The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol

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Abstract

The effects of intraperitoneally (IP) or intracerebroventricularly (ICV) administered neurosteroids [allopregnanolone (AP); 5β-tetrahydrodeoxycorticosterone (5β-THDOC); dehydroepiandrosterone sulfate (DHEAS); pregnenolone sulfate (PS)] and their precursors [progesterone (PROG), pregnanedione (PREG)] on N-methyl-d-aspartic acid (NMDA)-, picrotoxin (PTX)- and bicuculline (BIC)-induced seizures and ethanol-induced sleep were studied in mice. It was found that IP injections of (+)MK-801 most potently antagonized NMDA-, PTX- and BIC-induced seizures, as compared to diazepam (DZP), PROG and PREG. Both precursors of neurosteroids appeared only marginally active in the applied models of convulsions. ICV injections of AP selectively blocked PTX- and BIC-induced seizures, whereas 5β-THDOC and (+)MK-801 also antagonized NMDA-induced convulsions. ICV administered DHEAS induced seizures in a dose-dependent way. ICV injections of AP and midazolam shortened the latency and prolonged the duration of sleep induced by IP injections of ethanol (5.0 g/kg). On the contrary, DHEAS and PS significantly reduced the hypnotic-like effect of ethanol. The obtained results suggest that neurosteroids may modulate in an agonistic (AP, 5β-THDOC), or antagonistic way (PS, DHEAS), the GABAA receptor complex functions. Some of them (5β-THDOC) also interact with NMDA receptors. AP appeared to be the most selectively acting compound, with its profile of action fully comparable to that of midazolam. AP also enhanced the hypnotic effect of ethanol, pointing out to the propensity to interact with centrally depressant agents. These findings, together with the possibility of conversion of some neurosteroids in the brain to other steroid hormones (testosterone, estradiol and aldosterone), indicate the limitations of their use for the treatment of neurological and psychiatric disorders.

Section snippets

Subjects

The experiments were carried out on male albino Swiss mice weighing 20–25 g. All animals were acclimated to their home cages for 5 days before testing. They were housed with water and food ad libitum under a 12-h light–dark cycle, and at a controlled temperature (20°C). All experiments were done between 11 AM and 4 PM. The experiments were performed in accordance with the European Communities Council Directive of 24 November 1986 (86/609 EEC). All experimental procedures using animal subjects

Chemoconvulsants

PTX produced seizures and the lethal effect with a LD50=9.92 mg/kg (95% CL, CL=9.05–10.87). Subsequently, the dose of 12 mg/kg (LD85) was selected for further experiments (Fig. 2). In mice, IP and ICV injections of BIC produced convulsions and lethal effect with a respective LD50 of 11.41 mg/kg (CL=10.48–12.43) and 28.91 nmol (CL=18.97–43.99) (Fig. 2). The doses of 13 mg/kg and 54.44 nmol (LD85) were selected for further experiments. In case of NMDA, LD50 was found to be 100.72 mg/kg

Discussion

Both precursors of neurosteroids, PROG and PREG, appeared only marginally active in all examined models of seizures. The potencies of PROG and PREG in inhibiting convulsions were at least two orders of magnitude lower than those of DZP and (+)MK-801. Several factors may contribute to this finding, e.g. peripheral drugs metabolism and limited penetration of their active metabolites to the brain. It is noteworthy that PROG and PREG do not show any appreciable affinity towards GABAA receptors by

Uncited references

[17]

[22]

Acknowledgements

This work was supported by the State Committee for Scientific Research Grant No. 4PO5A06315.

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