engleski

Neurosteroid dehydroepiandrosterone improves active avoidance learning in the rat

Purpose of the study: Neurosteroid dehydroepiandrosterone (DHEA) has been associated to a variety of important functions in the central nervous system, including modulation of neuronal survival and death, memory, learning and behavior, also showing therapeutic potential in various neuropsychiatric and cognitive disorders [1]. It has been suggested that the effects of DHEA are mediated through several neurotransmitter systems, which are also involved in regulating the balance between excitation and inhibition in the brain ; however its mechanisms of action are not fully understood. This study aimed to investigate the behavioral profile of DHEA in rats in the active avoidance (AA) and spontaneous locomotor activity (SLA), primarily predictive of the effects on the memory, learning and basal locomotor activity. Methods used: The AA test was performed in automated two-way shuttle boxes (Campden Instruments, Sileby, UK), as described earlier [2]. The animals were submitted to two, 24-h- separated sessions. Training and test sessions were procedurally identical. During the first 5 s of each trial, a sound signal was presented (broadband noise of 69 dB), allowing the animal to avoid shocks by moving to the other compartment (avoidance response). If the animal did not respond within this period, a foot shock of 0.5 mA (7-s duration) was applied. Crossing to the adjacent compartment during the shock discontinued its delivery. The animal could move freely in the apparatus between trials (18-s intertrial intervals), and the intertrial crossings were automatically counted. The measurement of locomotor activity was performed in a clear Plexiglas box (40×25×35 cm) for 30 min without any habituation period. The data were assessed by a one-way ANOVA. If the ANOVA was significant, each treatment condition was compared with control by a Dunnett's test (α=0.05). Where appropriate, the assessment of the antagonist influence on DHEA effect was conducted by a Student's t-test. Summary of results: Treatment with DHEA significantly affected retrieval of avoidance responses on the second day of shuttle box testing (F(3, 20)=4.427, p<0.05). Dunnett’s test indicated that the DHEA avoidance-facilitatory dose was 10 mg/kg. This effect was antagonized by bicuculline, a competitive antagonist of GABA-A receptors. However, at higher doses (50 mg/kg) DHEA performance in the retention session was attenuated. Neither of the motor parameters measured (habituation crossings and intertrial crossings) differed significantly. Also, ANOVA did not show a significant effect of treatments on the locomotion of the animals during 30 min of monitoring of spontaneous locomotor activity (F(3, 20)=2.017, p>0.05). Conclusions: In conclusion, neurosteriod DHEA, in a manner resembling an inverted U shape, facilitates retrieval of memory task imposed to rats in active avoidance paradigm. The improvement of the performance in the retention session exerted by DHEA was not caused by changes in motor activity. Examination of the present results suggests that the modulation engendered by DHEA may be sufficient to effect enhanced formation of implicit, procedural and hippocampal-independent memory task. The molecular and neuronal substrates linking the actions of specific GABA-A receptors remain to be further elucidated. Reference: [1] Maninger, N., Wolkowitz, O.M., Reus, V.I., Epel, E.S., Mellon, S.H., 2009 Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Frontiers in Neuroendocrinology 30, 65-91. [2] Savic, M.M., Clayton, T., Furtmüller, R., Gavrilovic, I., Samardzic, J., Savic, S., Huck, S., Sieghart, W., Cook, J.M., 2008 PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA-A receptors containing a5 subunits, improves passive, but not active, avoidance learning in rats. Brain Research 1208, 150-159.

DHEA ; active avoidance ; spontaneous locomotor activity ; rat

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