Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress (2015)

Expanding on Neurosteroids as therapeutics:

Targeting neurosteroid synthesis as a therapy for schizophrenia-related alterations induced by early psychosocial stress

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.


  • Isolation rearing (IR) leads to significant reductions in pregnenolone, 5α-dihydroprogesterone, allopregnanolone and estradiol in the NAcc, but no significant changes in progesterone, DHEA or testosterone levels
  • the potent 5αR inhibitor finasteride (FIN) dose-dependently countered the deficits in PPI caused by isolation rearing
  • the effects of FIN were generally similar to those of  haloperidol; however, the 5αR blocker failed to induce catalepsy or other overt extrapyramidal manifestations.
  • while FIN reduced allopregnanolone levels and allopregnanolone/5α-dihydroprogesterone ratio in socially reared (SR) rats, this drug had surprisingly opposite effects in IR-subjected rats: enhancement of allopregnanolone synthesis in isolation reared rats may play a key contributory role in the effects of FIN (via GABA-A mediated effects).
    • functional changes in 3α-hydroxysteroid oxido-reductase (3α-HSOR), the reversible enzyme involved in the inter-conversion of allopregnanolone and 5α-dihydroprogesterone may be involved in allopregnanolone elevations
    • down-regulation of 5αR in IR rats may unmask other secondary mechanisms of FIN, such as the inhibition of 5β-reductase, which may paradoxically enhance the synthesis of allopregnanolone and other 5α-reduced neurosteroids.
  • Previous observations revealed ameliorative effects of FIN and other 5αR inhibitors on psychosis-related alterations elicited by direct and indirect DAergic agonists in rodents
  • On the contrary, a different study found that finasteride administration potentiates the disruption of prepulse inhibition induced by forced swim stress [1]

“… the effects of FIN on the regulation of PPI are likely supported by changes in the signaling of the postsynaptic DA receptors in the NAcc (Devoto et al., 2012). Furthermore, several studies have shown that the gating deficits induced by IR are primarily mediated by this region (Powell et al., 2003 and Leng et al., 2004). Our results showed that IR leads to significant reductions in pregnenolone, 5α-dihydroprogesterone, allopregnanolone and estradiol in the NAcc. These data are in substantial agreement with previous findings from our group and others, indicating that IR leads to an overall reduction in steroid levels in the cortex (Serra et al., 2000 and Bortolato et al., 2011). We also documented no significant changes in progesterone, DHEA and testosterone levels, suggesting that the generalized reduction in neurosteroid biosynthetic pathways may be partially offset by the down-regulation of catabolic enzymes and/or the activation of alternative anabolic processes. The significant changes in steroid ratios are in keeping with the previously documented down-regulation of 5αR in IR-subjected rats (as indicated by the reduction in 5α-dihydroprogesterone/progesterone ratio); furthermore, our data suggest that this manipulation may lead to functional alterations of other neurosteroidogenic enzymes, such as a potential enhancement of the activity of 3β-hydroxysteroid dehydrogenase (3β-HSD), which catalyze the conversion of pregnenolone into progesterone”

“[the effects of] FIN were paralleled by a marked increase in the concentrations of pregnenolone and a statistical trend for an enhancement of DHEA levels in the NAcc and striatum. The increased content of these 3β-hydroxy-Δ5-steroids may signify their accumulation in response to the inhibition of 5αR, given that they are the precursors of the two main 5αR substrates, i.e., progesterone and testosterone. The possibility that the antipsychotic-like actions of FIN may be contributed by the enhancement of pregnenolone (and, possibly, DHEA) levels is in keeping with emerging evidence supporting the therapeutic potential of these neurosteroids for cognitive and negative symptoms in schizophrenia”

Synoptic schematization of the observed effects of isolation rearing (IR) and finasteride (FIN) on neurosteroid levels in the nucleus accumbens (NAcc). Black and white arrows represent increased and decreased enzyme activities, respectively. CYP17A1, 17-hydroxylase/17,20 lyase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 5αR, 5α-reductase; 3α-HSOR, 3α-hydroxysteroid oxidoreductase; DHEA, dehydroepiandrosterone
Synoptic schematization of the observed effects of isolation rearing (IR) and finasteride (FIN) on neurosteroid levels in the nucleus accumbens (NAcc). Black and white arrows represent increased and decreased enzyme activities, respectively. CYP17A1, 17-hydroxylase/17,20 lyase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 5αR, 5α-reductase; 3α-HSOR, 3α-hydroxysteroid oxidoreductase; DHEA, dehydroepiandrosterone

“…our findings have confirmed FIN’s antipsychotic-like properties, by documenting its ability to correct the gating alterations associated with IR, a neurodevelopmental model of schizophrenia with high face, construct and predictive validity. The actions of FIN are accompanied by changes in neuroactive steroid levels, such as an increase in pregnenolone and allopregnanolone, which countered the effects of IR. These data further confirm previous evidence pointing to 5αR as a promising target for the development of novel treatments for schizophrenia and other neuropsychiatric disorders featuring stress-related gating impairments, such as Tourette syndrome and obsessive–compulsive disorder.”

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