Allopregnanolone and ganaxolone increase the firing activity of dorsal raphe nucleus serotonergic neurons in female rats

Abstract

Accumulating evidence suggest a reciprocal interaction between neurosteroids, especially 5alpha-pregnan-3alpha-ol,20-one (3alpha,5alpha-THP, allopregnanolone), and the serotonergic (5-HT) system. Both 5-HT and neurosteroids seem to play an important role in the pathophysiology of major depression. We have previously shown that a 7-d treatment with 3alpha,5alpha-THP drastically increases the spontaneous firing activity of dorsal raphe nucleus (DRN) 5-HT neurons in female rats. This study was thus undertaken to better characterize this modulation and to assess the effects of ganaxolone, a synthetic analogue of 3alpha,5alpha-THP. Female rats received 50 microg/kg.d of 3alpha,5alpha-THP or ganaxolone for 3 and 7 days. Others received 3alpha,5alpha-THP concomitantly with the antiprogestin RU486 (50 microg/kg.d, each), which was also administered alone. Acute experiments were also carried out with a single injection of 3alpha,5alpha-THP (1 microg/kg). Finally, both 3alpha,5alpha-THP and ganaxolone (50 microg/kg.d) were administered along with the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg/kg.d). In-vivo extracellular unitary recordings of 5-HT neurons from the DRN, revealed that 3alpha,5alpha-THP and ganaxolone increased their firing activity after 3 and 7 d of treatment. A 7-d treatment with RU486 had the same effect. Furthermore, an increase could be seen as soon as after 30-60 min following a single injection with 3alpha,5alpha-THP. Interestingly, both 3alpha,5alpha-THP and ganaxolone prevented the citalopram-induced reduction in firing activity after 3-d treatments. These data demonstrate the ability of 3alpha,5alpha-THP and ganaxolone to positively modulate the firing activity of DRN 5-HT neurons in female rats. Moreover, these results suggest that these neuroactive steroids might represent interesting adjuvants in the treatment of mood disorders in female patients.