Inhibition of 5α-reductase in the nucleus accumbens counters sensorimotor gating deficits induced by dopaminergic activation

Abstract

Summary Cogent evidence highlights a key role of neurosteroids and androgens in schizophrenia. We recently reported that inhibition of steroid 5α-reductase (5αR), the rate-limiting enzyme in neurosteroid synthesis and androgen metabolism, elicits antipsychotic-like effects in humans and animal models, without inducing extrapyramidal side effects. To elucidate the anatomical substrates mediating these effects, we investigated the contribution of peripheral and neural structures to the behavioral effects of the 5αR inhibitor finasteride (FIN) on the prepulse inhibition (PPI) of the acoustic startle reflex (ASR), a rat paradigm that dependably simulates the sensorimotor gating impairments observed in schizophrenia and other neuropsychiatric disorders. The potential effect of drug-induced ASR modifications on PPI was excluded by measuring this index both as percent (%PPI) and absolute values (ΔPPI). In both orchidectomized and sham-operated rats, FIN prevented the %PPI deficits induced by the dopamine (DA) receptor agonists apomorphine (APO, 0.25 mg/kg, SC) and d-amphetamine (AMPH, 2.5 mg/kg, SC), although the latter effect was not corroborated by ΔPPI analysis. Conversely, APO-induced PPI deficits were countered by FIN infusions in the brain ventricles (10 μg/1 μl) and in the nucleus accumbens (NAc) shell and core (0.5 μg/0.5 μl/side). No significant PPI-ameliorating effect was observed following FIN injections in other brain regions, including dorsal caudate, basolateral amygdala, ventral hippocampus and medial prefrontal cortex, although a statistical trend was observed for the latter region. The efflux of DA in NAc was increased by systemic, but not intracerebral FIN administration. Taken together, these findings suggest that the role of 5αR in gating regulation is based on post-synaptic mechanisms in the NAc, and is not directly related to alterations in DA efflux in this region.

Sociocommunicative and Sensorimotor Impairments in Male P2X4-Deficient Mice

“…Because the computation of this parameter is inherently dependent on the amplitude of the startle reflex, the interpretation of variations in %PPI in P2X4R KO mice is complicated by potential 'floor effects' consequent to the decrement in their baseline startle amplitude (Swerdlow and Geyer, 1993). However, the possibility that the %PPI changes may be artifactual was challenged by our finding of significant reductions in DPPI (Bortolato et al, 2004;Devoto et al, 2011). Thus, the reduction in PPI is likely to signify a deficit in the ability of P2X4R-deficient animals to extract and filter relevant information from the external milieu, possibly pointing to a role for this receptor in the regulation of information processing.…”

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

“…Thus, the altered phenotypic response to changes in allopregnanolone observed in women with PMDD could represent altered levels of allopregnanolone consequent to tissue specific polymorphic variants in the gene for type 1 5α-reductase. Dutasteride has been reported to have therapeutic benefits in a range of neuropsychiatric illnesses, and some of these effects are thought to be independent of its actions on androgen metabolism (Gulinello and Smith, 2003;Bortolato et al, 2008;Paba et al, 2011;Devoto et al, 2012). Thus, although no study has directly evaluated the CNS penetrance of dutasteride, both clinical reports and studies in rodents (GlaxoSmithKline Research Triangle Park NC, 2005) suggest that dutasteride does cross the blood-brain barrier.…”

How Individual Habits Fit/Unfit Social Norms: From the Historical Perspective to a Neurobiological Repositioning of an Unresolved Problem

“…This alteration determines a strong hedonistic feeling correlated to the habit of gambling which is an integral part of maintaining such a bad habit. Moreover, it is remarkable that drugs which depress the hedonistic components of a bad habit also decrease the "craving" related to the appetitive gambling behavior in these subjects (Muroni et al, 2011;Bortolato et al, 2012), thus suggesting a plastic modulation by the pleiotropic assembly of neurotransmitters and neuromodulators, though only few of them have hitherto been studied (Devoto et al, 2012). Furthermore, neuropathologists also consider "bad" habits a number of involuntary complex dystonic attitudes represented by the altered postures observed in several neurodegenerative conditions (i.e., Parkinson disease, Huntington's chorea, Tourette's syndrome, among the most common) .…”