂。我们推测，七氯给药后癫痫发作强度的性别差异是由于七氯在雌性大鼠中大幅增加PBR表达，而在雄性大鼠中却没有。因此，雌性大鼠中PBRs的更高表达会导致比雄性大鼠合成更多的别孕烯醇酮。所以，由于别孕烯醇酮的抗惊厥作用，雌性大鼠的癫痫发作强度低于雄性。相比之下，最大电休克（MES）在雄性和雌性发育中的大鼠中均会引发癫痫发作并增加大脑中的PBRs，在10 - 20日龄时无性别差异。
