The Allopregnanolone Response to Acute Stress in Females: Preclinical and Clinical Studies

The neuroactive steroid allopregnanolone ((3 alpha,5 alpha)-3-hydroxypregnan-20-one or 3 alpha,5 alpha-THP) plays a key role in the response to stress, by normalizing hypothalamic-pituitary-adrenal (HPA) axis function to restore homeostasis. Most studies have been conducted on male rats, and little is known about the allopregnanolone response to stress in females, despite that women are more susceptible than men to develop emotional and stress-related disorders. Here, we provide an overview of animal and human studies examining the allopregnanolone responses to acute stress in females in the context of stress-related neuropsychiatric diseases and under the different conditions that characterize the female lifespan associated with the reproductive function. The blunted allopregnanolone response to acute stress, often observed in female rats and women, may represent one of the mechanisms that contribute to the increased vulnerability to stress and affective disorders in women under the different hormonal fluctuations that occur throughout their lifespan. These studies highlight the importance of targeting neuroactive steroids as a therapeutic approach for stress-related disorders in women

Neurosteroidi: i modulatori endogeni delle emozioni

The discovery that facilitation or inhibition of γ aminobutyric acid (GABA)-mediated neurotransmission results in anxiolytic versus anxiogenic, hypnotic versus somnolitic, and anticonvulsant versus convulsant effects, respectively, provided important early insight into the physiology and pharmacology of central GABAergic transmission. This realization, together with subsequent evidence that high-affinity recognition sites for positive and negative allosteric modulators of GABAA receptors are located on these GABA-gated Cl– channels, led to the concept that GABAA receptors contribute directly not only to the pharmacology but also to the neurobiology and physiopathology of a variety of neurological and psychiatric diseases characterized by changes in emotional state, sleep pattern, or neuronal excitability. These findings have suggested the hypothesis that the brain and peripheral organs in mammals might produce endogenous compounds that selectively modulate central GABAA receptor function. Evidence directly supporting this hypothesis has been provided over the last decade by the discovery that steroid hormones synthesized in the brain or in peripheral organs are among the most selective, potent, and efficacious allosteric modulators of GABAA receptors. Neurosteroids are steroid derivatives that are synthesized de novo from cholesterol in the central nervous system (CNS), some of which modulate GABAA receptor function with potencies and efficacies similar to or greater than those of benzodiazepines and barbiturates. These molecules have thus been suggested to be the endogenous modulators of GABAA receptor–mediated neurotransmission. In fact some of these molecules have the capability to modulate synaptic activity by binding to membrane sites associated with ligand-gated ionotropic receptors including GABAA receptors. Here we summarize some of the most recent evidences obtained by our and other laboratories pertaining the role of two neuroactive steroids allopregnanolone (AP) and tetrahydrodeoxycorticosterone (THDOC) actives in modulating the function and plasticity of GABAA receptors in nature

An experimental analysis on driving behaviour for professional bus drivers

n/

Binge-like administration of alcohol mixed to energy drinks to male adolescent rats severely impacts on mesocortical dopaminergic function in adulthood: A behavioral, neurochemical and electrophysiological study

A growing body of evidence indicates that the practice of consuming alcohol mixed with energy drinks (ED) (AMED) in a binge drinking pattern is significantly diffusing among the adolescent population. This behavior, aimed at increasing the intake of alcohol, raises serious concerns about its long-term effects. Epidemiological studies suggest that AMED consumption might increase vulnerability to alcohol abuse and have a gating effect on the use of illicit drugs. The medial prefrontal cortex (mPFC) is involved in the modulation of the reinforcing effects of alcohol and of impulsive behavior and plays a key role in the development of addiction. In our study, we used a binge-like protocol of administration of alcohol, ED, or AMED in male adolescent rats, to mimic the binge-like intake behavior observed in humans, in order to evaluate whether these treatments could differentially affect the function of mesocortical dopaminergic neurons in adulthood. We did so by measuring: i) physiological sensorimotor gating; ii) voluntary alcohol consumption and dopamine transmission before, during, and after presentation of alcohol; iii) electrophysiological activity of VTA dopaminergic neurons and their sensitivity to a challenge with alcohol. Our results indicate that exposure to alcohol, ED, or AMED during adolescence induces differential adaptive changes in the function of mesocortical dopaminergic neurons and, in particular, that AMED exposure decreases their sensitivity to external stimuli, possibly laying the foundation for the altered behaviors observed in adulthood

Chronic treatment with hormonal contraceptives alters hippocampal BDNF and histone H3 post-translational modifications but not learning and memory in female rats

Hormonal contraceptives prevent ovulation with subsequent reduction in endogenous levels of estradiol, progesterone and its neuroactive metabolite allopregnanolone. These neurosteroids modulate several brain functions, including neuronal plasticity, cognition and memory. We hypothesized that hormonal contraceptives might affect synaptic plasticity, learning and memory, as a consequence of suppressed endogenous hormones levels. Female rats were orally treated with a combination of ethinyl estradiol (EE, 0.020 mg) and levonorgestrel (LNG, 0.060 mg) once daily for four weeks. Decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and altered histone H3 post-translational modifications (PTMs) were observed 14 days after discontinuation from chronic EE-LNG treatment. These effects were not accompanied by alterations in long-term plasticity at glutamatergic synapses, recognition memory in the novel object and novel place location tests, or spatial learning, memory, and behavioral flexibility in the Morris water maze test. Thus, decreased BDNF content does not affect synaptic plasticity and cognitive performance; rather it might be relevant for the occurrence of certain psychiatric symptoms, reported by some women using hormonal contraceptives. These results provide the first evidence of hippocampal epigenetic changes induced by hormonal contraceptives and complement previous studies on the neurobiological actions of hormonal contraceptives; the finding that effects of chronic EE-LNG treatment on BDNF content and histone PTMs are observed 14 days after drug discontinuation warrants further investigation to better understand the implications of such long-term consequences for women's health

The role of neuroactive steroids in ethanol/stress interactions: proceedings of symposium VII at the Volterra conference on alcohol and stress, May 2008

This report summarizes the proceedings of the symposium VII on the role of neuroactive steroids in stress/alcohol interactions. The production of GABAergic neuroactive steroids, including (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) and (3α,5α)-3,21-dihydroxypregnan-20-one (3α,5α-THDOC) is a consequence of both acute stress and acute ethanol exposure. Acute, but not chronic ethanol administration elevates brain levels of these steroids and enhances GABAA receptor activity. Neuroactive steroids modulate acute anticonvulsant effects, sedation, spatial memory impairment, anxiolytic-like, antidepressant-like and reinforcing properties of ethanol in rodents. Furthermore, these steroids participate in the homeostatic regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Therefore, it is not surprising that neuroactive steroids are involved in ethanol/stress interactions. Nevertheless, the interactions are complex and not well understood. This symposium addressed the role of neuroactive steroids in both stress and alcohol responses and their interactions. Professor Giovanni Biggio of the University of Cagliari, Italy presented the effects of juvenile isolation stress on neuroactive steroids, GABAA receptor expression and ethanol sensitivity. Professor Howard Becker of the Medical University of South Carolina, USA presented evidence for neuroactive steroid involvement in ethanol dependence and drinking behavior. Professor Patrizia Porcu of the University of North Carolina, USA described a potential neuroactive steroid biomarker that may predict heavy drinking in monkeys and mice. These presentations provide a framework for new theories on the nature of ethanol/stress interactions that may be amenable to therapeutic interventions

Radiosynthesis and in vivo evaluation of two imidazopyridineacetamides, [11C]CB184 and [11C]CB190, as a PET tracer for 18 kDa translocator protein: direct comparison with [11C](R)-PK11195

Objective: We report synthesis of two carbon-11 labeled imidazopyridines TSPO ligands, [11C]CB184 and [11C]CB190, for PET imaging of inflammatory process along with neurodegeneration, ischemia or brain tumor. Biodistribution of these compounds was compared with that of [11C]CB148 and [11C](R)-PK11195. Methods: Both [11C]CB184 and [11C]CB190 having 11C-methoxyl group on an aromatic ring were readily prepared using [11C]methyl triflate. Biodistribution and metabolism of the compounds were examined with normal mice. An animal PET study using 6-hydroxydopamine treated rats as a model of neurodegeneration was pursued for proper estimation of feasibility of the radioligands to determine neuroinflammation process. Results: [11C]CB184 and [11C]CB190 were obtained via O-methylation of corresponding desmethyl precursor using [11C]methyl triflate in radiochemical yield of 73 % (decay-corrected). In vivo validation as a TSPO radioligand was carried out using normal mice and lesioned rats. In mice, [11C]CB184 showed more uptake and specific binding than [11C]CB190. Metabolism studies showed that 36 % and 25 % of radioactivity in plasma remained unchanged 30 min after intravenous injection of [11C]CB184 and [11C]CB190, respectively. In the PET study using rats, lesioned side of the brain showed significantly higher uptake than contralateral side after i.v. injection of either [11C]CB184 or [11C](R)-PK11195. Indirect Logan plot analysis revealed distribution volume ratio (DVR) between the two sides which might indicate lesion-related elevation of TSPO binding. The DVR was 1.15 ± 0.10 for [11C](R)-PK11195 and was 1.15 ± 0.09 for [11C]CB184. Conclusion: The sensitivity to detect neuroinflammation activity was similar for [11C]CB184 and [11C](R)-PK11195

Role of cholinergic neurons in the cardiovascular responses evoked by central injection of bradykinin or angiotensin II in conscious rats

Intracerebroventricular (i.c.v.) injection of bradykinin (0.1-10 micrograms) or angiotensin II (0.01-10 micrograms) in conscious, freely moving rats evoked dose-related increases in arterial pressure. The pressor response to bradykinin (BK) was accompanied by an increase in heart rate while angiotensin II (ANG II) decreased heart rate. Pretreatment with hemicholinium-3 to deplete brain acetylcholine levels produced a choline-reversible blockade of the cardiovascular response to BK. In contrast, the pressor response to ANG II was only weakly inhibited by hemicholinium-3 and the bradycardia was unaffected. Central pretreatment with the nicotinic antagonist, hexamethonium (50 micrograms) was more effective than the muscarinic antagonist atropine (20 micrograms) at blocking the cardiovascular responses to i.c.v. injection of BK. Both blocking agents produced a weaker inhibitory effect on the pressor response to ANG II although no anticholinergic pretreatment significantly inhibited the fall in heart rate. These results are consistent with the possibility of a peptidergic-cholinergic interaction in the central cardiovascular actions of BK and perhaps for a component of the pressor response to ANG II

Neonatal stress tempers vulnerability of acute stress response in adult socially isolated rats

Adverse experiences occurred in early life and especially during childhood and adolescence can have negative impact on behavior later in life and the quality of maternal care is considered a critical moment that can considerably influence the development and the stress responsiveness in offspring. This review will assess how the association between neonatal and adolescence stressful experiences such as maternal separation and social isolation, at weaning, may influence the stress responsiveness and brain plasticity in adult rats. Three hours of separation from the pups (3-14 postnatal days) significantly increased frequencies of maternal arched-back nursing and licking-grooming by dams across the first 14 days postpartum and induced a long-lasting increase in their blood levels of corticosterone. Maternal separation, which per sedid not modified brain and plasma allopregnanolone and corticosterone levels in adult rats, significantly reduced social isolation-induced decrease of the levels of these hormones. Moreover, the enhancement of corticosterone and allopregnanolone levels induced by foot shock stress in socially isolated animals that were exposed to maternal separation was markedly reduced respect to that observed in socially isolated animals. Our results suggest that in rats a daily brief separation from the mother during the first weeks of life, which per se did not substantially alter adult function and reactivity of hypothalamic-pituitary-adrenal (HPA) axis, elicited a significant protection versus the subsequent long-term stressful experience such that induced by social isolation from weaning.   Proceedings of the 10th International Workshop on Neonatology · Cagliari (Italy) · October 22nd-25th, 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgio