The neurosteroidogenic enzyme 5α-reductase modulates the role of D1 dopamine receptors in rat sensorimotor gating

Abstract

Neurosteroid sexert diverse modulatory actions on dopamine neurotransmission and signaling. We previously documented that the enzyme 5α-reductase, which catalyzes the main rate-limiting step in neurosteroid synthesis, is required for the behavioral responses of Sprague-Dawley rats to non-selective dopaminergic agonists, such as the D1–D2 receptor agonist apomorphine. Specifically, systemic and intra-accumbal administrations of the 5α-reductase inhibitor finasteride countered apomorphine-induced deficits of sensorimotor gating, as measured by the prepulse inhibition (PPI) of the startle reflex; the classes of dopamine receptors involved in these effects, however, remain unknown. Prior rodent studies have revealed that the contributions of dopamine receptors to PPI regulation vary depending on the genetic background; thus, we analyzed the effect of finasteride on the PPI deficits induced by selective dopamine receptor agonists in Long-Evans (a strain exhibiting PPI deficits in response to both D1 and D2 receptor agonists) and Sprague-Dawley rats (which display PPI reductions following treatment with D2, and D3, but not D1 receptor agonists). In Long-Evans rats, finasteride opposed the PPI deficits induced by activation of D1, but not D2 receptors; conversely, in Sprague-Dawley rats, finasteride prevented the reductions in %PPI and accumbaldopamine extracellular levels caused by selective stimulation of D3, but not D2 receptors; however, the effects on %PPI were not confirmed by analyses on absolute PPI values. Our findings suggest that 5α-reductase modulates the effects of D1, but not D2 receptor agonists on sensorimotor gating. These data may help elucidate the role of neurosteroids in neuropsychiatric disorders featuring PPI deficits, including schizophrenia and Tourette syndrome.

Exploring the neural mechanisms of finasteride: a proteomic analysis in the nucleus accumbens

“…Taken together, this evidence suggests that the FIN-induced increase in CRMP2 expression in the NAcc may lead to changes in dopamine release from mesolimbic projections. In line with this idea, we recently showed that acute administration of the same doses of FIN used in this study (100 mg/kg, IP) produces a significant increase in the accumbal dopamine release in rats (Frau et al, 2016). The mechanisms whereby acute FIN treatment increases CRMP2 may reflect the action of neuroactive steroids on the multiple targets of this protein.…”

“…models of the conditions shown by Bortolato and coworkers (Bortolato et al, 2008;Frau et al, 2015Frau et al, , 2016, likely by reducing the effects of dopamine signaling at the level of D 1 , and possibly D 3 , receptors (Frau et al, 2016). Consistently with these findings, the antipsychotic-like actions of FIN have been shown to be primarily contributed by the nucleus accumbens (NAcc) (Devoto et al, 2012), the major terminal of the dopamine mesolimbic pathway.…”

“…Allopregnanolone and other 5αR substrates and/or products play an important role in the functional regulation of GABA-A receptors and are posited to modulate mitochondrial and bioenergetic functions (Klinge, 2008;Papadopoulos et al, 2006;Robertson et al, 2006). Taken together, these results reveal that FIN may induce a dis crete number of neurochemical alterations in the proteome of the NAcc, which may be related to its antidopaminergic properties (Frau et al, 2016). In the following sections, we will analyze how each of the 9 proteins affected by FIN treatment may be relevant to the behavioral and neurochemical effects of this drug.…”

What makes you tic? Translational approaches to study the role of stress and contextual triggers in Tourette syndrome

“…Along the same lines, opioid antagonists have been generally shown to reduce the severity of tics (Sandyk and Awerbuch, 1989; Kurlan et al, 1991; van Wattum et al, 2000; but see Erenberg and Lederman, 1992 for contrasting findings). Finally, our group has shown that inhibition of neurosteroid synthesis by the 5α-reductase inhibitor finasteride leads to a marked reduction of tic severity in TS patients (Bortolato et al, 2007; Muroni et al, 2011); these findings were paralleled by the discovery that finasteride reduces PPI deficits and stereotypies induced by dopaminergic agonists in rats and mice, likely through the attenuation of D 1 receptor signaling (Bortolato et al, 2008; Frau et al, 2013; 2016). …”

Endogenous neurosteroids influence synaptic GABAA receptors during postnatal development

“…113 In support, a recent investigation revealed abnormal neurosteroid levels in a population of schizophrenic patients. 144 Furthermore, Bortolato et al 145 have implicated altered neurosteroidogenesis in the accumbal-mediated expression of behavioural deficits (ie, altered pre-pulse inhibition), which is typically altered in animal models of schizophrenia. Thus, the impact of abnormal neurosteroid levels upon neurodevelopment may extend beyond the cortex.…”