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Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems
Abstract
This article will review neuroactive steroid effects on serotonin and GABA systems, along with the subsequent effects on cognitive functions. Neurosteroids (such as estrogen, progesterone, and allopregnanolone) are synthesized in the central and peripheral nervous system, in addition to other tissues. They are involved in the regulation of mood and memory, in premenstrual syndrome, and mood changes related to hormone replacement therapy, as well as postnatal and major depression, anxiety disorders, and Alzheimer's disease. Estrogen and progesterone have their respective hormone receptors, whereas allopregnanolone acts via the GABA(A) receptor. The action of estrogen and progesterone can be direct genomic, indirect genomic, or non-genomic, also influencing several neurotransmitter systems, such as the serotonin and GABA systems. Estrogen alone, or in combination with antidepressant drugs affecting the serotonin system, has been related to improved mood and well being. In contrast, progesterone can have negative effects on mood and memory. Estrogen alone, or in combination with progesterone, affects the brain serotonin system differently in different parts of the brain, which can at least partly explain the opposite effects on mood of those hormones. Many of the progesterone effects in the brain are mediated by its metabolite allopregnanolone. Allopregnanolone, by changing GABA(A) receptor expression or sensitivity, is involved in premenstrual mood changes; and it also induces cognitive deficits, such as spatial-learning impairment. We have shown that the 3beta-hydroxypregnane steroid UC1011 can inhibit allopregnanolone-induced learning impairment and chloride uptake potentiation in vitro and in vivo. It would be important to find a substance that antagonizes allopregnanolone-induced adverse effects.
... In adults, an activation of the GABA-A receptor leads to an inward flow of chloride ions. This leads to a hyperpolarization-that is, inhibition of the neuron [31]. In fetuses, in neuronal stem cells and certain neurological disorders, the chloride flow is reversed when the GABA-A receptor opens, and GABA thus becomes excitatory [32][33][34]. ...
... Thus, certain subtypes will be able to influence the function of the brain area where the receptor is located [38]. More information about receptor subtype area function is described elsewhere [31,39]. The receptor type with the α5 subunits is well known to be related to cognition and is found in the hippocampus. ...
... We chose the α1 subtype because it is the most common in the CNS and has been the receptor subtype most often investigated in previous studies [35,81,82]. The α5 subtype is found in the hippocampus and is related to memory, learning, and dementia development [31,83,84]. Depression is a common side effect of MPA, and the α2 subtype has been discussed in association with depressive symptoms [39,85]. ...
Bäckström T, Turkmen S, Das R, Dover-skog M, Blackburn TP. The GABA system, a new target for medications against cognitive impairment-Associated with neuroactive steroids. J Intern Med. 2023;00:1-14. The prevalence of cognitive dysfunction, demen-tia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopreg-nanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hep-atic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.
... It could also be the case that the serotonergic and GABAergic systems interact to cause RMD symptoms (66). As reviewed by Birzniece et al. (66), a clear interaction between the GABAergic and the serotonergic systems has been described in the hippocampus. ...
... It could also be the case that the serotonergic and GABAergic systems interact to cause RMD symptoms (66). As reviewed by Birzniece et al. (66), a clear interaction between the GABAergic and the serotonergic systems has been described in the hippocampus. In this particular area of the brain serotonin neurons have been found to frequently end at inhibitory GABAergic interneurons (67). ...
... Interactions Between the Serotonergic and the GABAergic system in PMDD As discussed by Birzniece et al. (66) SSRIs may increase inhibitory processes in the limbic structures of the brain involved in the emotional as well as cognitive regulation by hyperpolarization of neuronal membranes enhancing GABAstimulated Cl − uptake. Women diagnosed with PMDD have been shown to have a decreased sensitivity toward GABA A receptor active substances, especially during the luteal phase (102), when altered serotonergic activity is also observed [reviewed in Hantsoo and Epperson (103)]. ...
Women worldwide are two to three times more likely to suffer from depression in their lifetime than are men. Female risk for depressive symptoms is particularly high during the reproductive years between menarche and menopause. The term “Reproductive Mood Disorders” refers to depressive disorders triggered by hormonal fluctuations during reproductive transitions including the perimenarchal phase, the pre-menstrual phase, pregnancy, the peripartum period and the perimenopausal transition.
Here we focus on reproductive mood disorders manifesting in adult life. We propose a research agenda that draws together several reproductive mood disorders and investigates which genetic, endocrinological, neural, and psychosocial factors can explain depressive symptoms during phases of hormonal transitions in women. Based on current research it is assumed that some women experience an increased sensitivity to not only fluctuations in reproductive steroids (estrogen and progesterone), but also stress-related steroids. We integrate both dynamics into the concept of “steroid hormone sensitivity,” expanding on the concept of “reproductive hormone sensitivity.” We suggest that a differential response of the stress steroid system including corticosteroids, neurosteroids, like allopregnanolone and the GABA-A Receptor complex, as well as a differential (epi)genetic risk in serotonergic and GABAergic signaling, are moderators or mediators between changes in the reproductive steroid system and the physiological, affective, and cognitive outcomes manifesting in reproductive mood disorders. We point to the lack of research on the role of psychosocial factors in increasing a woman's stress level and at some point also the sensitivity of her stress steroid system within the etiology of Reproductive Mood Disorders.
Drawing together the evidence on various reproductive mood disorders we seek to present a basis for the development of more effective pharmacological, social, and psychological treatment interventions and prevention strategies for women susceptible to these disorders. This could pave the way for new research as well as medical and psychological teaching and practice- such as a new type of Practice for Gynecological Psychoneuroendocrinology- with the aim of working on and ultimately offering more integrative forms of support not yet available to women suffering from depression during hormonal transitions. In medical history women have been left alone with this integrative challenge.
... 9 Fermentation and sprouting can also lead to the formation of a variety of neuroactive compounds in grains, including γaminobutyric acid, serotonin, melatonin, and dopamine, which can affect human health and mood. 10,11 Several neuroactive compounds with different biological properties (regulation of mood and memory; 12 modulation of blood pressure, 13 gastric secretion, heart contractibility, cell growth, and circadian rhythm; 14 and involvement in depression, anxiety, or Alzheimer's disease 12 ) can be formed as a result of the amino acid metabolism via different pathways. An example is the formation of tyrosine derivative compounds catecholamines. ...
... 9 Fermentation and sprouting can also lead to the formation of a variety of neuroactive compounds in grains, including γaminobutyric acid, serotonin, melatonin, and dopamine, which can affect human health and mood. 10,11 Several neuroactive compounds with different biological properties (regulation of mood and memory; 12 modulation of blood pressure, 13 gastric secretion, heart contractibility, cell growth, and circadian rhythm; 14 and involvement in depression, anxiety, or Alzheimer's disease 12 ) can be formed as a result of the amino acid metabolism via different pathways. An example is the formation of tyrosine derivative compounds catecholamines. ...
... At least 19 different subunits have been described (6α, 3β, 3γ, δ, ε, θ, π, and 3ρ) (Olsen and Sieghart, 2009;Wisden et al., 1992). A more detailed description of the receptor localization and relation to function is given elsewhere (Birzniece et al., 2006b;Bäckström et al., 2008;Korpi et al., 2002). Still, the receptor type containing the α5 subunit is wellknown to be related to memory and learning and is highly expressed in hippocampus and subtypes containing α4,βx,δ is very sensitive to APα and the expression of the receptor is regulated by APα (Belelli et al., 2002;Locci and Pinna, 2017). ...
... Also, the selective blockade of α5 subunit containing GABA-A receptors increased rat learning and memory (Maubach, 2003). For further details on the GABA-A receptor subunits and memory care for a review on the subject (Birzniece et al., 2006b). ...
Cognitive dysfunction, dementia and Alzheimer’s disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APα), it’s role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APα depend on administration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APα and APα-antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials
... The mechanisms by which this neurosteroid improves the cognitive performance remain unclear. There is increasing evidence linking neurosteroid modulation with several neurotransmitters, such as serotonin (Birzniece et al. 2006;Do Rego et al. 2009). ...
... Serotonergic axon terminals in the hippocampus have been shown to preferentially target GABAergic inhibitory neurons (Freund et al. 1990;Lesch and Waider 2012). In addition, it is known that the serotonergic system is influenced by changes in plasma and brain levels of neuroactive steroids (Birzniece et al. 2006) proportional to modifications in gonadal steroid hormone levels (Lu and Bethea 2002), and is also responsible in fear reduction leading to poor performance in passive avoidance test (Myhrer 2003). ...
Previously, we found out that in ovariectomized female rats, estrogen and progesterone produce a memory deficit which is reverted by the intrahippocampal administration of allopregnanolone. Here, we study the possible interplay between allopregnanolone and hippocampal serotonergic activity. Ovariectomized rats injected subcutaneously with estrogen and progesterone were subsequently injected in the dorsal hippocampus with vehicle, allopregnanolone alone or allopregnanolone shortly after 8OH-DPAT, a predominantly 5HT1A-7 receptor agonist. Then, the subjects were sequentially tested in: (1) an inhibitory avoidance task and (2) K⁺-evoked [3H]-serotonin ex vivo release through superfusion experiments. Allopregnanolone increased the K⁺-evoked [3H]-serotonin release compared to control. 8OH-DPAT infusions reversed the effects of allopregnanolone on memory and K⁺-evoked [3H]-serotonin release. These results suggest that allopregnanolone memory improvement could be mediated, at least in part, through modulation of the hippocampal serotonergic system reactivity.
... Progesterone can influence and regulate endolymph and affect the central and peripheral auditory systems, due to it acts indirectly by interaction with steroid-binding sites on GABA-A receptors acting as a GABA-A agonist, which are widely distributed throughout the audiovestibular apparatus. Progesterone also has an inhibitory effect by lowering serotonin levels, which indirectly affects signal processing (14,15) . ...
... Considering the neurotoxic role of bile acids, along with the oxidative properties of DCAs, the detection of decreased levels of bile acid metabolites and DCA products in the present study is therefore not surprising. Similarly, allopregnanolone has already been reported to have harmful effects on cognitive functions through GABA signalling [147]. Also, increased bile acid levels have been reported in MCI and AD. ...
Background
Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress.
Methods
Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L -serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl- L -cysteine (12.75%), and 3.73 g L -carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.
Results
We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 ( P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline ( P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment.
Conclusion
Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis.
Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131
... Considering the neurotoxic role of bile acids, along with the oxidative properties of DCAs, the detection of decreased levels of bile acid metabolites and DCA products in the present study is therefore not surprising. Similarly, allopregnanolone has already been reported to have harmful effects on cognitive functions through GABA signalling [147]. Also, increased bile acid levels have been reported in MCI and AD. ...
... Progesterone and its metabolites may also influence the auditory system through its interaction with the steroid binding sites on GABA-A receptors acting as a GABA-A agonist, which are present throughout the auditory system. Progesterone was found to decrease 5-HT (5-hydroxy tryptamine) levels and this may affect auditory processing indirectly (13). The higher level of estrogen during the follicular phase of ovarian cycle is also associated with a rise in other hormone levels. ...
Background: Changes in auditory function have been noted in post-menopausal women attributed in part to the lower levels of ovarian hormones. Decreased levels of ovarian hormones may alter auditory neurotransmission time, as evaluated by Auditory Brainstem Responses (ABR). Thus, objective of this study was comparison of mean inter-peak ABR latencies in post-menopausal women compared to non-menopausal women. Methods: In this cross-sectional study, research sample consisted of 60 women as case group in the age range of 45-55 years, who were post-menopausal and had normal hearing. The control group with similar characteristics were non-menopausal. Two groups were estimated by ABR and then the means of the variables that had a normal distribution were compared with each other by independent t-test. Results: All differences between two groups were not significant, as follows; Mean I-III inter-peak ABR latencies (p-value=0.714), mean III-V inter-peak ABR latencies (p-value=0.691) and mean I-V inter-peak ABR latencies (p-value=0.483). Conclusion: Menopause does not cause abnormal results in auditory brainstem responses.
... The α1 subunit is thought to be involved in sedation and anesthesia and, 35-reduced progesterone metabolites are potent positive modulators of GABA A J o u r n a l P r e -p r o o f receptors with sedative effect (Norberg et al., 1987), but as MPA can induce anesthesia, the α1 subunit was an obvious choice (Meyerson, 1967). GABA A receptors including the α5 subunit are mainly found in the hippocampus, have been implicated in memory and learning and are discussed in relation to dementia development (Schumaker et al., 2003;Johansson et al., 2002;Collinson et al., 2002;Maubach et al., 2003;Birzniece et al., 2006). MPA is also known to induce negative mood, and α2 subunit containing GABA A receptors are present in the amygdala and seem to be related to disturbed mood (Löw et al., 2000;Korpi et al., 2002). ...
Medroxyprogesterone acetate (MPA) is a progestin widely used in humans as hormone replacement therapy and at other indications. Many progestin metabolites, as the progesterone metabolite allopregnanolone, have GABAA-receptor modulatory effects and are known to affect memory, learning, appetite, and mood. In women, 4 years chronic treatment with MPA doubles the frequency of dementia and in rats, MPA causes cognitive impairment related to the GABAergic system. Activation of the membrane bound GABAA receptor results in a chloride ion flux that can be studied by whole-cell patch-clamp electrophysiological recordings. The purpose of this study was to clarify the modulatory effects of MPA and specific MPA metabolites, with structures like known GABAA-receptor modulators, on different GABAA-receptor subtypes. An additional aim was to verify the results as steroid effects on GABA response in single cells taken from rat hypothalamus. HEK-293 cell-lines permanently expressing the recombinant human GABAA-receptor subtype α1β2γ2 L or α5β3γ2 L or α2β3γ2 S were created. The MPA metabolites 3α5α-MPA,3β5α-MPA and 3β5β-MPA were synthesised and purified for electrophysiological patch-clamp measurements with a Dynaflow system. The effects of MPA and tetrahydrodeoxycorticosterone were also studied. None of the studied MPA metabolites affected the responses mediated by α1β2γ2 L or α5β3γ2 L GABAA receptors. Contrary, MPA clearly acted both as a positive modulator and as a direct activator of the α5β3γ2 L and α2β3γ2 S GABAA receptors. However, in concentrations up to 10 μM, MPA was inactive at the α1β2γ2 L GABAA receptor. In the patch-clamp recordings from dissociated cells of the preoptic area in rats, MPA increased the amplitude of responses to GABA. In addition, MPA alone without added GABA, evoked a current response. In conclusion, MPA acts as a positive modulator of specific GABAA receptor subtypes expressed in HEK cells and at native GABA receptors in single cells from the hypothalamic preoptic area.
... Considering the neurotoxic role of bile acids, along with the oxidative properties of DCAs, the detection of decreased levels of bile acid metabolites and DCA products in the present study is therefore not surprising. Similarly, allopregnanolone has already been reported to result in deleterious effects on cognitive functions through gamma-aminobutyric acid (GABA) signalling118 . Also, increased bile acid This preprint research paper has not been peer reviewed. ...
... Isoallopregnanolone is formed in parallel with progesterone and allopregnanolone in women during the luteal phase of the menstrual cycle. Unlike progesterone, isoallopregnanolone lacks classical hormonal effects (Jewgenow et al., 1998;Hedström et al., 2009) and has no effect per se on the GABA A receptor but works as an antagonist to positive GABA A modulating steroids e.g., allopregnanolone (Birzniece et al., 2006;Lundgren et al., 2003). ...
Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified.
... EST's effects on behavior and brain function has been widely studied (Comasco & Sundström-Poromaa, 2015;Luine, 2014;Poromaa & Gingnell, 2014;Sacher, Okon-Singer, & Villringer, 2013;Sherwin & Grigorova, 2011) and results suggest that EST may boost neuronal excitability by interacting with glutaminergic neurotransmission (Barth, Villringer, & Sacher, 2015;Del Río et al., 2018;Finocchi & Ferrari, 2011;Foy et al., 1999;Pelligrino & Galea, 2001;Woolley, 2007). On the other hand, PROG, along with its derivatives pregnanolone and allopregnanolone, interacts with gamma amino butyric acid (GABA) receptors (Barth et al., 2015;Birzniece et al., 2006;Bitran, Purdy, & Kellog, 1993;Carver & Reddy, 2013;Del Río et al., 2018;Reddy, 2018;Smith, Shen, Gong, & Zhou, 2007) and inhibit neuronal activity (Belelli, Bolger, & Gee, 1989;Bitran et al., 1993;Gee, Bolger, Brinton, Coirini, & McEwen, 1988;Jeffrey et al., 2014;Puia, Gullo, Dossi, Lecchi, & Wanke, 2012;Taubøll & Lindström, 1993). For example, intravenous injection of 200 μg/kg PROG has been found to decrease the spontaneous spiking of cortical excitatory neurons by $50% in animals (Phillis, 1986). ...
Sex hormones estrogen (EST) and progesterone (PROG) have received increased attention for their important physiological action outside of reproduction. While studies have shown that EST and PROG have significant impacts on brain function, their impact on the cerebrovascular system in humans remains largely unknown. To address this, we used a multi-modal magnetic resonance imaging (MRI) approach to investigate the link between serum hormones in the follicular phase and luteal phase of the menstrual cycle (MC) with measures of cerebrovascular function (cerebral blood flow [CBF]) and structure (intracranial artery diameter). Fourteen naturally cycling women were recruited and assessed at two-time points of their MC. CBF was derived from pseudo-continuous arterial spin labeling while diameters of the internal carotid and basilar artery was assessed using time of flight magnetic resonance angiography, blood samples were performed after the MRI. Results show that PROG and EST had opposing and spatially distinct effects on CBF: PROG correlated negatively with CBF in anterior brain regions (r = −.86, p < .01), while EST correlations were positive, yet weak and most prominent in posterior areas (r = .78, p < .01). No significant correlations between either hormone or intracranial artery diameter were observed. These results show that EST and PROG have opposing and regionally distinct effects on CBF and that this relationship is likely not due to interactions with large intracranial arteries. Considering that CBF in healthy women appears tightly linked to their current hormonal state, future studies should consider assessing MC-related hormone fluctuations in the design of functional MRI studies in this population.
... La alopregnenolona mediante la vía de receptores GABAa, produce alteraciones en el aprendizaje y memoria, inhibiendo la actividad neural de la región CA-1. En contraste, los estrógenos que antagonizan los receptores GABAa incrementan estas funciones 18 . ...
Aprendizaje y memoria son dos procesos cerebrales estrechamente ligados que originan cambios adaptativos en el comportamiento de los organismos. Existen una gran variedad de neurotransmisores, así como hormonas, que ejecutan un papel importante en el proceso del aprendizaje y memoria, entre las cuales se encuentran los estrógenos, que además de actuar como agentes estimulantes del crecimiento, también interfieren con el desarrollo neuronal en la etapa de neurogénesis y afectan la migración de neuroblastos, los cuales posteriormente formarán núcleos cerebrales. Basados en lo anterior nosotros decidimos realizar el siguiente proyecto para determinar el efecto de la suplementación con 17β- estradiol a dosis de 12.5 mg/ml en el aprendizaje de ratas ovariectomizadas al igual que, someter a dos grupos de ratas ovariectomizadas con y sin suplementación a tareas de aprendizaje y memoria utilizando el laberinto acuático de Morris (LAM). Resultados: Nosotros encontramos que las ratas ovariectomizadas y suplementadas con 17β- estradiol tardan significativamente menor tiempo en recorrer el LAM que las ratas ovariectomizadas y no suplementadas en el día uno del estudio (p<0.05). Al medir memoria a las 24 horas posterior a un día de entrenamiento y después de 10 ensayos no se observa ninguna diferencia estadística, sin embargo a las 24 horas después de 2 días de entrenamiento se aprecia una diferencia significativa con p< 0.05. Discusión: Los resultados que se obtuvieron nos permiten demostrar que los estrógenos aumentan la capacidad plástica de áreas específicas para el aprendizaje y la memoria, como el hipocampo. Sin embargo la diferencia que se encuentra entre las ratas suplementadas y las ovariectomizadas, no es lo bastante significativa como para afirmar que el efecto de los estrógenos aumenta la capacidad de aprendizaje, sino más bien, lo que se observa con la suplementación es la reversión de los efectos adversos que produce la deficiencia de estrógenos en el sistema nervioso, lo cual traduce un efecto neuroprotector de los estrógenos.
... About 50% of synapses in the central nervous system use GABA as the neurotransmitter, which can seriously affect the function of prefrontal cortex 77 83 , and then regulate the activity of 5-HT neurons 84 . The increase of GABA increased its inhibition on 5-HT synthesis 85 , and eventually resulted in the decrease of 5-HT content and function. In this study, we found that GABA concentration in DRN increased, BXD and SY can effectively reduce GABA concentration ( Figure 3D) and then regulate the anger-out and anger-in, which need to take 7 days to achieve curative effect( Figure 2D). ...
Background: To explore the intervention mechanism of Baixiangdan Capsule(BXD) and Shuyu Capsule(SY) in the treatment of anger-out and anger-in. A kind of GABABR1(GB1) mediated GABA in the dorsal raphe nucleus(DRN) regulating serotonin(5-HT) levels in the Prefrontal Cortex(PFC), Hippocampus and Hypothalamus in Anger-out and Anger-in male rats. To further explore the difference of Baixiangdan Capsule(BXD) and Shuyu Capsule(SY) in the treatment of anger-out and anger-in.
Methods: The anger rat model was established by social isolation combined with resident-intruder paradigm, and behavioral evaluation was used to screen and distinguish anger-out and anger-in model rats. BXD and SY were intervention drugs of anger–out and anger-in rats respectively. On this basis, ELISA was used to detect GABA content in DRN and 5-HT contents in PFC, hippocampus and hypothalamus after different time course (0,1,3,5,7 days) treated with BXD and SY. The co expression of 5-HT and GB1 in DRN was detected by immunofluorescence double labeling technique. Finally, brain stereotactic localization was performed after baclofen, the GB1 specific agonist, and CGP35348, the GB1 specific inhibitor, were injected into the DRN, the 5-HT contents in PFC, hippocampus and hypothalamus was detected by ELISA.
Results: After drug treatment, ABT scores and OFT total distance in BXD group were significantly decreased to the level of control group (P<0.05). On the contrary, that in SY group were significantly increased to the level of control group (P<0.05). The sugar water preference coefficient of BXD group and SY group was significantly increased to the normal level (P<0.05). With the increase of the medication duration, 5-HT levels in PFC, hypothalamus and hippocampus increased, gradually corrected its abnormal decline, and returned to the normal level on the 7th day. Besides, GABA level in DRN decreased, gradually corrected its abnormal increase, and also returned to normal level on the 7th day. A large number of 5-HT positive cells (red) in DRN could be seen on immunofluorescence section, and GB1 positive cells (green) could also be seen. Besides, after the drug intervention, 5-HT level in DRN was elevated to normal level (P<0.05). GB1 level in DRN was decreased to normal level in BXD group and SY group (P<0.05). Compared with saline injection, 5-HT levels in PFC, hypothalamus and hippocampus in each group was significantly decreased after injection of baclofen into the DRN (P < 0.05). On the contrary, 5-HT levels in PFC, hypothalamus and hippocampus in each group was significantly increased after the injection of CGP35348 into the DRN.
Conclusions: BXD and SY can effectively improve the abnormal behavior changes of anger-out and anger-in rats, and the optimal duration of action is 7 days. The improvement way is to correct the following abnormal changes: The significantly increased GABA in DRN combined with a significantly increased GB1 on 5-HT neurons in DRN, which further mediated the synaptic inhibition effect, thereby reducing 5-HT level of 5-HT neurons in DRN, resulting in a significant decrease of 5-HT levels in PFC, hypothalamus and hippocampus. Therefore, GB1 mediated GABA in DRN can regulate 5-HT levels in PFC, hypothalamus and hippocampus, which may be one of the ways that BXD and SY treat anger-out and anger-in.
... Other neuroactive steroids and allopregnanolone (progesterone metabolites) have a significant influence on brain physiology and its system. Allopregnanolone has been found to exhibit an inhibitory effect on serotonergic neurons of the raphe nucleus (Genazzani et al. 2000;Birzniece et al. 2006). Progesterone has also been described to antagonize sigma-1 receptor activation, thereby inhibiting the release of norepinephrine (Genazzani et al. 2000;Pluchino et al. 2006). ...
Neurotransmitters are chemical messengers synthesized by neurons, which enable interconnection of nerve fibers within their vicinity. Neurotransmitters traditionally consist of amino acids and their derivatives, chains of amino acids, peptides or proteins. However, several studies report that steroids and hormones also exert an acute effect on the physiology of neuronal activity and the expression of behavior that can happen within minutes. Those steroids that can bind to the neurotransmitter receptors and modulate the neurotransmission signal are included together within the term neurosteroids or neuroactive steroids. The examples of neuroactive steroids include progesterone, estradiol, testosterone, DHEA, glucocorticoid, allotetrahydrodeoxycorticosterone (THDOC), androstanediol (AD), ganaloxone, androsterone, pregnenolone, allopregnanolone and their sulfate esters. Additionally, several synthetic steroids such as alphaxalone and 3ɑ-hydroxy-5β-pregnan-20-one hemisuccinate possess similar characteristics of modulating neuronal activities to the endogenous steroids. These hormonal steroids exert their neuronal excitability functions through various receptors and ion channels such as the estrogen receptor, progesterone receptor, androgen receptor, GABAA, AMPA and NMDA receptors. These neuroactive steroids are also involved in the pathology and physiology of various neurological disorders such as epilepsy, schizophrenia and traumatic brain injury. Additionally, these neuroactive steroids have agonistic or antagonistic effects toward the neurotransmission action of various other neurotransmitters some of which have undergone clinical trials for the treatment of various neurological disorders. Thus, these steroids and hormones can act as neurotransmitters, exert either agonistic or antagonistic effects on receptors and have potential benefits in the treatment of neurological disorders.
... Previous studies have shown that neuron-specific metabolite abnormalities in N-acetyl aspartate (NAA), brain-derived neurotrophic factor (BDNF), GSH, glutamate (Glu) and γ-aminobutyric acid (GABA) levels could modulate and predict different aspects of cognitive performance. [22][23][24][25][26][27][28] Research has shown that oxidative stress can act on BDNF in the injured brain to affect synaptic plasticity and cognition; 29 therefore, the sulforaphane-mediated antioxidative effect might influence BDNF levels to improve cognitive function. Several studies also show that sulforaphane augments whole brain and peripheral GSH levels to attenuate oxidative stress, which also supports its potential application in cognitive improvement. ...
Introduction
Many patients with frontal brain damage show serious cognitive function deficits, which hamper their quality of life and result in poor clinical outcomes. Preclinical research has shown that sulforaphane can significantly improve spatial localisation and working memory impairment after brain injury. The primary aim of this double-blind randomised controlled clinical trial is to assess the efficacy of sulforaphane for improving cognitive function in patients with frontal brain damage.
Methods and analysis
Ninety eligible patients will be randomly allocated to an active treatment or a placebo group in a 2:1 ratio. Participants will undergo a series of cognitive and neuropsychiatric tests at baseline (week 0) and after 12 weeks to determine the effect of sulforaphane on cognition. Magnetic resonance spectrum of the brain will be studied using the 3T MRIs of the brain to detect brain metabolites markers, including N-acetyl aspartate, glutamate (Glu), glutathione (GSH) and γ-aminobutyric acid (GABA). Blood brain-derived neurotrophic factor, Glu, GSH and GABA levels and gut microbiota will also be assessed over this period. This study will also evaluate long-term outcomes of brain trauma, brain tumours and cerebrovascular disease via exploratory analyses. The primary outcome will be the difference in scores of a battery of cognitive tests after 12 weeks of sulforaphane treatment. The secondary outcomes will be changes in the Functional Activities Questionnaire (FAQ), the Patient Health Questionnaire (PHQ-9), the Self-Rating Anxiety Scale, the changes in T1-weighted MRI and resting-state functional MRI findings, and changes in brain and blood metabolic markers and gut microbiota at weeks 0 and 12. We expect that sulforaphane will yield favourable results in treating memory and learning deficits for patients with frontal brain damage. Cognitive functional treatment may also improve brain trauma, brain tumours and cerebrovascular outcomes.
Ethics and dissemination
The study protocol has been approved by the Medical Ethics committee of the Xiangya Hospital of Central South University (No. 2017121019). The results will be disseminated in peer-reviewed journals and at international conferences.
Trial registration number
This trial was registered on Clinicaltrials.gov on 31 January 2020 ( NCT04252261 ). The protocol version is V.1.0 (20 December 2019).
... Allopregnanolone, similar to benzodiazepines, produces this change via its action as a potent positive allosteric modulator of the GABAA receptor. By binding to the neurosteroidal site on the GABAA receptor allopregnanolone potentiates the effect of GABA, leading to an overall increase in inhibition of neuronal excitability (Birzniece et al., 2006;Majewska, Harrison, Schwartz, Barker, & Paul, 1986). While the effect of allopregnanolone on the balance of cortical excitation and inhibition is beginning to become apparent in animal research (Smith, Shen, Gong, & Zhou, 2007), limitations in measuring functional changes in vivo in humans has meant a major gap in understanding remains. ...
Fluctuations in gonadal hormones over the course of the menstrual cycle are known to cause functional brain changes and are thought to modulate changes in the balance of cortical excitation and inhibition. Animal research has shown this occurs primarily via the major metabolite of progesterone, allopregnanolone, and its action as a positive allosteric modulator of the GABA A receptor. Our study used EEG to record gamma oscillations induced in the visual cortex using stationary and moving gratings. Recordings took place during twenty females’ mid-luteal phase when progesterone and oestradiol are highest, and early follicular phase when progesterone and oestradiol are lowest. Significantly higher (~5 Hz) gamma frequency was recorded during the luteal compared to the follicular phase for both stimuli types. Using dynamic causal modelling these changes were linked to stronger self-inhibition of superficial pyramidal cells in the luteal compared to the follicular phase. In addition the connection from inhibitory interneurons to deep pyramidal cells was found to be stronger in the follicular compared to the luteal phase. These findings show that complex functional changes in synaptic microcircuitry occur across the menstrual cycle and that menstrual cycle phase should be taken into consideration when including female participants in research into gamma-band oscillations.
... The effect of estradiol on spatial cognition could be explained through its relationships with the activity and volume of prefrontal, posterior parietal cortex and hippocampus, i.e. brain areas closely related to the spatial strategy, decision making, and transformation-specific computations 5,21,86 . Progesterone can influence cognition and behaviour through binding to the GABA receptors and exerting an inhibitory effect on a neural signal transmission (for review see 87,88 ). In addition, communication between the two hemispheres, which has been shown to have high importance in mental rotation performance 36 , can also be affected by sex steroids. ...
Mental rotation of 3D objects demonstrates one of the largest sex differences. We investigated sex and sex hormones-related differences in behaviour and event related potentials (ERP) using a modified Shepard and Metzler task composed of sequentially presented 3D figures in 29 men and 32 women. We demonstrated a significant increase in response time and decrease in both accuracy and positivity of the parietal ERP with increasing angular disparity between the figures. Higher angular disparity evoked an increase of global field power (GFP) from 270 to 460 ms and different activation topographies from 470 to 583 ms with lower parietal, but higher left frontal positivity. Flatter slopes in higher angular disparity condition suggest distinct strategies being implemented depending on the difficulty of the rotation. Men performed the task more accurately than women. Performance accuracy in women tended to be negatively related to estradiol while the response time tended to increase with increasing progesterone. There were no associations with testosterone. Women demonstrated higher GFP and an increased positivity over the parietal scalp area, while men showed higher activation in the left frontal cortex. Together these findings indicate dynamic angular disparity- and sex-related differences in brain activity during mental rotation of 3D figures.
... 10 Ultimately, the inability to treat SE results in epileptogenesis, performance deficits, and extensive neuronal loss, including loss of GABAergic interneurons. 2,[10][11][12][13][14][15] One means to treat pharmacoresistant seizures is through the use of neurosteroids, which are positive allosteric modulators of synaptic and extrasynaptic GABA A receptors, and have the potential to produce anticonvulsant effects similar to diazepam but with fewer side effects (reviewed in Birzniece, et al 16 , and Reddy 17 ). Neurosteroids, such as progesterone and its metabolites, bind to the GABA A receptor at binding sites distinct from benzodiazepines and potentiate GABA-induced Clinflux. ...
Objective
Our objective was to evaluate the protective efficacy of the neurosteroid pregnanolone (3α‐hydroxy‐5β pregnan‐20‐one), a GABAA receptor positive allosteric modulator, as an adjunct to benzodiazepine therapy against the chemical warfare nerve agent (CWNA) sarin (GB), using whole body exposure, an operationally relevant route of exposure to volatile GB.
Methods
Rats implanted with telemetry transmitters for the continuous measurement of cortical electroencephalographic (EEG) activity were exposed for 60 minutes to 3.0 LCt50 of GB via whole body exposure. At the onset of toxic signs, rats were administered an intramuscular injection of atropine sulfate (2 mg/kg) and the oxime HI‐6 (93.6 mg/kg) to increase survival rate and, 30 minutes after seizure onset, treated subcutaneously with diazepam (10 mg/kg) and intravenously with pregnanolone (4 mg/kg) or vehicle. Animals were evaluated for GB‐induced status epilepticus (SE), spontaneous recurrent seizures (SRS), impairment in spatial memory acquisition and brain pathology, and treatment groups were compared.
Results
Delayed dual therapy with pregnanolone and diazepam reduced time in SE in GB‐exposed rats compared to those treated with delayed diazepam monotherapy. The combination therapy of pregnanolone with diazepam also prevented impairment in the Morris water maze, and reduced the neuronal loss and neuronal degeneration, evaluated at one and three months after exposure.
Significance
Neurosteroid administration as an adjunct to benzodiazepine therapy offers an effective means to treat benzodiazepine‐refractory SE, such as occurs following delayed treatment of GB exposure. This study is the first to present data on the efficacy of delayed pregnanolone and diazepam dual therapy in reducing seizure activity, performance deficits and brain pathology following an operationally relevant route of exposure to GB and supports the use of a neurosteroid as an adjunct to standard anticonvulsant therapy for the treatment of CWNA‐induced SE.
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... Thus, this cohort is too small to establish any gender-specific differences in the response to ICH. Gender differences in brain structure, function and chemistry have previously been described [33][34][35] and in a previous traumatic brain injury (TBI) study the levels of glutamate and the lactate/pyruvate ratio in CSF were lower in females compared to males patients 36 . Similarly, significant gender differences on CSF markers of excitotoxicity, ischemia and oxidative damage were observed after TBI 37 . ...
The secondary injury cascades exacerbating the initial brain injury following intracerebral haemorrhage (ICH) are incompletely understood. We used dual microdialysis (MD) catheters placed in the perihaemorrhagic zone (PHZ) and in seemingly normal cortex (SNX) at time of surgical ICH evacuation in ten patients (range 26–70 years). Routine interstitial MD markers (including glucose and the lactate/pyruvate ratio) were analysed and remaining microdialysate was analysed by two-dimensional gel electrophoresis (2-DE) and nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS). Two time intervals were analysed; median 2–10 hours post-surgery (time A) and median 68–76 hours post-ICH onset (time B). Using 2-DE, we quantified 232 ± 31 different protein spots. Two proteins differed between the MD catheters at time A, and 12 proteins at time B (p < 0.05). Thirteen proteins were significantly altered between time A and time B in the SNX and seven proteins in the PHZ, respectively. Using nLC-MS/MS ca 800 proteins were identified out of which 76 were present in all samples. At time A one protein was upregulated and two downregulated, and at time B, seven proteins were upregulated, and four downregulated in the PHZ compared to the SNX. Microdialysis-based proteomics is feasible for study of secondary injury mechanisms and discovery of biomarkers after ICH.
... Changes in serotonin and γ-aminobutyric acid (GABA) levels with estrogen and progesterone metabolites have interaction with the GABA-A receptor complex in neurobiology of PMDD. [24][25][26][27][28][29][30] Studies report that administration of progesterone/ allopregnenolone during the follicular phase enhances amygdala reactivity. 31,32 Other hormones such as thyroid hormone, melatonin, cortisol and relaxin [33][34][35][36][37][38][39] also have been implicated in the pathophysiology of PMDD. ...
Introduction: Premenstrual dysphoric disorder (PMDD) is a distressing disorder amongst women of reproductive age group with significant implication in the productivity and quality of life of women who suffer from it. It is generally neglected as it is mostly undifferentiated from premenstrual symptoms—milder presentation of the same spectrum of problem but of lesser intensity and impairment.
Objective: Here, in this article, we aim to highlight various studies and the research done on PMDD in the context of Indian women.
Method: Reviewing the last 40 years’ database including Medline (PUBMED), Cochrane Library, EMBASE, Trip, Psych INFO, CINAHL, the Allied and Complementary Medicine Database (AMED), and the British Nursing Index.
Results: PMDD is a troublesome disorder, often underdiagnosed. A thorough history including menstrual and sexual history, conducting a thorough physical examination, assessing the comorbidities, and finally using a proper and structured treatment protocol for managing the condition are recommended. Sertraline is the most widely studied drug which is found to be effective in PMDD.
... Estradiol augments LTP, elevates dendritic spine density in the hippocampus, and enhances cognitive performance in hippocampaldependent memory tasks [49][50][51]. Moreover, progesterone metabolites target the inhibitory GABA A receptor and can therefore influence cognitive function [52]. In addition, androgens maintain hippocampal-dependent plasticity and cognitive function [53]. ...
Background
The identification of biomarkers that predict susceptibility to major depressive disorder and treatment response to antidepressants is a major challenge. Vortioxetine is a novel multimodal antidepressant that possesses pro-cognitive properties and differentiates from other conventional antidepressants on various cognitive and plasticity measures. The aim of the present study was to identify biological systems rather than single biomarkers that may underlie vortioxetine’s treatment effects.
Results
We show that the biological systems regulated by vortioxetine are overlapping between mouse and rat in response to distinct treatment regimens and in different brain regions. Furthermore, analysis of complexes of physically-interacting proteins reveal that biomarkers involved in transcriptional regulation, neurodevelopment, neuroplasticity, and endocytosis are modulated by vortioxetine. A subsequent qPCR study examining the expression of targets in the protein–protein interactome space in response to chronic vortioxetine treatment over a range of doses provides further biological validation that vortioxetine engages neuroplasticity networks. Thus, the same biology is regulated in different species and sexes, different brain regions, and in response to distinct routes of administration and regimens.
Conclusions
A recurring theme, based on the present study as well as previous findings, is that networks related to synaptic plasticity, synaptic transmission, signal transduction, and neurodevelopment are modulated in response to vortioxetine treatment. Regulation of these signaling pathways by vortioxetine may underlie vortioxetine’s cognitive-enhancing properties.
Electronic supplementary material
The online version of this article (doi:10.1186/s12868-017-0376-x) contains supplementary material, which is available to authorized users.
... 34 Third, progesterone reduces serotonin levels, and therefore indirectly influences auditory processing. 35 Fourth, progesterone may counterbalance the main excitatory action of oestrogen through inhibition of the central nervous system; for example, allopregnanolone, a metabolite of progesterone, inhibits chloride ion conductance and subsequently reduces neuronal excitability. 36 37 Fifth, the use of a combination of oestrogen and progesterone may potentiate progesterone function. ...
Objective
The purpose of this study was to determine the relationship between hormone replacement therapy (HRT) and tinnitus in South Korea using data from the Korea National Health and Nutrition Examination Surveys (KNHANES) (2010–2012).
Study design
Cross-sectional analysis of a nationwide health survey.
Methods
KNHANES is a nationally representative cross-sectional survey of South Korea population. Only postmenopausal women aged 19–65 years were included in the study (n=2736). Auditory function was evaluated using pure-tone audiometric testing according to established KNHANES protocols. Subjects were questioned about their experience with tinnitus. Exogenous hormone-related factors included the starting age and duration of HRT.
Results
The overall prevalence of tinnitus was 22.2% among postmenopausal women. (1) Tinnitus severity was significantly higher in women using HRT (p=0.0024) and (2) significantly lower in women who breast fed their children (p=0.0386). (3) According to logistic regression models, the longer duration of HRT was significantly associated with increasing tinnitus (OR=1.323, 95% CI 1.007 to 1.737, p=0.0441).
Conclusion
A longer duration of HRT was associated with developing tinnitus in Korean postmenopausal women. Further experimental and epidemiological researches are needed to elucidate the causal relationship between HRT and tinnitus.
... Overall, heightened estrogen levels have been related to improved mood which has been at least partly attributed to its influence on the serotonergic system (Pletzer and Kerschbaum, 2014). However, estrogens diversely affect the serotonergic system in different parts of the brain and exert distinct effects on different serotonin receptor subtypes (overview in: Birzniece et al., 2006). Still, since EE acts as an agonist on estrogen receptors (Stanczyk et al., 2013) while simultaneously lowering endogenous estradiol levels (Fleischman et al., 2010) differences in serotonergic function of COC are probable. ...
Combined oral contraceptives (COC) are used by millions of women worldwide. Although findings are not entirely consistent, COC have been found to impact on brain function and, thus, to modulate affective processes. Here, we investigated electro-physiological responses to emotional stimuli in free cycling women in both the early follicular and late luteal phase as well as in COC users. Skin conductance response (SCR), startle reflex, corrugator and zygomaticus activity were assessed. COC users showed reduced overall startle magnitude and SCR amplitude, but heightened overall zygomaticus activity, although effect sizes were small. Thus, COC users displayed reduced physiological reactions indicating negative affect and enhanced physiological responses signifying positive affect. In free cycling women, endogenous 17β-estradiol levels were associated with fear potentiated startle in both cycle phases as well as with SCR and zygomaticus activity during the follicular phase. Testosterone was associated with corrugator and zygomaticus activity during the luteal phase, while progesterone levels correlated with corrugator activity in the follicular phase. To the contrary, in COC users, endogenous hormones were not associated with electro-physiological measures. The results further underscore the importance of considering COC use in psychophysiological studies on emotional processing.
... Combined action of E 2 and P reduces the occurrence of respiratory disorders like sleep obstructive apnea [8,36], but the mechanisms of action and the effects of ovarian steroids are not yet fully elucidated. It is suggested that E 2 's main actions are mediated primarily through the activation of intracellular estrogen receptors, which are distributed throughout multiple organs, such as the uterus, breast, ovary, lungs, kidneys, bones, and brain [7,33]. Estrogen and progesterone receptors are also found in the carotid body of adult and neonate rats [23] where they exert an excitatory effect on baseline activity and hypoxic chemoresponsiveness [19,25,46,47], and are, therefore, potential protective factors against the occurrence of sleep apneas in women [36,39,55]. ...
Sex hormones may influence many physiological processes. Recently, we demonstrated that hormonal fluctuations of cycling female rats do not affect respiratory parameters during hypercapnia. However, it is still unclear whether sex hormones and hormonal fluctuations that occur during the estrous cycle can affect breathing during a hypoxic challenge. Our study aimed to evaluate respiratory, metabolic, and thermal responses to hypoxia in female rats on different days of the estrous cycle (proestrus, estrus, metestrus, and diestrus) and in ovariectomized rats that received replacement with oil (OVX), estradiol (OVX + E2), or a combination of estradiol and progesterone (OVX + E2P). Ventilation (V E), tidal volume (V T), respiratory frequency (fR), oxygen consumption (VO2), and V E/VO2 were not different during the estrous cycle in normoxia or hypoxia. Body temperature (Tb) was higher during estrus, but decreased similarly in all groups during hypoxia. Compared with intact females in estrus, gonadectomized rats also had lower Tb in normoxia, but not in hypoxia. OVX rats experienced a significant drop in the ventilatory response to hypoxia, but hormonal replacement did not restore values to the levels of an intact animal. Our data demonstrate that the different phases of the estrous cycle do not alter ventilation during normoxia and hypoxia, but OVX animals display lower ventilatory responses to hypoxia compared with ovary-intact rats. Because estradiol and progesterone replacement did not cause significant differences in ventilation, our findings suggest that a yet-to-be-defined non-steroidal ovarian hormone is likely to stimulate the ventilatory responses to hypoxia in females.
... For example, when combined with estrogens, progestogens seem to increase serotonergic activity. On the other hand, allopregnanolone, one of the most potent progesterone metabolites, inhibits the activity of serotonergic neurons of the raphe nucleus, and long-term progesterone treatment downregulates serotonin receptors [89][90][91]. Also, in contrast to estrogens, progestogens decrease sigma-1 receptor activation, involved in the release of norepinephrine, and increase the activity of monoamine oxidase [89,92]. ...
Sex steroids are thought to play a critical developmental role in shaping both cortical and subcortical structures in the human brain. Periods of profound changes in sex steroids invariably coincide with the onset of sex differences in mental health vulnerability, highlighting the importance of sex steroids in determining sexual differentiation of the brain. Yet, most of the evidence for the central effects of sex steroids relies on non-human studies, as several challenges have limited our understanding of these effects in humans: the lack of systematic assessment of the human sex steroid metabolome, the different developmental trajectories of specific sex steroids, the impact of genetic variation and epigenetic changes, and the plethora of interactions between sex steroids, sex chromosomes, neurotransmitters, and other hormonal systems. Here we review how multimodal strategies may be employed to bridge the gap between the basic and clinical understanding of sex steroid-related changes in the human brain.
... Neuroactive steroids such as cortisol (CORT), progesterone (PROG), testosterone (T), dehydroepiandrosterone (DHEA), and estrogens play an important role in shaping the central nervous system (CNS) structure and function throughout the lifespan [1]. Neuroactive steroids modulate a wide array of functions in the brain, spanning from the neurodevelopment to adult neurogenesis [2] and cognition [3]. In adult life, they exert a significant influence on the activity of several neurotransmitter systems that are relevant to the pathophysiology of psychosis, such as the dopaminergic [4], glutamatergic, and GABAergic systems [5]. ...
Neuroactive steroids may play a role in the pathophysiology of psychotic disorders, but few studies examined this issue. We compared serum levels of cortisol, testosterone, dehydroepiandrosterone, and progesterone between a representative sample of first-episode psychosis (FEP) patients and age- and gender-matched healthy subjects. Furthermore, we analyzed the associations between neuroactive steroids levels and the severity of psychotic symptom dimensions. Male patients had lower levels of progesterone than controls ( p = 0.03 ). Progesterone levels were inversely associated with the severity of positive symptoms ( p = 0.007 ). Consistent with preclinical findings, results suggest that progesterone might have a role in the pathophysiology of psychotic disorders.
... In line with this finding, a review concerning biological explanations of PMS concluded that the gonadal hormones (estrogen and progesterone) influence transmitter systems, especially the 5-HT-and the GABA-system. However, the exact relationship still remains unclear (Birzniece et al., 2006). ...
Background and objectives:
Premenstrual syndrome (PMS) is characterized by menstrual cycle-related affective, behavioral, and/or somatic symptoms. By applying the emotional Stroop task (EST) the current study examined if changes in processing emotional information, which have been demonstrated in affective disorders, are also present in PMS.
Methods:
Via online screening, telephone interviews, and daily records over two months 55 women for the PMS group (on the basis of the specific inclusion criteria and a prospectively confirmed PMS) and 55 'non-PMS' controls were recruited. All participants completed three emotional Stroop tasks (EST) with neutral and negative word, picture, and facial stimuli, during the follicular and luteal phase of the menstrual cycle.
Results:
Mixed 2 × 2 univariate analyses of variance and post-hoc comparisons showed primarily a greater emotional Stroop effect with respect to picture and facial stimuli in the luteal menstrual cycle phase in women with PMS, compared to the control group. No significant group differences were observed for word stimuli. With respect to the facial stimuli, a kind of paradox effect was revealed (Stroop facilitation) in the PMS group.
Limitations:
This study provides important information regarding cognitive processes in women suffering from PMS that have to be interpreted in the light of the following limitations: a limited representativeness of the sample, the determination of menstrual cycle phases based on symptom diaries but not hormone levels, and a limited interpretability of our results as causal relationships.
Conclusions:
Our findings are in line with the assumption that alterations in cognitive-emotional processes are associated with PMS. Further research on the etiology of PMS should focus more on cognitive-emotional processing and its interaction with biological changes relating to the menstrual cycle.
... Although PMS is a highly prevalent symptomatology in women, knowledge about the etiology of PMS is still lacking. On the one hand, previous research demonstrated that biological factors, such as genetic aspects, hormones, and neurotransmitters, play a role as etiological factors (Bäckström et al. 2003;Birzniece et al. 2006;Kendler et al. 1998). On the other hand, biological factors do not seem to be sufficient for completely explaining the etiology of PMS-especially the considerable differences in symptomrelated burden described by women experiencing premenstrual symptoms . ...
Psychological factors, such as cognitive-emotional processes, are proposed to play an important role in the etiology of premenstrual syndrome (PMS). Our aim was to determine whether there are differences in emotion regulation between women with PMS and non-PMS controls. The study included 54 women who suffered from PMS (confirmed by prospective daily ratings during two menstrual cycles), as well as 52 non-PMS controls. All participants completed the Cognitive Emotion Regulation Questionnaire (CERQ) as an explicit and the affect misattribution procedure (AMP) as an implicit measure of emotion regulation. Each participant conducted the self-report as well as the experimental assessments twice, once during the follicular phase and once during the luteal phase of the menstrual cycle. The AMP was conducted with neutral and negative picture and facial stimuli. Three different interstimulus intervals (100, 500, 1500 ms) were used to examine implicit emotion regulation processes. Women with PMS reported a significantly higher use of three dysfunctional emotion regulation strategies in the CERQ (p values < .001). In the AMP with picture stimuli, women with PMS showed stronger implicit negative affective reactions compared to non-PMS women, independent of menstrual cycle phase (p = .008). In the AMP with facial stimuli, this stronger negative affect misattribution appeared in women with PMS compared to the control group only in the luteal phase and only for medium interstimulus intervals of 500 ms (p = .050). The results suggest that PMS is associated with alterations in the processes of emotion regulation, as assessed both on an explicit and on an implicit level. Further research on the etiology of PMS should focus more on cognitive-emotional processing and its interaction with biological changes relating to the menstrual cycle.
... The etiology of PMS and PMDD is still unknown. Biological factors such as genetic factors (e.g., [8]), hormonal factors, and neurotransmitter factors (e.g., [9,10]) seem to play an important role but do not provide a sufficient account of premenstrual distress. Models based on interactions between biomedical and psychosocial factors, such as the cognitive model of PMS [11], seem to encompass the complexity of PMS more successfully. ...
Purpose:
According to modern bio-psychosocial theories of premenstrual syndrome (PMS), the aim of this study is to investigate systematically associations between selected psychosocial factors and premenstrual symptoms in different menstrual cycle phases.
Method:
Several psychosocial variables were assessed, in a sample of German women with PMS (N = 90) and without premenstrual complaints (N = 48) during the follicular and luteal phase of the menstrual cycle. Presence of PMS was indicated by analysis of contemporary daily ratings of premenstrual symptom severity and impairment for one menstrual cycle.
Results:
Regarding perceived chronic stress (ƞ (2) = 0.34), self-efficacy (ƞ (2) = 0.12), and two dimensions of self-silencing (0.06 ≤ ƞ (2) ≤ 0.11) analyses revealed only a significant effect of group. Regarding body dissatisfaction and somatosensory amplification, a significant effect of group (0.07 ≤ ƞ (2) ≤ 0.16) and additionally a group by menstrual cycle phase interaction (ƞ (2) = 0.06) was identified. Regarding relationship quality, a significant effect of menstrual cycle phase (ƞ (2) = 0.08) and a group by menstrual cycle phase interaction (ƞ (2) = 0.06) was demonstrated. In respect to sexual contentment, acceptance of premenstrual symptoms, and the remaining two dimensions of self-silencing statistical analyses revealed no effects at all. Linear multiple regression analysis revealed that 20 % of the variance in PMS symptom severity was explained by the psychosocial variables investigated. Body dissatisfaction (ß = 0.26, p = 0.018) and the divided self-dimension of self-silencing (ß = 0.35, p = 0.016) were significant correlates of PMS severity.
Conclusion:
Results of this study are consistent with previous research and additionally show patterns of associations between specific psychosocial factors and PMS in dependence of menstrual cycle phase that have not been researched before. The role of the psychosocial variables we investigated in regard to the development and maintenance of PMS should be clarified in future research.
... For instance, Colzato with colleagues (Colzato et al. 2010;Colzato et al. 2012) suggest that the effects of estradiol are process-specific and impact executive control function in humans. However, little evidence exists of the effects of progesterone on human cognition, although this hormone and its derivates have a profound effect on inhibitory/excitatory balance (Birzniece et al. 2006). ...
Rationale
The behavioral and electrophysiological responses in a Go/NoGo task are objective measures of executive functioning that may be impaired in clinical conditions. Prior to the wider application of Go/NoGo tasks in clinics, it is tempting to evaluate factors causing modulation of the responses.
Objective
We aimed to evaluate the effect of different levels of female sex steroids on Go/NoGo task-related ERPs in healthy females.
Methods
Thirty-four young healthy females performed an equiprobable (50/50) auditory Go/NoGo task. Amplitudes and latencies of N2 and P3 peaks from Fz, Cz, and Pz electrodes were evaluated. 17β-estradiol and progesterone levels in saliva samples were measured. Electrophysiological measures were correlated to 17β-estradiol and progesterone concentrations.
Results
The diverse pattern of modulation of P3 latencies was shown: higher levels of 17β-estradiol contributed to Go-P3 latency prolongation, and higher levels of progesterone contributed to NoGo-P3 latency shortening. Higher levels of 17β-estradiol were associated with more negative frontal N2 amplitude in both conditions.
Conclusions
The relationship between electrophysiological correlates of executive functioning to individual hormonal levels points to a broader range of variation sources in healthy subjects which might mask or pronounce between-group differences in clinical studies.
... A significant neurobiological line of research has focused on the correlation between SAD, Translocator Protein (TSPO) and oxytocin (OXT). The TSPO is a polypeptide implicated in the synthesis of neurosteroids that can influence the cognitive and behavioral functions associated to anxiety (Birzniece et al., 2006), probably through the allosteric modulation of the complex GABA A /BDZ. ...
Separation anxiety disorder was described in DSM-IV-TR as a childhood disorder that rarely persists into adulthood, but several empirical studies have demonstrated that adult separation anxiety disorder (ASAD) is more common than suggested. This could be due to either of two possibilities: 1) a higher proportion of childhood-onset cases persist into adulthood than was assumed in DSM-IV-TR; 2) a substantial proportion of first onsets occur in adulthood (these subjects never having had childhood separation anxiety disorder). The position of separation anxiety disorder in the DSM-5 is different. Indeed, the DSM-5 discontinues the section for disorders that have their first onset in childhood, where separation anxiety disorder was previously placed. Differently, in the DSM-5, it moves within the general section for anxiety disorders. Moreover, a crucial change in the criteria is the removal of the assertion that onset of the disorder must be before the age of 18 years, a modification that is consistent with clinical and population-level research evidence. Finally, symptoms have been reworded to remove any implicit bias towards childhood. However, the relationships of ASAD with other psychopathological conditions are not clear. In particular, studies of pathological mechanisms, including the role of attachment, shared by both separation anxiety disorder and other anxiety and mood disorders are needed and deserve further neurobiological and clinical research. Finally, from a treatment perspective, there is increasing evidence that unaddressed separation anxiety lessens the effects of both medication and psychotherapy.
Background: Gender plays a role in the mechanisms of depression, but fewer studies have focused on gender differences in the abnormal activation of brain regions when patients perform specific cognitive tasks.Methods: A total of 110 major depressive disorder (MDD) patients and 106 healthy controls were recruited. The relative change in oxygen-hemoglobin (oxy-Hb) concentration during the verbal fluency task were measured by a 52-channel near-infrared spectroscopy (NIRS) system. Differences in brain region activation between patients and healthy controls and between genders of depression patients were compared.Results: MDD patients demonstrated significantly decreased [oxy-Hb] changes in the right inferior frontal gyrus (p = 0.043) compared to healthy controls. A marked increase in leftward functional language lateralization in the inferior frontal gyrus was observed in the MDD group in contrast to the HC group (p = 0.039). Furthermore, female patients in the MDD group exhibited significant reductions in [oxy-Hb] changes in the right frontal region (specifically, the superior and middle frontal gyrus; p = 0.037) compared with male patients.Conclusions: Gender impacts depression-related brain activation during cognitive tasks, potentially influencing depression's pathogenesis.
Background
Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administrated Combined Metabolic Activators (CMA) to the AD rat model and observed that administration of CMA activated the mitochondrial functions and eventually improved the AD-associated histological parameters in the animals. CMA consists of NAD + and glutathione precursors and includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate.
Methods
Here, we designed a randomised, double-blinded, placebo-controlled phase-II trial and studied the effect of CMA administration on the global metabolism of AD patients. The primary endpoint was on the difference in cognitive and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. We also performed a comprehensive human plasma metabolome and proteome analysis.
Results
Based on our analysis, we showed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (p = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant enhancement (p = 0.0073) in ADAS-Cog scores between CMA and placebo groups in patients with higher ADAS-Cog scores. Improved cognitive functions were endorsed with relevant hippocampal volumes and cortical thickness alterations. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism are significantly improved after treatment.
Conclusion
In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions associated with the improved metabolome, proteome and structural neuroimaging parameters, suggesting a role for such a therapeutic regimen in treating patients, especially with severe AD.
Trial registration
ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131
Sleep disturbance is a common clinical concern throughout the menopausal transition. However, the pathophysiology and causes of these sleep disturbances remain poorly understood, making it challenging to provide appropriate therapy. Our goal was to i) review the literature about the influence of ovarian hormones on sleep in perimenopausal women, ii) summarize the potential underlying pathophysiology of menopausal sleep disturbances and iii) evaluate the implications of these findings for the therapeutic approach to sleep disturbances in the context of menopause. A systematic literature search using the databases Embase, MEDLINE and Cochrane Library was conducted. Keywords relating to ovarian hormones, sleep disturbances and menopause were used. Ultimately, 86 studies were included. Study Quality Assessment Tools of the National Institutes of Health were used for quality assessment. Results from good-quality studies demonstrated that the postmenopausal decline in estrogen and progesterone contributes to sleep disturbances in women and that timely treatment with estrogen and/or progesterone therapy improved overall sleep quality. Direct and indirect effects of both hormones acting in the central nervous system and periphery, as well as via secondary effects (e.g. reduction in vasomotor symptoms), can contribute to improvements in sleep. To strengthen external validity, studies examining neurobiological pathways are needed. Keywords Sleep disturbances Insomnia Estrogen Progesterone Menopause Hormone therapy Systematic review
Adolescence is generally defined as beginning at the onset of puberty, and ending when adult independence is reached. The adolescent period reflects a time of peak sensation seeking, which supports information seeking and exploration that is necessary to gain new experiences required to support the transition to adulthood. Although adaptive, sensation seeking can also lead to risk-taking behavior, contributing to an increased risk for deleterious activities such as delinquency, substance use, and reckless driving. Adolescence is also a time of heightened vulnerability to the emergence of psychopathology, including mood disorders, substance use disorders, and psychosis. Thus, the significant developmental potential and risk during this period underscores the importance of understanding the neurobiological mechanisms supporting normative adolescent brain and behavioral development.
During adolescence, affective processes, including reward and emotion, have a disproportionate effect on behavior relative to cognitive processes which, according to Dual Systems models, reflects differing developmental trajectories of these systems. Behavioral findings indicate that adolescents can access many cognitive processes, such as inhibitory control, at adult-like levels in certain contexts (i.e., when offered rewards), but their cognitive processes are inconsistent and unreliable. Studies have also found that adolescents are more sensitive to rewards and are still developing the ability to process and regulate emotions. These behavioral changes are supported by changes in functional brain activation and connectivity across affective and cognitive networks. Additionally, it has been suggested that adolescence may be a critical period of plasticity for prefrontal cortical development, during which experience interacts with neurobiological factors to affect normative brain development. This critical period is likely initiated and maintained by neurobiological processes that support adolescent development in general, including large-scale changes in GABA, glutamate, and dopamine neurotransmitter systems. Cortical gray matter decreases across childhood, adolescence, and into early adulthood, believed to reflect synaptic pruning mechanisms of brain specialization, while white matter volume increases across this period to facilitate greater communication across brain regions. Furthermore, the myelination of these white matter tracts increases through adolescence and young adulthood, allowing for more effective signaling and contributing to the closing of the adolescent critical period.
Taken as a whole, the current literature suggests that the adolescent period encompasses key development of neurobiological and cognitive processes. These critical maturational processes, coupled with the increased risk of psychiatric disorders and life-threatening behaviors, highlight the importance of understanding normative adolescent neurocognitive development, its underlying mechanisms, and how these processes can go awry. Further research will seek to expand on our current knowledge of brain maturation and its mechanisms in order to improve mental health and cognitive outcomes during adolescence and into adulthood.
Background: Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administrated Combined Metabolic Activators (CMA) to the AD rat model and observed that administration of CMA activated the mitochondrial functions and eventually improved the AD-associated histological parameters in the animals. CMA consists of NAD+ and glutathione precursors and includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate.
Methods: Here, we designed a randomised, double-blinded, placebo-controlled phase-II trial and studied the effect of CMA administration on the global metabolism of AD patients. The primary endpoint was on the difference in cognitive and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. We also performed a comprehensive human plasma metabolome and proteome analysis.
Results: Based on our analysis, we showed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (p=0.00001, 29% improvement) in the CMA group. Moreover, there was a significant enhancement (p=0.0073) in ADAS-Cog scores between CMA and placebo groups in patients with higher ADAS-Cog scores. Improved cognitive functions were endorsed with relevant hippocampal volumes and cortical thickness alterations. Moreover, the plasma levels of proteins and metabolites associated with NAD+ and glutathione metabolism are significantly improved after treatment.
Conclusion: In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions associated with the improved metabolome, proteome and structural neuroimaging parameters, suggesting a role for such a therapeutic regimen in treating patients, especially with severe AD.
Trial registration: ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131
The identity of the mechanism that controls aggressive behavior in rodents is unclear. Serotonin (5-HT) and GABA are associated with aggressive behavior in rodents. However, the regulatory relationship between these chemicals in the different brain regions of rats has not been fully defined. This study aimed to clarify the role of GABABR1 in DRN-mediated GABA to regulate 5-HT expression in multiple brain regions in male rats with high and low aggressive behavior. Rat models of highly and less aggressive behavior were established through social isolation plus resident intruder. On this basis, GABA content in the DRN and 5-HT contents in the PFC, hypothalamus, hippocampus and DRN were detected using ELISA. Co-expression of 5-HT and GB1 in the DRN was detected by immunofluorescence and immunoelectron microscopy at the tissue and subcellular levels, respectively. GB1-specific agonist baclofen and GB1-specific inhibitor CGP35348 were injected into the DRN by stereotaxic injection. Changes in 5-HT levels in the PFC, hypothalamus and hippocampus were detected afterward. After modeling, rats with highly aggressive behavior exhibited higher aggressive behavior scores, shorter latencies of aggression, and higher total distances in the open field test than rats with less aggressive behavior. The contents of 5-HT in the PFC, hypothalamus and hippocampus of rats with high and low aggressive behavior (no difference between the two groups) were significantly decreased, but the change in GABA content in the DRN was the opposite. GB1 granules could be found on synaptic membranes containing 5-HT granules, which indicated that 5-HT neurons in the DRN co-expressed with GB1, which also occurred in double immunofluorescence results. At the same time, we found that the expression of GB1 in the DRN of rats with high and low aggressive behavior was significantly increased, and the expression of GB1 in the DRN of rats with low aggressive behavior was significantly higher than that in rats with high aggressive behavior. Nevertheless, the expression of 5-HT in DRN was opposite in these two groups. After microinjection of baclofen into the DRN, the 5-HT contents in the PFC, hypothalamus and hippocampus of rats in each group decreased significantly. In contrast, the 5-HT contents in the PFC, hypothalamus and hippocampus of rats in each group increased significantly after injection with CGP35348. The significant increase in GABA in the DRN combined with the significant increase in GB1 in the DRN further mediated the synaptic inhibition effect, which reduced the 5-HT level of 5-HT neurons in the DRN, resulting in a significant decrease in 5-HT levels in the PFC, hypothalamus and hippocampus. Therefore, GB1-mediated GABA regulation of 5-HT levels in the PFC, hypothalamus and hippocampus is one of the mechanisms of highly and less aggressive behavior originating in the DRN. The increased GB1 level in the DRN of LA-behavior rats exhibited a greater degree of change than in the HA-group rats, which indicated that differently decreased 5-HT levels in the DRN may be the internal mechanisms of high and low aggression behaviors.
Alpha-casozepine (α CZP), a tryptic hydrolysate of milk casein is a decapeptide that has shown to promote sleep, and produce anxiolytic or anticonvulsant activity. Intriguingly, studies indicate structural similarities to benzodiazepine (BZD)-like molecules (e.g., diazepam), resulting in positive modulation of GABAA receptors. However, some unexplained anomalous behaviour of α-CZP includes 1) 1000 times less affinity in vitro whereas in vivo it showed 10-fold increased affinity when compared to diazepam less affinity for BZD site; 2) anxiolytic effects was observed only in stressed situation and 3) unlike diazepam it failed to exhibit dependence or habituation. Captivatingly, neurosteroids like allopregnanolone or its analogues that are synthesized de novo have both genomic and non-genomic actions. The rapid nongenomic neuronal inhibition of these compounds is mediated by GABAA receptors through autocrine and paracrine actions. Studies have shown that levels of neurosteroids rise rapidly during acute stress and are perturbed in chronic, consequently altering the GABAA receptor subunits. Neurosteroids even at low concentration (nanomolar range) potentiate the response of GABA indirectly, while at higher concentrations they directly activate the receptor-channel complex. Interestingly, coadministration of neurosteroids and BZPs have shown not only to prevent the development of tolerance of BZP and augmented recovery from BZP withdrawal anxiety and hyperactivity in mice, the combination also produced synergetic effect. Taken together, the evidence suggests possible implications of neurosteroids in the actions of CZP. The present hypothesis brings out the possible role of neurosteroids and the various factors that might participate in CZP-induce anxiolytic effects.
Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. Here, we analysed the brain transcriptomics data of more than 600 AD patients using genome-scale metabolic models and provided supporting evidence of mitochondrial dysfunction related to the pathophysiologic mechanisms of AD progression. Subsequently, we investigated, in a rat model of AD, the oral administration of Combined Metabolic Activators (CMAs), consisting of NAD+ and glutathione precursors, to explore the effect for improvement of biological functions in AD. CMAs includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate, salt form of L-carnitine. The study revealed that supplementation of the CMAs improved the AD-associated histological parameters in the animals. Finally, we designed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial and showed that the administration of CMAs improves cognitive functions in AD patients. As decreased AD Assessment Scale-cognitive subscale (ADAS-Cog) score is the indicator of the improved cognitive function in AD patients, we observed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (Log2FC= -0.37, (29% improvement), p-value=0.00001) in the CMA group. We also observed a significant decrease in the placebo group on Day 84 vs Day 0 (Log2FC= -0.19, (14% improvement), p-value=0.001) due to the recommendations of exercise and Mediterranean diet to all AD patients participated in the trial. A comprehensive analysis of the human plasma metabolome and proteome revealed that plasma levels of proteins and metabolites associated with redox metabolism are significantly improved after treatment. In conclusion, our results show that treating AD patients with CMAs leads to enhanced cognitive functions, suggesting a role for such a therapeutic regime in treating AD and other neurodegenerative diseases.
HIGHLIGHTS
• Brain transcriptomics data of more than 600 AD patients is analysed.
• Performed an in vivo study using Combined Metabolic Activators (CMAs) in AD rat models.
• We performed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial.
• We showed that cognitive functions in AD patients is improved 29% in the CMA group whereas 14% in the placebo group.
Most psychiatric disorders demonstrate sex differences in their prevalence and symptomatology, and in their response to treatment. These differences are particularly pronounced in mood disorders. Differences in sex hormone levels are among the most overt distinctions between males and females and are thus an intuitive underpinning for these clinical observations. In fact, treatment with estrogen and testosterone was shown to exert antidepressant effects, which underscores this link. Changes to monoaminergic signaling in general, and serotonergic transmission in particular, are understood as central components of depressive pathophysiology. Thus, modulation of the serotonin system may serve as a mechanism via which sex hormones exert their clinical effects in mental health disorders. Over the past 20 years, various experimental approaches have been applied to identify modes of influence of sex and sex hormones on the serotonin system. This chapter provides an overview of different molecular components of the serotonin system, followed by a review of studies performed in animals and in humans with the purpose of elucidating sex hormone effects. Particular emphasis will be placed on studies performed with positron emission tomography, a method that allows for human in vivo molecular imaging and, therefore, assessment of effects in a clinically representative context. The studies addressed in this chapter provide a wealth of information on the interaction between sex, sex hormones, and serotonin in the brain. In general, they offer evidence for the concept that the influence of sex hormones on various components of the serotonin system may serve as an underpinning for the clinical effects these hormones demonstrate.
Post-finasteride syndrome (PFS) is a constellation of serious adverse side effects manifested in clinical symptoms that develop and persist in patients during and/or after discontinuing finasteride treatment in men with pattern hair loss (androgenetic alopecia) or benign prostatic hyperplasia. These serious adverse side effects include persistent or irreversible sexual, neurological, physical and mental side effects. To date, there are no evidence-based effective treatments for PFS. Although increasing number of men report persistent side effects, the medical community has yet to recognize this syndrome nor are there any specific measures to address this serious and debilitating symptoms. Here we evaluate the scientific and clinical evidence in the contemporary medical literature to address the very fundamental question: Is PFS a real clinical condition caused by finasteride use or are the reported symptoms only incidentally associated with but not caused by finasteride use? One key indisputable clinical evidence noted in all reported studies with finasteride and dutasteride was that use of these drugs is associated with development of sexual dysfunction, which may persist in a subset of men, irrespective of age, drug dose or duration of study. Also, increased depression, anxiety and suicidal ideation in a subset of men treated with these drugs were commonly reported in a number of studies. It is important to note that many clinical studies suffer from incomplete or inadequate assessment of adverse events and often limited or inaccurate data reporting regarding harm. Based on the existing body of evidence in the contemporary clinical literature, the author believes that finasteride and dutasteride induce a constellation of persistent sexual, neurological and physical adverse side effects, in a subset of men. These constellations of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. Indeed, delineating the pathophysiological mechanisms underlying PFS will be of paramount importance to the understanding of this syndrome and to development of potential novel therapeutic modalities.
Indications exist that use of oral contraceptives affects women's socio-emotional behaviour, brain function and, cognitive abilities, but the information is still scarce and ambiguous. We aimed to examine affective processing of visual stimuli between oral contraceptive users (OC, n = 33) and naturally cycling women (NC, n = 37) using the event-related potential (ERP) method. The main findings are: (i) emotionally arousing stimuli elicited significantly enlarged late positive potential (LPP) amplitudes compared to neutral stimuli, (ii) anti-androgenic OC users demonstrated diminished brain reactivity to visual stimuli, and (iii) significantly blunted reaction to highly unpleasant images. In addition, a positive relationship between GFP evoked by the highly unpleasant and highly pleasant visual emotional stimuli and progesterone was observed in NC women, while OC users demonstrated a trend of negative relationship between GFP and progesterone level. These findings suggest possible modulations of affective processing of visual stimuli when hormonal contraceptives are used.
Fluctuations in gonadal hormones over the course of the menstrual cycle are known to cause functional brain changes and are thought to modulate changes in the balance of cortical excitation and inhibition. Animal research has shown this occurs primarily via the major metabolite of progesterone, allopregnanolone, and its action as a positive allosteric modulator of the GABAA receptor. Our study used EEG to record gamma oscillations induced in the visual cortex using stationary and moving gratings. Recordings took place during twenty females’ mid‐luteal phase when progesterone and estradiol are highest, and early follicular phase when progesterone and estradiol are lowest. Significantly higher (∼5 Hz) gamma frequency was recorded during the luteal compared to the follicular phase for both stimuli types. Using dynamic causal modeling, these changes were linked to stronger self‐inhibition of superficial pyramidal cells in the luteal compared to the follicular phase. In addition, the connection from inhibitory interneurons to deep pyramidal cells was found to be stronger in the follicular compared to the luteal phase. These findings show that complex functional changes in synaptic microcircuitry occur across the menstrual cycle and that menstrual cycle phase should be taken into consideration when including female participants in research into gamma‐band oscillations.
Estrogens act in diverse brain regions to regulate reproductive and nonreproductive behaviors and neuronal functions, including mood, cognition, pain, seizures, sensorimotor integration, energy homeostasis, and neural degeneration due to aging, ischemia, and other insults. This chapter reviews evidence that estrogens act at multiple levels in many brain regions to modify synaptic neurotransmission. Identified targets of estrogen action include classical neurotransmitters and diverse peptides that function as neuromodulators. Estrogens act both presynaptically, regulating transmitter availability and/or release, and postsynaptically, governing cellular responses to released transmitter. Hormone-dependent alterations in neural responses to transmitters involve regulation of transmitter receptor expression and the efficacy of transmembrane signal transduction. Estrogens also determine which intracellular signal transduction pathways are activated when neurotransmitters bind their receptors. Emerging evidence suggests that estrogens can activate downstream molecules associated with growth factors and modify the crosstalk between growth factor and neurotransmitter receptor signaling pathways. Therefore, we also summarize findings indicating that physiologically relevant cross talk occurs among estrogen receptor, neurotransmitter receptor, and growth factor receptor signal transduction pathways. The data show that estrogens act throughout the brain to modulate neuronal excitability, synaptic efficacy, and neurogenesis, suggesting that these are fundamental mechanisms of steroid hormone action in the brain.
IntroductionBackground
Effect of hormonal contraceptives on mood in women without mood disordersEffect of hormonal contraceptives on mood in women with mood symptoms or disordersConclusions
N-methyl-d-aspartate (NMDA) receptor antagonists disrupt acquisition of the water maze and cause sensorimotor disturbances. In a detailed behavioral analysis in male rats, it was found that the NMDA antagonist dl -2-aminophosphonovaleric acid (APV) caused sensorimotor disturbances in behaviors required for maze performance and that these correlated with acquisition impairments in both hidden and visible platform versions of the maze. Behavioral disturbances included thigmotaxic swimming, swimming over and deflecting off the platform, abnormal swim behavior, and hyperactivity. Rats familiar with the behavioral strategies involved in the task performed normally under APV. The results are consistent with the known role of NMDA receptors in sensorimotor mechanisms and suggest that drug-induced sensorimotor disturbances contributed to poor acquisition scores in naive rats. NMDA may contribute to but does not appear to be essential for spatial learning in the water maze.
Gonadal steroids are known to influence hippocampal physiology in adulthood. It is presently unknown whether gonadal steroids influence the morphology of hippocampal neurons in the adult intact rat brain. In order to determine whether female sex hormones influence hippocampal morphology in the intact adult, we performed Golgi impregnation on brains from ovariectomized rats and ovariectomized rats which received estradiol or estradiol and progesterone replacement. Removal of circulating gonadal steroids by ovariectomy of adult female rats resulted in a profound decrease in dendritic spine density in CA1 pyramidal cells of the hippocampus. Estradiol replacement prevented the observed decrease in dendritic spine density; progesterone augmented the effect of estradiol within a short time period (5 hr). Ovariectomy or gonadal steroid replacement did not affect spine density of CA3 pyramidal cells or granule cells of the dentate gyrus. These results demonstrate that gonadal steroids are necessary for the maintenance of normal adult CA1 hippocampal pyramidal cell structure. The short time course required to observe these effects (3 d for the estradiol effect and 5 hr for the progesterone effect) implies that CA1 pyramidal cell dendritic spine density may fluctuate during the normal (4–5 d) rat estrous cycle.
Studies of patients and animals with brain lesions have implicated the hippocampal formation in
spatial, declarative/relational and episodic types of memory. These and other types of memory consist
of a series of interdependent but potentially dissociable memory processes—encoding, storage,
consolidation and retrieval. To identify whether hippocampal activity contributes to these processes
independently, we used a novel method of inactivating synaptic transmission using a water-soluble
antagonist of AMPA/kainate glutamate receptors. Once calibrated using electrophysiological and
two-deoxyglucose techniques in vivo, drug or vehicle was infused chronically or acutely into the dorsal
hippocampus of rats at appropriate times during or after training in a water maze. Our findings
indicate that hippocampal neural activity is necessary for both encoding and retrieval of spatial
memory and for either trace consolidation or long-term storage.
We have found that the density of synapses in the stratum radiatum of the hippocampal CA1 region in the adult female rat is sensitive to estradiol manipulation and fluctuates naturally as the levels of ovarian steroids vary during the 5 d estrous cycle. In both cases, low levels of estradiol are correlated with lower synapse density, while high estradiol levels are correlated with a higher density of synapses. These synaptic changes occur very rapidly in that within approximately 24 hr between the proestrus and estrus stages of the estrous cycle, we observe a 32% decrease in the density of hippocampal synapses. Synapse density then appears to cycle back to proestrus values over a period of several days. To our knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain.
Interactions between transcription factors are an important means of regulating gene transcription. The present study describes the mutual repression of two transcription factors, the RelA(p65) subunit of NF-kappaB and the progesterone receptor (PR). This trans-repression is shown to occur independent of PR isoform, reporter construct, or cell type used. Together with the demonstration of an interaction between PR and RelA in vitro, these findings suggest that the mutual repression is due to a direct interaction between these proteins. Furthermore, activation of NF-kappaB by tumor necrosis factor-alpha also results in repression of PR, while PR is able to repress tumor necrosis factor-alpha-induced NF-kappaB activity. Since NF-KB-regulating cytokine receptors are expressed in progesterone target tissues, like breast and endometrium, the mutual repression of PR and RelA could play an important role in a wide variety of physiological processes in these tissues, including maintenance of pregnancy, immunosuppression, and tumorigenesis.
The hippocampus is a major limbic target of the brainstem serotonergic neurons that modulate fear, anxiety, and learning through postsynaptic serotonin(1A) receptors (5-HT1A receptors). Because chronic stress selectively down-regulates the 5-HT1A receptors in the hippocampus, we hypothesized that mice lacking these receptors may exhibit abnormalities reminiscent of symptoms of stress-related psychiatric disorders. In particular, a hippocampal deficit in the 5-HT1A receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT1A receptors impairs hippocampus-related functions, we studied hippocampal-dependent learning and memory, synaptic plasticity in the hippocampus, and limbic neuronal excitability in 5-HT1A-knockout (KO) mice. 5-HT1A-KO animals showed a deficit in hippocampal-dependent learning and memory tests, such as the hidden platform (spatial) Version of the Morris water maze and the delayed version of the Y maze. The performance of KO mice was not impaired in nonhippocampal memory tasks such as the visible platform (nonspatial) version of the Morris water maze, the immediate version of the Y maze, and the spontaneous-alternation test of working memory. Furthermore, paired-pulse facilitation in the dentate gyrus of the hippocampus was impaired in 5-HT1A-KO mice. Finally, 5-HT1A-KO mice, as compared with wild-type animals, displayed higher limbic: excitability manifested as lower seizure threshold and higher lethality in response to kainic acid administration. These results demonstrate that 5-HT1A receptors are required for maintaining normal hippocampal functions and implicate a role for the 5-HT1A receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders.
Treatment of women with uterine myomas with GnRH agonists results in symptoms of hypoestrogenism which can be prevented by concurrent "add-back" estrogen administration. We took advantage of these induced endocrine changes to investigate their effects on cognitive functioning in young women with myomas. Nineteen women with uterine myomas were tested before treatment. They all received the GnRH agonist, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks and were then randomized to receive LAD plus estrogen or LAD plus placebo every 4 weeks for 8 additional weeks. Levels of all sex hormones decreased after 12 weeks of LAD treatment (P < 0.01), and only estradiol (E2) levels increased (P < 0.01) following 8 weeks of subsequent treatment in the group that received LAD plus E2. Scores on neuropsychological tests of verbal memory decreased from pretreatment to 12 weeks posttreatment with LAD (P < 0.05). These memory deficits were reversed in the group that received LAD plus E2 for 8 weeks coincident with an increase in plasma E2, whereas memory scores remained depressed in the group that received LAD plus placebo. These findings are consistent with those from studies on surgically menopausal women and strongly suggest that estrogen serves to maintain verbal memory in women. These results provide support for the efficacy of add-back estrogen regimens in women treated with GnRH agonists and also imply that estrogen may be important for maintaining memory in the postmenopause.
The clustering of neurotransmitter receptors at the postsynaptic terminals is a critical requirement for efficient neurotransmission and neuronal communication. This process is facilitated by adaptor proteins, which bridge the postsynaptic receptors and the underlying cytoskeleton. One such molecule, the GABA(A) receptor-associated protein, GABARAP, was identified as a potential linker between GABA(A) receptors and microtubules. GABARAP belongs to an expanding family of proteins that are implicated in a variety of intracellular transport processes. GABARAP has been shown to interact with myriad binding partners, including the gamma2 subunit of the GABA(A) receptor, tubulin and microtubules, the N-ethyl maleimide sensitive factor, gephyrin, and the transferin receptor. The recent determination of the GABARAP crystal structure has revealed individual GABARAP domains, motifs, and surface regions involved in specific protein-protein interactions. Currently, a more general role is emerging for GABARAP, including shipping GABA(A) receptors to and from the cell surface, organizing them into postsynaptic clusters, and regulating the steady-state receptor density.
The responses of vertebrate neurones to glutamate involve at least three receptor types. One of these, the NMDA receptor (so called because of its specific activation by N-methyl-D-aspartate), induces responses presenting a peculiar voltage sensitivity. Above resting potential, the current induced by a given dose of glutamate (or NMDA) increases when the cell is depolarized. This is contrary to what is observed at classical excitatory synapses, and recalls the properties of 'regenerative' systems like the Na+ conductance of the action potential. Indeed, recent studies of L-glutamate, L-aspartate and NMDA-induced currents have indicated that the current-voltage (I-V) relationship can show a region of 'negative conductance' and that the application of these agonists can lead to a regenerative depolarization. Furthermore, the NMDA response is greatly potentiated by reducing the extracellular Mg2+ concentration [( Mg2+]o) below the physiological level (approximately 1 mM). By analysing the responses of mouse central neurones to glutamate using the patch-clamp technique, we have now found a link between voltage sensitivity and Mg2+ sensitivity. In Mg2+-free solutions, L-glutamate, L-aspartate and NMDA open cation channels, the properties of which are voltage independent. In the presence of Mg2+, the single-channel currents measured at resting potential are chopped in bursts and the probability of opening of the channels is reduced. Both effects increase steeply with hyperpolarization, thereby accounting for the negative slope of the I-V relationship of the glutamate response. Thus, the voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependence of the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent 'gate'.
Two progesterone metabolites 3 alpha-hydroxy-5 alpha-pregnan-20-one (5-alpha) and 3 alpha-hydroxy-5 beta-pregnan-20-one (5-beta) were investigated for anaesthetic potency in male rats with an EEG-threshold method. Dose rate curves were obtained by infusing 5-alpha and 5 beta intravenously with different rates until an EEG-criterion (a burst suppression of one sec. or more, the "silent second") was seen in the EEG. The potency of the investigated drugs has been estimated by comparing threshold doses at optimal infusion rates. 5-alpha and 5-beta were tested on both young (44 to 46 days) and adult (109 to 118 days) rats. The relation between age and the anaesthetic sensitivity of 5-beta was tested by weekly threshold determinations. 5-alpha and 5-beta infused separately with different infusion rates gave almost V-shaped dose rate curves. The optimal infusion rate was in all age groups 2 mg/kg/min. In young rats 5-alpha (6.7 mg/kg) was more potent than 5-beta (8.9 mg/kg). In adult rats the sensitivity was increased but the relation in potency between 5-alpha (5.1 mg/kg) and 5-beta (6.6 mg/kg) was unchanged. With 5-beta the main change in this age-related increase in anaesthetic sensitivity was seen between 49 and 70 days of age. Both 5-alpha and 5-beta exhibited an excitatory action seen as jerks during induction of the EEG-criterion.
The etiology of the cyclical mood changes seen in the premenstrual syndrome is still unknown. A close relation to the luteal phase has been shown. One of the differences between the follicular and the luteal phase is the higher plasma progesterone concentration during the luteal phase. The present investigation has been conducted to study the effect of exogenously administered estrogen/gestagen sequential postmenopausal replacement therapy on mood and physical signs. Twenty-two women requiring postmenopausal estrogen treatment were recruited and divided into two groups. Eleven women were given estradiol treatment only (Oestrogel creme 3 mg percutaneously/day) for 21 days with a subsequent break of 7 days. The other 11 women were in addition given progestagen (Lynestrenol, Orgametril 5 mg/day) during the last 11 days of treatment. The women were asked to keep a daily record of their mood, using a visual analogue scale earlier tested in women with premenstrual syndrome. They also kept a record of physical signs and sexual feelings. The records were kept for between one and 6 months. The group with estrogen treatment only did not show any cyclical worsening in mood or physical signs during the treatment. The women who in the latter stage of the estrogen treatment cycle also received progestagen, showed significant cyclicity in both moods and physical signs, with a maximum symptom degree during the final days of gestagen treatment. The negative mood change started 1-3 days after the progestagen was added to the treatment. The results suggest that progestagens are involved in the provocation of cyclical symptom changes seen in the premenstrual syndrome.
In the premenstrual syndrome the negative symptoms appear during the luteal phase of the menstrual cycle. Ovulation and the formation of a corpus luteum seem to be of great importance in precipitating the syndrome. In a large group of women with premenstrual syndrome investigated daily with symptom ratings and weekly plasma estradiol and progesterone assays, 8 were found to have one ovulatory and one spontaneously occurring anovulatory menstrual cycle. In both these cycles, the post- and premenstrual phases were compared by testing for recurrence of symptoms. All patients showed a highly significant cyclical worsening of negative premenstrual symptoms during the ovulatory cycles, whereas in the anovulatory cycles the cyclical symptoms disappeared, resulting in relief of the premenstrual syndrome. These results support earlier hypotheses, suggesting that the premenstrual syndrome appears as a result of provoking factors produced by the corpus luteum. This view is in line with earlier therapeutic findings showing that induced anovulation can relieve the premenstrual syndrome.
The relationship between symptoms of premenstrual syndrome (PMS) and serum levels of pregnenolone (Pe), pregnenolone sulfate (PS), 5 alpha-pregnane-3,20-dione (5 alpha-DHP), 3 alpha-hydroxy-5 alpha- pregnan-20-one (5 alpha-THP), LH, 17 beta-estradiol (E2), and progesterone (P) was investigated during 2 consecutive menstrual cycles in 12 patients using daily measurements. Corresponding hormones were also measured during 1 cycle in 8 control women. Pe, PS, 5 alpha-DHP, and 5 alpha-THP showed a significant cyclicity within menstrual cycles and a high rate of correlation with P variation in both PMS patients and controls. No significant difference was found between PMS patients and controls in average serum concentrations of Pe, PS, 5 alpha-DHP, 5 alpha-THP, and LH during the luteal phase, whereas a significantly higher level of E2 and a lower level of P were observed in PMS patients. The variation in symptom scores was compared with that in hormone levels within each woman. The symptom peak showed a delay of 3-4 days after the serum P, Pe, 5 alpha-DHP, and 5 alpha-THP peaks. However, the plasma PS peak appeared on the same day or only 1 day before the symptom peak in PMS patients. When comparing the 2 cycles studied, more negative symptoms occurred in cycles with higher luteal phase E2, Pe, and PS concentrations, whereas higher luteal phase 5 alpha-DHP and 5 alpha-THP concentrations were associated with improved symptom ratings in PMS patients. These results suggest that the mentioned steroids are related to the severity of distressing symptoms in PMS patients.
In a double-blind trial, the selective serotonin reuptake inhibitor citalopram was administered to women with severe irritability and/or depressed mood in the luteal but not in the follicular phase of the menstrual cycle (premenstrual dysphoria). Treatment continued for three consecutive menstrual cycles. One group (N = 17 completers) was administered citalopram continuously at a constant dosage (20+/-10 mg/day) throughout the menstrual cycle. A second group (N = 17) also received citalopram continuously throughout the cycle, but at a lower dosage in the follicular phases (5 mg/day) than in the luteal phases (20+/-10 mg/day) (semi-intermittent treatment). A third group (N = 18) received citalopram (20+/-10 mg/day) in the luteal phase only and placebo during the follicular phase (intermittent treatment). A fourth group (N = 17) received placebo throughout the cycles. The side effects of active treatment were generally mild and transient. Intermittent administration of citalopram was clearly more effective than placebo with respect to both reduction in self-rated irritability and self-rated global improvement; it is of interest that intermittent treatment with citalopram also seemed more effective than continuous or semi-intermittent administration of the drug.
Hippocampal “place cells” fire selectively when an animal is in a specific location. The fine-tuning and stability of place
cell firing was compared in two types of mutant mice with different long-term potentiation (LTP) and place learning impairments.
Place cells from both mutants showed decreased spatial selectivity. Place cell stability was also deficient in both mutants
and, consistent with the severities in their LTP and spatial learning deficits, was more affected in mice with a point mutation
[threonine (T) at position 286 mutated to alanine (A)] in the α calmodulin kinase II (αCaMKIIT286A) than in mice deficient for the α and Δ isoforms of adenosine 3′5′-monophosphate–responsive element binding proteins (CREBαΔ
−). Thus, LTP appears to be important for the fine tuning and stabilization of place cells, and these place cell properties
may be necessary for spatial learning.
We have investigated the ability of citalopram, a serotonin reuptake inhibitor, to alter the functional sensitivity to a neuroactive steroid during the late luteal phase in twelve women with premenstrual syndrome. Sensitivity to pregnanolone was assessed by comparing the effect of three increasing doses of intravenous pregnanolone on saccadic eye velocity (SEV) and self-rated sedation. Testings were performed in two consecutive menstrual cycles; without treatment and during citalopram treatment. During citalopram treatment, pregnanolone injections induced a significant SEV reduction compared to vehicle, whereas during the pre-treatment cycle there was no significant change in SEV response between vehicle and pregnanolone injections. Citalopram treatment did not alter the self-rated sedation response to pregnanolone compared to vehicle in either study cycle. These findings indicate that treatment with a selective serotonin reuptake inhibitor in the luteal phase increases the pregnanolone sensitivity in patients with premenstrual syndrome.
Post-mortem concentrations of progesterone, 5alpha-pregnane-3,20-dione (5alpha-DHP) and 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone) were measured in 17 brain areas and serum in five fertile and five postmenopausal women. Steroid concentrations were measured with radioimmunoassay after extraction of brain tissue with ethanol and purification with celite chromatography. There were regional differences in brain concentrations of all three steroids. The highest progesterone levels were noted in the amygdala, cerebellum and hypothalamus and the highest levels of 5alpha-DHP and allopregnanolone were seen in the substantia nigra and basal hypothalamus. Brain concentrations of all three steroids were significantly higher in the fertile women in luteal phase compared to their postmenopausal controls (P < 0.01). In general, the study showed that there is a variation in brain concentrations depending on ovarian steroid production, indicating that the secretion pattern during the menstrual cycle is reflected in the brain. However, regional differences in brain steroid levels imply local mechanisms for steroid uptake and binding as well. Investigations of gonadal steroid distributions in the human brain might be of importance considering the actions of these steroids in the central nervous system. Such studies could provide information about physiological mechanisms, such as the ovulation, and also form a baseline for comparative studies of normal and pathological conditions involving steroids, for instance, catamenial epilepsy and the premenstrual tension syndrome.
Selective serotonin-reuptake inhibitors (SSRIs), including fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, represent an important advance in the pharmacotherapy of mood and ct her disorders. They are chemically unrelated to tricyclic, heterocyclic, and other first-generation antidepressants. SSRIs are the treatment of choice for many indications, including major depression, dysthymia, panic disorder, obsessive-compulsive disorder, eating disorders, and premenstrual dysphoric disorder, because of their efficacy, good side-effect profile, tolerability, and safety in overdose, as well as patient compliance. A review of the literature was conducted using Medline and the terms "SSRls," "fluoxetine," "sertraline," "paroxetine," "fluvoxamine," and "citalopram." Articles were limited to those published in English within the last 15 yeats. The search revealed that indications for antidepressants include unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in the medically ill, panic disorder, obsessive-compulsive disorder, eating disorders, social phobia, and premenstrual dysphoric disorder. One SSRI, fluoxetine, has demonstrated safety in pregnancy. Side effects of SSRIs include gastrointestinal disturbances, headache, sedation, insomnia, activation, weight gain, impaired memory, excessive perspiration, paresthesia, and sexual dysfunction.
Serotonin 5-HT(1A) receptors play an important role in serotonin neurotransmission and mental health. We previously demonstrated that estradiol (E) and progesterone (P) decrease 5-HT(1A) autoreceptor mRNA levels in macaques. In this study, we questioned whether E and P regulate 5-HT(1A) binding and function and G(alpha) subunit protein expression. Quantitative autoradiography for 5-HT(1A) receptors and G proteins using [3H]8-OH-DPAT and [35S]GTP-gamma-S, respectively, was performed on brain sections of rhesus macaques from four treatment groups: ovariectomized controls (OVX), E (28 d), P (28 d), and E (28 d) plus P (the last 14 d) treated. Western blot analysis for G(alpha) subunits was performed on raphe extracts from cynomolgus macaques that were OVX or OVX treated with equine estrogens (EE, 30 months). In the hypothalamus, E or E + P but not P alone decreased postsynaptic 5-HT(1A) binding sites. In the dorsal raphe nucleus (DRN), E, P, and E + P treatments decreased 5-HT(1A) autoreceptor binding. The Kd values for 8-OH-DPAT were the same for each treatment group. Both the basal and the R-(+)-8-OH-DPAT stimulated [35S]GTP-gamma-S binding were decreased during hormone replacement whereas the coupling efficiency between the receptor and G proteins was maintained. Finally, EE treatment reduced the level of G(alphai3), but not G(alphai1), G(alphao), and G(alphaz) in the DRN. In conclusion, these observations suggest that ovarian hormones may increase serotonin neurotransmission, in part, by decreasing 5-HT(1A) autoreceptors, 5-HT(1A) postsynaptic receptors, and the inhibitory G proteins for intracellular signal transduction.
Nine periods in seven women with partial epilepsy have been invetigated with respect to frequency of fits, and estrogen-progesterone levels in blood plasma. Six cycles with ovulation showed a positive correlation between the number of secondary generalized seizures and the mean estrogen/progesterone (E/P) ratios and a negative correlation to plasma progesterone levels. Three periods without ovulation showed an increase in the number of fits during days of high estrogen. The number of fits seemed not to be correlated to changes in body weight.
The present study demonstrated the antidepressant-like effect of neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α, 5α THP) in mouse forced swim test of depression and its modulation by different serotonergic agents. Pretreatment with the selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), the 5-HT releaser, fenfluramine (10 mg/kg, i.p.), the 5-HT1A receptor agonist, 8-OH-DPAT (0.1 mg/kg, s.c.), the 5-HT1B/1C receptor agonist, TFMPP (4 mg/kg, s.c.) and the 5-HT2A/1C receptor agonist, DOI (2 mg/kg, s.c.) potentiated the antidepressant-like effect of 3α, 5α THP. At these doses the serotonergic agents per se did not modify the duration of immobility. However, fluoxetine (20 mg/kg, i.p.), fenfluramine (20 mg/kg, i.p.) or imipramine (5 or 20 mg/kg, i.p.) not only reduced immobility but also enhanced the antidepressant-like effect of 3α, 5α THP. Such a potentiating effect of the 5-HT1A or the 5-HT2A/1C receptor agonist was not antagonized by the sub-effective dose (0.1 mg/kg, s.c.) of their respective antagonists p-MPPI or ketanserin. Pretreatment with p-CPA (300×3 mg/kg, i.p.), a depleter of 5-HT neuronal store failed to block the influence of fluoxetine and fenfluramine on antidepressant-like effect of 3α, 5α THP. The accelerated effect of 3α, 5α THP in presence of serotonergic agents was antagonized by the GABAA receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3α-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). These findings for the first time demonstrate that serotonergic agents potentiate the antidepressant-like action of 3α, 5α THP, by enhancing the GABAergic tone as a likely consequence of increased brain content of this neurosteroid.
Estrogen exerts a profound effect on mood and mental function in man. Based on our finding that estradiol selectively stimulates the expression of 5-hydroxytryptamine2A (5-HT2A) receptor mRNA in the dorsal raphe nucleus of the female rat, we investigated the effects of estradiol on the density of 5-HT2A receptors in brain. The distribution and density of 5-HT2A receptors were determined by in vitro binding of [3H]ketanserin in the presence of prazosin to exclude binding to α1-adrenoreceptors. Brains were collected, processed and analysed in pairs from six estradiol- and six vehicle-treated animals. Our results show that a single pulse of estradiol induces a significant increase in the density of 5-HT2A receptors in female rat forebrain, particularly the anterior frontal, anterior cingulate and primary olfactory cortex and the nucleus accumbens. Since these brain regions play a pivotal role in cognition and emotion, as well as neuroendocrine and motor control, our findings provide the first experimental evidence for the fact that estrogen could alter mood and mental state by increasing the density of 5-HT2A receptors in cerebral cortex and nucleus accumbens.