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Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress
Frau, Roberto Abbiati, Federico Bini, Valentina Casti, Alberto Caruso, Donatella Devoto, Paola Bortolato, Marco
Frau, Roberto
Abbiati, Federico
Bini, Valentina
Casti, Alberto
Caruso, Donatella
Devoto, Paola
Bortolato, Marco
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Abstract
Background
Cogent evidence has shown that schizophrenia vulnerability is enhanced by psychosocial stress in adolescence, yet the underpinnings of this phenomenon remain elusive. One of the animal models that best capture the relationship between juvenile stress and schizophrenia is isolation rearing (IR). This manipulation, which consists in subjecting rats to social isolation from weaning through adulthood, results in neurobehavioral alterations akin to those observed in schizophrenia patients. In particular, IR-subjected rats display a marked reduction of the prepulse inhibition (PPI) of the startle reflex, which are posited to reflect imbalances in dopamine neurotransmission in the nucleus accumbens (NAcc). We recently documented that the key neurosteroidogenic enzyme 5α-reductase (5αR) plays an important role in the dopaminergic regulation of PPI; given that IR leads to a marked down-regulation of this enzyme in the NAcc, the present study was designed to further elucidate the functional role of 5αR in the regulation of PPI of IR-subjected rats.
Methods
We studied the impact of the prototypical 5αR inhibitor finasteride (FIN) on the PPI deficits and NAcc steroid profile of IR-subjected male rats, in comparison with socially reared (SR) controls.
Results
FIN (25–100 mg/kg, i.p.) dose-dependently countered IR-induced PPI reduction, without affecting gating integrity in SR rats. The NAcc and striatum of IR-subjected rats displayed several changes in neuroactive steroid profile, including a reduction in pregnenolone in both SR and IR-subjected groups, as well as a decrease in allopregnanolone content in the latter group; both effects were significantly opposed by FIN.
Conclusions
These results show that 5αR inhibition counters the PPI deficits induced by IR, possibly through limbic changes in pregnenolone and/or allopregnanolone concentrations.
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Date
2015-05-18
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Elsevier
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Keywords
5α-reductase, Isolation rearing, Sensorimotor, Neurosteroids, Schizophrenia, Prepulse inhibition
Citation
Frau, Roberto et al. “Targeting Neurosteroid Synthesis as a Therapy for Schizophrenia-Related Alterations Induced by Early Psychosocial Stress.” Schizophrenia research 168.3 (2015): 640–648.