Efectos de la alteración de los niveles de allopregnanolona durante periodos críticos del neurodesarrollo en la vulnerabilidad al consumo de alcohol

Abstract

Neuroactive steroids (NAS), such as allopregnanolone, play a critical role in the maturation of the nervous system and influence a wide variety of behaviors. Previous experiments have shown that the manipulation of NAS levels during crucial stages of neurodevelopment can induce an alteration in new environments exploration behavior and a greater ethanol consumption together with a decrease in the dopamine and serotonin levels in the ventral striatum. The consumption in initial stages can play a key role in the vulnerability to drug abuse, as well as the different factors that precipitate it. This thesis tries to provide more information about the role which can play the levels of NAS in the crucial periods of neurodevelopment in the vulnerability to drug use such as alcohol. Therefore, we carried out a first experiment with the purpose of studying the effect of neonatal and adolescent manipulation of NAS levels on the sensitivity to the stimulant effects of alcohol in adulthood, which have been related to the risk of alcohol use and dependence. The main data indicated that neonatal administration of finasteride (5α-reductase inhibitor) during postnatal days 5 and 9 (PN5-PN9) reduced sensitivity to the stimulatory effects of low doses of alcohol (0.5g/kg) compared to the rest of the groups. Furthermore, this difference was not observed in those animals which had been treated with the main precursor of allopregnanolone (progesterone) during early adolescence (PN30). On the other hand, the modulation of neonatal NAS levels manipulation on the novelty preference (related to the vulnerability to drug use and abuse), as well as, on the effect of the 5-HT3 receptor antagonist ondansetron during alcohol intake was evaluated in a second experiment. In addition, the alteration in the expression of 5-HT3 receptor (involved in the release of mesolimbic dopamine) was analyzed in a second phase of this experiment. In the first phase, the results indicated that the animals treated neonatally with finasteride (PN5-PN9) shown an increase in the novelty preference, additionally to an increase in alcohol intake. On the other hand, the alcohol intake was decreased by the administration of ondansetron (0.1mg/kg) during the first days of consumption, but only in the finasteride group. In the second phase of this experiment, the results obtained of early postnatal midbrain tissue showed an increase in the expression of 5-HT3 receptor in the control group in PN12. In contrast, subjects administered with allopregnanolone during the early postnatal period exhibited an increase in the expression of this receptor like the control group, although it appeared days before (PN9). On the other hand, animals neonatally treated with finasteride didn’t show any difference in 5-HT3 receptor expression between days. However, any difference in the expression of 5-HT3 receptor in adult tissue samples (ventral striatum) were not observed. In conclusion, the present work exposes that NAS levels in the crucial stages of neurodevelopment can play an important role in vulnerability to alcohol use, through risk factors such as sensitivity to the stimulant effects of this drug, novelty preference and the initial stages of alcohol consumption. Moreover, this work shows the protective action that NAS could perform during early adolescence.

Date of Award	12 Nov 2018
Original language	Spanish
Awarding Institution	Universitat Autònoma de Barcelona (UAB)
Supervisor	Marcos Pallares Año (Co-director) & Sonia Darbra Marges (Co-director)