Allopregnanolone reduces immobility in the forced swimming test and increases the firing rate of lateral septal neurons through actions on the GABA(A) receptor in the rat

Since altopregnanolone reduces the total time of immobility in rats submitted to the forced swimming test, we decided to explore whether this neuroactive steroid shares other antidepressant-tike actions, such as increasing the neuronal firing rate in the Lateral septal nucleus (LSN). In order to discard the influence of the oestrous cycle on immobility and on the firing rate of LSN neurons, all Wistar rats used in the study underwent ovariectomy before treatments. A group of rats received different doses of allopregnanolone (0.5, 1.0, 2.0 and 3.0 mg/kg, i.p.) 1 hour before being forced to swim in order to identify the minimum effective dose diminishing immobility. None of the tested doses of allopregnanolone produced significant changes in motor activity in the open-field test. The minimum dose of altopregnanolone producing a significant reduction in the total time of immobility (p < 0.05) against the vehicle was 1.0 mg/kg, while 2.0 mg/kg and above also increased the Latency to the first period of immobility (p < 0.05). The minimum effective dose of allopregnanolone reducing immobility in the forced swimming test (1.0mg/kg) significantly (p < 0.05) produced a higher (twofold) neuronal firing rate in LSN neurons, but did not produce any change in septofimbrial nucleus neurons, which fired at a rate similar to that of vehicle-treated rats. The pretreatment with the non-competitive GABA(A) receptor antagonist, picrotoxin (1.0mg/kg), blocked the aforementioned actions of allopregnanolone on both immobility and LSN firing rate. In conclusion, altopregnanolone produces an antidepressant-like effect in the forced swimming test, associated with an increase in the LSN neuronal firing rate, seemingly mediated by the GABAA receptor.