A post-training intrahippocampal anxiogenic dose of the neurosteroid pregnenolone sulfate impairs passive avoidance retention

Pregnenolone sulfate (PregS) is a neurosteroid that acts as a negative modulator of the GABA_A receptor complex and a positive modulator of glutamate NMDA receptors. PregS improves learning and memory when centrally or systemically administered. However, systemic high doses of PregS, which facilitate the passive avoidance retention, have been shown to impair this learning when a high foot-shock punishment was used. Moreover, moderate or high PregS doses present a well documented anxiogenic-like profile in several animal models of anxiety. In previous experiments, we have shown that unilateral intrahippocampal 5 ng of PregS improves spatial recognition memory and reverses learning impairment induced by co-administration of alcohol and nicotine. In the present experiment, we analyzed the effects of bilateral intrahippocampal 5 ng of PregS on the passive avoidance task, using a high foot-shock punishment (0.5 mA), as well as on anxiety-like behaviour measured in the open field test in the same experimental subjects. As a control, we have injected the neurosteroid allopregnanolone (AlloP) into the hippocampus, which produces opposite behavioural and neurochemical profiles to those of PregS, by acting as a positive GABA_A modulator and showing anxiolytic and sedative behavioural effects. Results showed that bilateral intrahippocampal 5 ng of PregS deteriorated passive avoidance retention but also presented an anxiogenic-like profile in the open field test, decreasing the locomotion and the time spent in the central zone without affecting either total activity or time spent in the periphery of the field (thigmotaxis). AlloP administration did not affect passive avoidance retention, and also showed a non anxiolytic-like profile, possibly related to fluctuations of endogenous AlloP concentrations induced by the stress generated by the high foot-shock punishment received before the anxiety tests. In conclusion, a post-training intrahippocampal anxiogenic dose of the neurosteroid PregS impairs passive avoidance retention. These results highlight the important role of the hippocampus in several behavioural effects of neurosteroids on learning, memory processes and anxiety.