The influence of progesterone and testosterone on the incidence of seizures after administration of intraperitoneal pentylenetetrazol and subcutaneous strychnine was evaluated in mice. Pentylenetetrazol and strychnine were administered in doses that induced seizures in 40-50% of control mice in dioestrus (48 and 0.9 mg/kg, respectively). The percentage of seizures induced by pentylenetetrazol and strychnine was significantly lower in female mice in prooestrus/oestrus, when progesterone levels are high, than in dioestrus, when progesterone levels are low. Pretreatment of pentylenetetrazol-challenged mice with progesterone (250 microg/kg) increased the incidence of seizures in prooestrus/oestrus, without affecting seizures in dioestrus. The same pretreatment in strychnine-challenged mice also increased the incidence of seizures in prooestrus-dioestrus, but significantly reduced the incidence of seizures in dioestrus. In addition, progesterone pretreatment significantly increased the percentage of deaths induced by strychnine in prooestrus-oestrus, reducing deaths in dioestrus. Orchidectomized male mice had a significantly higher incidence of seizures after administration of pentylenetetrazol and strychnine than control mice. Administration of 11 daily doses of 250 microg/kg of testosterone to castrated mice significantly reduced the incidence of seizures induced by pentylenetetrazol. These results confirm the modulatory influence of reproductive steroids on the excitability of the central nervous system and the possible clinical importance of progesterone and testosterone in the management of partial epilepsy.

The present work was designed to study the influence of testosterone and oestrogens on the benzodiazepine withdrawal syndrome in mice. Several withdrawal signs were induced by 15 mg/kg intraperitoneally of flumazenil in diazepam-treated mice. The most noticeable were jerks, usually accompanied by tail lifts, and seizures. The intensity of the diazepam withdrawal syndrome was significantly lower in male than in female mice, especially in relation to the incidence of seizures. Castrated male mice showed a significant increase in the intensity of withdrawal syndrome. In addition, diazepam produced a significant increase of body weight in males but not in females. The principal finding of the present work is that the incidence of seizures produced by the administration of flumazenil was significantly lower in male than in female diazepam-treated mice. This fact suggests that the mechanism of action of benzodiazepines is modulated by the action of sexual hormones, and that testosterone plays a relevant role.

The influence of progesterone and oestrogens on the benzodiazepine withdrawal syndrome in mice was studied. The intraperitoneal administration of 15 mg/kg of flumazenil induced a withdrawal syndrome in chronic diazepam-treated mice, characterized by jerks, usually accompanied by tail lifts, and seizures. The principal finding of the present work is that the intensity of diazepam withdrawal syndrome was significantly reduced by acute administration of progesterone as revealed by a low incidence of jerks and seizures. The action of progesterone could be due to a modulatory role of the hormone on neuronal activity as an anxiolytic agent. The modulatory activity of progesterone appears to be related to changes in the pharmacological properties of benzodiazepine receptors.

The influence of progesterone and testosterone on the incidence of seizures after administration of intraperitoneal pentylenetetrazol and subcutaneous strychnine was evaluated in mice. Pentylenetetrazol and strychnine were administered in doses that induced seizures in 40-50% of control mice in dioestrus (48 and 0.9 mg/kg, respectively). The percentage of seizures induced by pentylenetetrazol and strychnine was significantly lower in female mice in prooestrus/oestrus, when progesterone levels are high, than in dioestrus, when progesterone levels are low. Pretreatment of pentylenetetrazol-challenged mice with progesterone (250 mg/kg) increased the incidence of seizures in prooestrus/oestrus, without affecting seizures in dioestrus. The same pretreatment in strychnine-challenged mice also increased the incidence of seizures in prooestrus-dioestrus, but significantly reduced the incidence of seizures in dioestrus. In addition, progesterone pretreatment significantly increased the percentage of deaths induced by strychnine in prooestrus-oestrus, reducing deaths in dioestrus. Orchidectomized male mice had a significantly higher incidence of seizures after administration of pentylenetetrazol and strychnine than control mice. Administration of 11 daily doses of 250 mg/kg of testosterone to castrated mice significantly reduced the incidence of seizures induced by pentylenetetrazol. These results confirm the modulatory influence of reproductive steroids on the excitability of the central nervous system and the possible clinical importance of progesterone and testosterone in the management of partial epilepsy.Several investigations have shown a relationship between reproductive steroids and central nervous system excitability. The active metabolite of progesterone, allopregnanolone, is a neurosteroid which exhibits hypnotic, anxiolytic and anticonvulsant actions (Bitran et al. 1991(Bitran et al. & 1995Galli et al. 1996;Korneyev & Costa 1996;Wilson & Biscardi 1997). Allopregnanolone exhibits potent inhibitory actions in the central nervous system, acting on the GABA-benzodiazepine-chloride channel macromolecular complex by an allosteric interaction with the GABA A receptor, with potentiation of the chloride channel current (Schumacher & Baulieu 1995;Rupprecht et al. 1996;Brot et al. 1997; Kellog et al. 1998). Neurosteroids are also synthetized within the central and peripheral nervous systems, mainly by glial cells (Schumacher & Baulieu 1995). Testosterone has more inconsistent actions, since it is metabolized to oestradiol, which can exacerbate seizures, and dihydrotestosterone, which inhibits NMDA-type glutamate transmission and may have antiseizure effects (Herzog 1999a). On the other hand, ovarian steroids modify the behavioural response to activation of the benzodiazepine receptor, reducing withdrawal anxiety and hyperactivity in mice (Bitran & Dowd 1996;Reddy & Kulkarni 1997). The number of seizures occurring during the benzodiazepine withdrawal syndrome is significantly less in prooestrus-oestrus, where p...

Abstract:The frequency of oestrus cycles in female mice was significantly reduced by the implantation of a pellet of subcutaneous ketoconazole (50 mg every 6 days). The effect was more pronounced after 22 days than after 13 days and it was probably related with the progressive reduction in steroid synthesis induced by the inhibition of key steroidogenic P450 cytochromes by the drug. In addition, the influence of ketoconazole on the incidence of seizures after the administration of intraperitoneal pentylenetetrazol was evaluated in female mice. Pentylenetetrazol produced a higher percentage of seizures during dioestrus than during oestrus. Pretreatment with ketoconazole significantly increased the percentage of animals with induced seizures in oestrus but not in dioestrus as compared to controls, probably through reduced progesterone levels. The reduced seizure threshold confirm the modulatory role exerted by progesterone on central nervous system excitability, and may be relevant in epileptic patients undergoing antifungal therapy.Several experimental investigations have shown that ketoconazole, an antifungal agent related to imidazol, inhibits testicular, ovarian and adrenal biosynthesis of steroids by inhibiting key steroidogenic cytochromes, namely P450ssc (side-chain cleavage enzyme that converts cholesterol to pregnenolone), P450-17a (17-a-hydroxilase) and P450arom (steroid aromatase) (Mason et al. 1987;Weber et al. 1993;Carlson et al. 1995;Cummings et al. 1997;Adams et al. 1998;Tsafriri et al., 1998). Consequently, progesterone, testosterone and oestrogen levels tend to be reduced during ketoconazole treatment. On the other hand, the relationship between reproductive steroids and central nervous system excitability has been clearly demonstrated. Hypnotic, anxiolytic and anticonvulsivant effects are mediated by an active metabolite of progesterone, the neurosteroid allopregnanolone (Bitran et al. 1991;Korneyev & Costa 1996). The inhibitory actions of the neurosteroid in the central nervous system are due to interaction with the GABA A receptor of the GABA-benzodiazepine-chloride channel macromolecular complex, resulting in potentiation of the chloride channel current (Rupprecht et al. 1996;Brot et al. 1997). Neurosteroids are also synthetized within the central and peripheral nervous systems, mainly by glial cells (Schumacher & Baulieu 1995). On the other hand, progesterone and testosterone modulate the excitability of the central nervous system, as assessed by behavioural effects related to the oestrus cycle during benzodiazepine withdrawal syndrome and by evaluating the convulsant actions of pentylenetetrazol and strychnine (Pesce et al. 1994(Pesce et al. , 1996(Pesce et al. & 2000.The present investigation was designed to study the effect of chronic administration of high doses of ketoconazole in the inhibition of progesterone biosynthesis as judged by alterations in the oestral cycle and in the convulsivant action of pentylenetetrazol. Material and MethodsCF/1 female mice (20-30 g) were used throughout...