The implication of neuroactive steroids in Tourette's syndrome pathogenesis: A role for 5α-reductase?

Tourette's syndrome (TS) is a neurodevelopmental disorder characterised by recurring motor and phonic tics. The pathogenesis of TS is considered to reflect dysregulations in the signalling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G × E × S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of approximately 4 : 1. Converging lines of evidence point to neuroactive steroids as being likely molecular candidates to account for G × E × S interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalysing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesise that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the 'backdoor' pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signalling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioural abnormalities in TS.

Translational physiology and SND recordings in humans and rats: a glimpse of the recent past with an eye on the future.

The sympathetic nervous system (SNS) plays an important role in cardiovascular function, and based on the critical mechanistic relationship between altered sympathetic neural mechanisms and cardiovascular disease, it is important that the autonomic research community identifies deficiencies in the translational exchange of information and strives for a more thorough understanding of the translational significance of findings from studies involving sympathetic nerve discharge (SND) regulation in human and animal subjects. The present review assesses the state of the literature regarding studies that have used direct recordings of SND during the past three decades in humans and rats, focusing on; 1) identifying the number of studies reporting SND recordings in humans and rats, 2) briefly describing the translational exchange of SND regulation information from these studies, 3) contrasting the number of studies completed in anesthetized and conscious rats, and 4) assessing the prevalence of long-term SND recording studies in conscious rats. The majority of SND recordings in rats have been completed using anesthetized preparations, although a substantial number of studies have been completed in conscious rats. However, few studies have completed long-term (>5 days) SND recordings in freely-behaving rats, and even fewer studies have used experimental preparations that combine long-term nerve recordings with the capacity for completing central neural microinjections, or have been completed in animal models of cardiovascular disease. The wide-spread implementation of long-term SND recordings in rodent models of cardiovascular disease would be expected to enhance the translational exchange of clinically-relevant information between animals and humans.

Bacillus anthracis lethal toxin induces complex changes in sympathetic nerve discharge regulation.

Bacillus anthracis lethal toxin (LeTx) alters blood pressure and visceral sympathetic nerve discharge (SND) regulation (Garcia et al., 2012). The present results indicate that LeTx infusions produce similar response profiles in peripheral (lumbar) and visceral (renal) SND; an initial widespread activation of sympathetic nerve outflow, followed by a generalized reduction in lumbar and renal SND from peak levels, although the sympathoinhibition tended to be attenuated in lumbar SND. Combined hypoxia+hypercapnia during the hypotensive phase of LeTx infusions increased lumbar and renal SND, indicating that sympathetic neural circuits can be activated during the circulatory shock phase of B. anthracis septicemia.

Bacillus anthracis lethal toxin alters regulation of visceral sympathetic nerve discharge.

Bacillus anthracis infection is a pathophysiological condition that is complicated by progressive decreases in mean arterial pressure (MAP). Lethal toxin (LeTx) is central to the pathogenesis of B. anthracis infection, and the sympathetic nervous system plays a critical role in physiological regulation of acute stressors. However, the effect of LeTx on sympathetic nerve discharge (SND), a critical link between central sympathetic neural circuits and MAP regulation, remains unknown. We determined visceral (renal, splenic, and adrenal) SND responses to continuous infusion of LeTx [lethal factor (100 µg/kg) + protective antigen (200 µg/kg) infused at 0.5 ml/h for ≤6 h] and vehicle (infused at 0.5 ml/h) in anesthetized, baroreceptor-intact and baroreceptor (sinoaortic)-denervated (SAD) Sprague-Dawley rats. LeTx infusions produced an initial state of cardiovascular and sympathetic nervous system activation in intact and SAD rats. Subsequent to peak LeTx-induced increases in arterial blood pressure, intact rats demonstrated a marked hypotension that was accompanied by significant reductions in SND (renal and splenic) and heart rate (HR) from peak levels. After peak LeTx-induced pressor and sympathoexcitatory responses in SAD rats, MAP, SND (renal, splenic, and adrenal), and HR were progressively and significantly reduced, supporting the hypothesis that LeTx alters the central regulation of sympathetic nerve outflow. These findings demonstrate that the regulation of visceral SND is altered in a complex manner during continuous anthrax LeTx infusions and suggest that sympathetic nervous system dysregulation may contribute to the marked hypotension accompanying B. anthracis infection.