Neuroactive Steroids: Receptor Interactions and Responses

PubMed Central

Tuem, Kald Beshir; Atey, Tesfay Mehari

2017-01-01

Neuroactive steroids (NASs) are naturally occurring steroids, which are synthesized centrally as de novo from cholesterol and are classified as pregnane, androstane, and sulfated neurosteroids (NSs). NASs modulate many processes via interacting with gamma-aminobutyric acid (GABA), N-methyl-d-aspartate, serotonin, voltage-gated calcium channels, voltage-dependent anion channels, α-adrenoreceptors, X-receptors of the liver, transient receptor potential channels, microtubule-associated protein 2, neurotrophin nerve growth factor, and σ1 receptors. Among these, NSs (especially allopregnanolone) have high potency and extensive GABA-A receptors and hence demonstrate anticonvulsant, anesthetic, central cytoprotectant, and baroreflex inhibitory effects. NSs are also involved in mood and learning via serotonin and anti-nociceptive activity via T-type voltage-gated Ca2+ channels. Moreover, they are modulators of mitochondrial function, synaptic plasticity, or regulators of apoptosis, which have a role in neuroprotective via voltage-dependent anion channels receptors. For proper functioning, NASs need to be in their normal level, whereas excess and deficiency may lead to abnormalities. When they are below the normal, NSs could have a part in development of depression, neuro-inflammation, multiple sclerosis, experimental autoimmune encephalitis, epilepsy, and schizophrenia. On the other hand, stress and attention deficit disorder could occur during excessive level. Overall, NASs are very important molecules with major neuropsychiatric activity. PMID:28894435

Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice

PubMed Central

Mihalek, Robert M.; Banerjee, Pradeep K.; Korpi, Esa R.; Quinlan, Joseph J.; Firestone, Leonard L.; Mi, Zhi-Ping; Lagenaur, Carl; Tretter, Verena; Sieghart, Werner; Anagnostaras, Stephan G.; Sage, Jennifer R.; Fanselow, Michael S.; Guidotti, Alessandro; Spigelman, Igor; Li, Zhiwei; DeLorey, Timothy M.; Olsen, Richard W.; Homanics, Gregg E.

1999-01-01

γ-Aminobutyric acid (GABA) type A receptors mediate fast inhibitory synaptic transmission and have been implicated in responses to sedative/hypnotic agents (including neuroactive steroids), anxiety, and learning and memory. Using gene targeting technology, we generated a strain of mice deficient in the δ subunit of the GABA type A receptors. In vivo testing of various behavioral responses revealed a strikingly selective attenuation of responses to neuroactive steroids, but not to other modulatory drugs. Electrophysiological recordings from hippocampal slices revealed a significantly faster miniature inhibitory postsynaptic current decay time in null mice, with no change in miniature inhibitory postsynaptic current amplitude or frequency. Learning and memory assessed with fear conditioning were normal. These results begin to illuminate the novel contributions of the δ subunit to GABA pharmacology and sedative/hypnotic responses and behavior and provide insights into the physiology of neurosteroids. PMID:10536021

Circulating neuroactive C21- and C19-steroids in young men before and after ejaculation.

PubMed

Stárka, L; Hill, M; Havlíková, H; Kancheva, L; Sobotka, V

2006-01-01

Twelve neuroactive and neuroprotective steroids, androgens and androgen precursors i.e. 3alpha,17beta-dihydroxy-5alpha-androstane, 3alpha-hydroxy-5alpha-androstan-17-one, 3alpha-hydroxy-5beta-androstan-17-one, androst-5-ene-3beta,17beta-diol, 3beta,17alpha-dihydroxy-pregn-5-en-20-one (17alpha-hydroxy-pregnenolone), 3beta-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA), testosterone, androst-4-ene-3,17-dione (androstenedione), 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), 3beta-hydroxy-pregn-5-en-20-one (pregnenolone), 7alpha-hydroxy-DHEA, and 7beta-hydroxy-DHEA were measured using the GC-MS system in young men before and after ejaculation provoked by masturbation. The circulating level of 17alpha-hydroxypregnenolone increased significantly, whereas the other circulating steroids were not changed at all. This fact speaks against the hypothesis that a drop in the level of neuroactive steroids, e.g. allopregnanolone may trigger the orgasm-related increase of oxytocin, reported by other authors.

Simultaneous Determination of Seven Neuroactive Steroids Associated with Depression in Rat Plasma and Brain by High Performance Liquid Chromatography-Tandem Mass Spectrometry.

PubMed

Wang, Youqiong; Tang, Lipeng; Yin, Wei; Chen, Jiesi; Leng, Tiandong; Zheng, Xiaoke; Zhu, Wenbo; Zhang, Haipeng; Qiu, Pengxin; Yang, Xiaoxiao; Yan, Guangmei; Hu, Haiyan

2016-01-01

Sensitive and specific biomarkers are required for the diagnosis and treatment of depression because the existing diagnostic criteria are subjective and could produce false positives or negatives. Some endogenous neuroactive steroids that have shown either antidepressant effects or concentration changes in individuals with depression could provide potential biomarkers. In this study, a simple and specific method was developed to simultaneously determine seven endogenous neuroactive steroids in biological samples: cortisone, cortisol, dehydroepiandrosterone, estradiol, progesterone, pregnenolone, and testosterone. After liquid-liquid extraction, chromatographic separation was achieved on a C18 column with gradient elution using water-methanol at a flow rate of 300 μL min(-1). Detection and quantitation were performed by tandem mass spectrometry with atmospheric pressure chemical ionization and selected reaction monitoring. Plasma and brain neuroactive steroid levels were then determined in control rats and rats exposed to forced swimming, a classical rodent model of depression. The results showed that the plasma concentrations of testosterone, pregnenolone, and progesterone significantly increased in rats exposed to the forced swimming test. In contrast, brain homogenate levels of cortisol, estradiol, and progesterone decreased, while pregnenolone levels were elevated in this model of depression. In conclusion, a new method to quantify neuroactive steroids was successfully developed and applied to their investigation in rat plasma and brain. The findings of this study indicated that plasma testosterone, pregnenolone, and progesterone levels could provide potential biomarkers for the diagnosis and treatment of depression.

Anticipation and consumption of food each increase the concentration of neuroactive steroids in rat brain and plasma.

PubMed

Pisu, Maria Giuseppina; Floris, Ivan; Maciocco, Elisabetta; Serra, Mariangela; Biggio, Giovanni

2006-09-01

Stressful stimuli and anxiogenic drugs increase the plasma and brain concentrations of neuroactive steroids. Moreover, in rats trained to consume their daily meal during a fixed period, the anticipation of food is associated with changes in the function of various neurotransmitter systems. We have now evaluated the effects of anticipation and consumption of food in such trained rats on the plasma and brain concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH DOC), two potent endogenous positive modulators of type A receptors for gamma-aminobutyric acid (GABA). The abundance of these neuroactive steroids was increased in both the cerebral cortex and plasma of the rats during both food anticipation and consumption. In contrast, the concentration of their precursor, progesterone, was increased in the brain only during food consumption, whereas it was increased in plasma only during food anticipation. Intraperitoneal administration of the selective agonist abecarnil (0.1 mg/kg) 40 min before food presentation prevented the increase in the brain levels of 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC during food anticipation but not that associated with consumption. The change in emotional state associated with food anticipation may thus result in an increase in the plasma and brain levels of 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC in a manner sensitive to the activation of GABA(A) receptor-mediated neurotransmission. A different mechanism, insensitive to activation of such transmission, may underlie the changes in the concentrations of these neuroactive steroids during food consumption.

Neuroactive steroids modulate HPA axis activity and cerebral brain-derived neurotrophic factor (BDNF) protein levels in adult male rats.

PubMed

Naert, Gaëlle; Maurice, Tangui; Tapia-Arancibia, Lucia; Givalois, Laurent

2007-01-01

Depression is characterized by hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity. In this major mood disorder, neurosteroids and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), seem to be implicated and have some antidepressant effects. BDNF is highly involved in regulation of the HPA axis, whereas neurosteroids effects have never been clearly established. In this systematic in vivo study, we showed that the principal neuroactive steroids, namely dehydroepiandrosterone (DHEA), pregnenolone (PREG) and their sulfate esters (DHEA-S and PREG-S), along with allopregnanolone (ALLO), stimulated HPA axis activity, while also modulating central BDNF contents. In detail, DHEA, DHEA-S, PREG, PREG-S and ALLO induced corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP) synthesis and release at the hypothalamic level, thus enhancing plasma adrenocorticotropin hormone (ACTH) and corticosterone (CORT) concentrations. This stimulation of the HPA axis occurred concomitantly with BDNF modifications at the hippocampus, amygdala and hypothalamus levels. We showed that these neurosteroids induced rapid effects, probably via neurotransmitter receptors and delayed effects perhaps after metabolization in other neuroactive steroids. We highlighted that they had peripheral effects directly at the adrenal level by inducing CORT release, certainly after estrogenic metabolization. In addition, we showed that, at the dose used, only DHEA, DHEA-S and PREG-S had antidepressant effects. In conclusion, these results highly suggest that part of the HPA axis and antidepressant effects of neuroactive steroids could be mediated by BDNF, particularly at the amygdala level. They also suggest that neurosteroids effects on central BDNF could partially explain the trophic properties of these molecules.

Voluntary Ethanol Consumption Reduces GABAergic Neuroactive Steroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP) in the Amygdala of the Cynomolgus Monkey

PubMed Central

Beattie, Matthew C.; Maldonado-Devincci, Antoniette M.; Porcu, Patrizia; O’Buckley, Todd K.; Daunais, James B.; Grant, Kathleen A.; Morrow, A. Leslie

2016-01-01

Neuroactive steroids such as (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) enhance the GABAergic effects of ethanol and modulate excessive drinking in rodents. Moreover, chronic ethanol consumption reduces 3α,5α-THP levels in human plasma, rat hippocampus, and mouse limbic regions. We explored the relationship between 3α,5α-THP levels in limbic brain areas and voluntary ethanol consumption in the cynomolgus monkey following daily self-administration of ethanol for 12 months and further examined the relationship to HPA axis function prior to ethanol exposure. Monkeys were subjected to scheduled induction of ethanol consumption followed by free access to ethanol or water for 22 hours/day over twelve months. Immunohistochemistry was performed using an anti-3α,5α-THP antibody. Prolonged voluntary drinking resulted in individual differences in ethanol consumption that ranged from 1.2 – 4.2 g/kg/day over 12 months. Prolonged ethanol consumption reduced cellular 3α,5α-THP immunoreactivity by 13±2% (p<0.05) in the lateral amygdala and 17±2% (p<0.05) in the basolateral amygdala. The effect of ethanol was most pronounced in heavy drinkers that consumed ≥3 g/kg≥20% of days. Consequently, 3α,5α-THP immunoreactivity in both the lateral and basolateral amygdala was inversely correlated with average daily ethanol intake (Spearman r = −0.87 and −0.72, respectively, p<0.05). However, no effect of ethanol and no correlation between drinking and 3α,5α-THP immunoreactivity was observed in the basomedial amygdala. 3α,5α-THP immunoreactivity following ethanol exposure was also correlated with HPA axis function prior to ethanol exposure. These data indicate that voluntary ethanol drinking reduces amygdala levels of 3α,5α-THP in nonhuman primates and that amygdala 3α,5α-THP levels may be linked to HPA axis function. PMID:26625954

Variation in Genes Encoding the Neuroactive Steroid Synthetic Enzymes 5α-Reductase Type 1 and 3α-Reductase Type 2 is Associated with Alcohol Dependence

PubMed Central

Milivojevic, Verica; Kranzler, Henry R.; Gelernter, Joel; Burian, Linda; Covault, Jonathan

2010-01-01

Background Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABAA receptors. We used a case-control sample to test the association with alcohol dependence (AD) of single nucleotide polymorphisms (SNPs) in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids: 5α–reductase, type I (5α-R) and 3α-hydroxysteroid dehydrogenase, type 2 (3α-HSD), both of which are expressed in human brain. Methods We focused on markers previously associated with a biological phenotype. For 5α-R, we examined the synonymous SRD5A1 exon 1 SNP rs248793, which has been associated with the ratio of dihydrotestosterone to testosterone. For 3α-HSD, we examined the non-synonymous AKR1C3 SNP rs12529 (H5Q), which has been associated with bladder cancer. The SNPs were genotyped in a sample of 1,083 non-Hispanic Caucasians including 552 controls and 531 subjects with AD. Results The minor allele for both SNPs was more common among controls than subjects with AD: SRD5A1 rs248793 C-allele (χ2(1)=7.6, p=0.006) and AKR1C3 rs12529 G-allele (χ2(1)=14.6, p=0.0001). There was also an interaction of these alleles such that the “protective” effect of the minor allele at each marker for AD was conditional on the genotype of the second marker. Conclusions We found evidence of an association with AD of polymorphisms in two genes encoding neuroactive steroid biosynthetic enzymes, providing indirect evidence that neuroactive steroids are important mediators of alcohol effects in humans. PMID:21323680

Variation in genes encoding the neuroactive steroid synthetic enzymes 5α-reductase type 1 and 3α-reductase type 2 is associated with alcohol dependence.

PubMed

Milivojevic, Verica; Kranzler, Henry R; Gelernter, Joel; Burian, Linda; Covault, Jonathan

2011-05-01

Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABA(A) receptors. We used a case-control sample to test the association with alcohol dependence (AD) of single nucleotide polymorphisms in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids: 5α-reductase, type I (5α-R), and 3α-hydroxysteroid dehydrogenase, type 2 (3α-HSD), both of which are expressed in human brain. We focused on markers previously associated with a biological phenotype. For 5α-R, we examined the synonymous SRD5A1 exon 1 SNP rs248793, which has been associated with the ratio of dihydrotestosterone to testosterone. For 3α-HSD, we examined the nonsynonymous AKR1C3 SNP rs12529 (H5Q), which has been associated with bladder cancer. The SNPs were genotyped in a sample of 1,083 non-Hispanic Caucasians including 552 controls and 531 subjects with AD. The minor allele for both SNPs was more common among controls than subjects with AD: SRD5A1 rs248793 C-allele (χ(2)(1) = 7.6, p = 0.006) and AKR1C3 rs12529 G-allele (χ(2)(1) = 14.6, p = 0.0001). There was also an interaction of these alleles such that the "protective" effect of the minor allele at each marker for AD was conditional on the genotype of the second marker. We found evidence of an association with AD of polymorphisms in two genes encoding neuroactive steroid biosynthetic enzymes, providing indirect evidence that neuroactive steroids are important mediators of alcohol effects in humans. Copyright © 2011 by the Research Society on Alcoholism.

Voluntary ethanol consumption reduces GABAergic neuroactive steroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP) in the amygdala of the cynomolgus monkey.

PubMed

Beattie, Matthew C; Maldonado-Devincci, Antoniette M; Porcu, Patrizia; O'Buckley, Todd K; Daunais, James B; Grant, Kathleen A; Morrow, A Leslie

2017-03-01

Neuroactive steroids such as (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) enhance the gamma-aminobutyric acid (GABA)-ergic effects of ethanol and modulate excessive drinking in rodents. Moreover, chronic ethanol consumption reduces 3α,5α-THP levels in human plasma, rat hippocampus and mouse limbic regions. We explored the relationship between 3α,5α-THP levels in limbic brain areas and voluntary ethanol consumption in the cynomolgus monkey following daily self-administration of ethanol for 12 months and further examined the relationship to hypothalamic-pituitary-adrenal (HPA) axis function prior to ethanol exposure. Monkeys were subjected to scheduled induction of ethanol consumption followed by free access to ethanol or water for 22 h/day over 12 months. Immunohistochemistry was performed using an anti-3α,5α-THP antibody. Prolonged voluntary drinking resulted in individual differences in ethanol consumption that ranged from 1.2 to 4.2 g/kg/day over 12 months. Prolonged ethanol consumption reduced cellular 3α,5α-THP immunoreactivity by 13 ± 2 percent (P < 0.05) in the lateral amygdala and 17 ± 2 percent (P < 0.05) in the basolateral amygdala. The effect of ethanol was most pronounced in heavy drinkers that consumed ≥3 g/kg ≥ 20 percent of days. Consequently, 3α,5α-THP immunoreactivity in both the lateral and basolateral amygdala was inversely correlated with average daily ethanol intake (Spearman r = -0.87 and -0.72, respectively, P < 0.05). However, no effect of ethanol and no correlation between drinking and 3α,5α-THP immunoreactivity were observed in the basomedial amygdala. 3α,5α-THP immunoreactivity following ethanol exposure was also correlated with HPA axis function prior to ethanol exposure. These data indicate that voluntary ethanol drinking reduces amygdala levels of 3α,5α-THP in non-human primates and that amygdala 3α,5α-THP levels may be linked to HPA axis function. �

[Neurological and psychiatric aspects of some endocrine diseases. The role of neurosteroids and neuroactive steroids].

PubMed

Aszalós, Zsuzsa

2007-10-14

Regardless of their origin, neuroactive steroids are capable of modifying neural activities by modulating different types of membrane receptors. Neurosteroids are synthesized de novo in neurones and glia. Steroidogenic enzymes are found in the central nervous system. Classical steroid receptors are localized in the cytoplasm, they exert regulatory actions on the genome, and their activation causes medium- and long-term effects. Non-classical receptors are located within the membrane and act as mediators of short-term effects. Other important players are co-repressors and co-activators that can interfere with or enhance the activity of steroid receptors. Beyond their function in stress, corticosteroids play a very important role in fear, anxiety, and memory functions. Patients with Cushing's syndrome frequently develop mood disorder, reversible brain atrophy with transient memory loss, rarely delirium or psychosis. Well-known peripheral symptom is steroidal myopathy. In patients with Addison's disease the main signs are weakness of muscles, lack of energy, decreased mental functions and reduced quality of life. Estrogen and progesterone have their own respective hormone receptors, whereas allopregnanolone acts via the GABA receptors. These hormones have significant role in the development of brain, the architecture of neural circuits and dendrites, density of axonal connections, and the number of neurons. They influence maturation, neuroprotection, seizures, cognitive functions, mood, anxiety, pain, and restitution of peripheral nerves. Androgens also affect cognitive functions, pain, anxiety, mood, and additionally aggression.

Variation in AKR1C3, which encodes the neuroactive steroid synthetic enzyme 3α-HSD type 2 (17β-HSD type 5), moderates the subjective effects of alcohol.

PubMed

Milivojevic, Verica; Feinn, Richard; Kranzler, Henry R; Covault, Jonathan

2014-09-01

Animal models suggest that neuroactive steroids contribute to alcohol's acute effects. We previously reported that a common nonsynonymous polymorphism, AKR1C3 2 in the gene encoding the enzyme 3α-HSD2/17β-HSD5, and a synonymous single nucleotide polymorphism (SNP), rs248793, in SRD5A1, which encodes 5α-reductase, were associated with alcohol dependence (AD). The aim of the study was to investigate whether these polymorphisms moderate subjective effects of alcohol in humans and whether AKR1C3 2 affects neuroactive steroid synthesis. Sixty-five Caucasian men (34 lighter and 31 heavier drinkers; mean age 26.2 years) participated in a double-blind laboratory study where they consumed drinks containing no ethanol or 0.8 g/kg of ethanol. Breath alcohol, heart rate (HR), and self-reported alcohol effects were measured at 40-min intervals, and genotype was examined as a moderator of alcohol's effects. Levels of the neuroactive steroid 5α-androstane-3α,17β-diol and its precursors, 3α,5α-androsterone and dihydrotestosterone, were measured at study entry using GC/MS. Initially, carriers of the AD-protective AKR1C3 2 G allele had higher levels of 5α-androstane-3α,17β-diol relative to the precursor 3α,5α-androsterone than C allele homozygotes. AKR1C3 2 G allele carriers exhibited greater increases in heart rate and stimulant and sedative effects of alcohol than C allele homozygotes. The genotype effects on sedation were observed only in heavier drinkers. The only effect of the SRD5A1 SNP was to moderate HR. There were no interactive effects of the two SNPs. The observed effects of variation in a gene encoding a neuroactive steroid biosynthetic enzyme on the rate of 17β-reduction of androsterone relative to androstanediol and on alcohol's sedative effects may help to explain the association of AKR1C3 2 with AD.

Variation in AKR1C3, which Encodes the Neuroactive Steroid Synthetic Enzyme 3α-HSD Type 2 (17β-HSD Type 5), Moderates the Subjective Effects of Alcohol

PubMed Central

Milivojevic, Verica; Feinn, Richard; Kranzler, Henry R.; Covault, Jonathan

2014-01-01

Rationale Animal models suggest that neuroactive steroids contribute to alcohol’s acute effects. We previously reported that a common non-synonymous polymorphism, AKR1C3*2 in the gene encoding the enzyme 3α-HSD2/17β-HSD5 and a synonymous SNP, rs248793, in SRD5A1, which encodes 5α-reductase, were associated with alcohol dependence (AD). Objectives To investigate whether these polymorphisms moderate subjective effects of alcohol in humans and whether AKR1C3*2 affects neuroactive steroid synthesis. Methods 65 Caucasian men (34 lighter and 31 heavier drinkers; mean age 26.2 y) participated in a double-blind laboratory study where they consumed drinks containing no ethanol or 0.8 g/kg of ethanol. Breath alcohol, heart rate (HR), and self-reported alcohol effects were measured at 40-min intervals and genotype was examined as a moderator of alcohol’s effects. Levels of the neuroactive steroid 5α-androstane-3α,17β-diol and its precursors, 3α,5α-androsterone and dihydrotestosterone, were measured at study entry using GC/MS. Results Initially, carriers of the AD-protective AK1C3*2 G-allele had higher levels of 5α-androstane-3α,17β-diol relative to the precursor 3α,5α-androsterone than C-allele homozygotes. AKR1C3*2 G-allele carriers exhibited greater increases in heart rate and stimulant and sedative effects of alcohol than C-allele homozygotes. The genotype effects on sedation were observed only in heavier drinkers. The only effect of the SRD5A1 SNP was to moderate HR. There were no interactive effects of the two SNPs. Conclusions The observed effects of variation in a gene encoding a neuroactive steroid biosynthetic enzyme on the rate of 17p–reduction of androsterone relative to androstanediol and on alcohol’s sedative effects may help to explain the association of AKR1C3*2 with AD. PMID:24838369

Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys

PubMed Central

Grant, Kathleen A.; Helms, Christa M.; Rogers, Laura S.M.; Purdy, Robert H.

2008-01-01

Positive modulation of GABAA and antagonism of NMDA receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol suggesting that these steroids may modulate ethanol addiction. The 4 isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione (progesterone) [allopregnanolone (3α,5α-P), pregnanolone (3α,5β-P), epiallopregnanolone (3β,5α-P), epipregnanolone (3β,5β-P)], a synthetic analogue of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3α,5β-P HS)], and a structurally-similar, adrenally-derived steroid [3α-hydroxy-5-androstan-17-one (3α,5α-A, androsterone)], were assessed for ethanol-like discriminative stimulus effects 30 or 60 min after administration in male (n=9) and female (n=8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pre-treatment interval. The 3α-hydroxysteroids completely substituted for ethanol (80% of cases) whereas the 3β-hydroxysteroids and 3α,5β-P HS rarely substituted for ethanol (6% of cases). There were no sex differences. Compared to monkeys trained to discriminate 2.0 g/kg ethanol, 3α,5β-P and 3α,5α-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared to the 5β-reduced isomer (3α,5β-P), the 5α isomer of pregnanolone (3α,5α-P) substituted for ethanol with 3–40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3α,5β-P-and 3α,5α-A-sensitive receptors compared to higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at binding sites that are particularly sensitive to 3α,5α-P. PMID:18436788

Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys.

PubMed

Grant, Kathleen A; Helms, Christa M; Rogers, Laura S M; Purdy, Robert H

2008-07-01

Positive modulation of GABA(A) and antagonism of N-methyl-D-aspartate receptors mediate the discriminative stimulus effects of ethanol. Endogenous neuroactive steroids produce effects similar to ethanol, suggesting that these steroids may modulate ethanol addiction. The four isomers of the functional esters at C-3 of the 3-hydroxy metabolites of 4-pregnene-3,20-dione (progesterone) [allopregnanolone (3alpha,5alpha-P), pregnanolone (3alpha,5beta-P), epiallopregnanolone (3beta,5alpha-P), and epipregnanolone (3beta,5beta-P)], a synthetic analog of steroids modified by endogenous sulfation [pregnanolone hemisuccinate (3alpha,5beta-P HS)], and a structurally similar, adrenally derived steroid [3alpha-hydroxy-5-androstan-17-one (3alpha,5alpha-A, androsterone)] were assessed for ethanol-like discriminative stimulus effects at 30 or 60 min after administration in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) with a 30-min pretreatment interval. The 3alpha-hydroxysteroids completely substituted for ethanol (80% of cases), whereas the 3beta-hydroxysteroids and 3alpha,5beta-P HS rarely substituted for ethanol (6% of cases). There were no sex differences. Compared with monkeys trained to discriminate 2.0 g/kg ethanol, 3alpha,5beta-P and 3alpha,5alpha-A substituted more potently in monkeys trained to discriminate 1.0 g/kg ethanol. Compared with the 5beta-reduced isomer (3alpha,5beta-P), the 5alpha isomer of pregnanolone (3alpha,5alpha-P) substituted for ethanol with 3 to 40-fold greater potency but was least efficacious in female monkeys trained to discriminate 2.0 g/kg ethanol. The data suggest that the discriminative stimulus effects of lower doses (1.0 g/kg) of ethanol are mediated to a greater extent by 3alpha,5beta-P- and 3alpha,5alpha-A-sensitive receptors compared with higher doses (2.0 g/kg). Furthermore, the discriminative stimulus effects of ethanol appear to be mediated by activity at

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

PubMed Central

Bortolato, Marco; Frau, Roberto; Godar, Sean C; Mosher, Laura J; Paba, Silvia; Marrosu, Francesco; Devoto, Paola

2013-01-01

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G×E×S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of ~4:1. Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS. PMID:23795653

Cellular GABAergic neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) immunostaining levels are increased in the ventral tegmental area of the human Alcohol Use Disorder patients: A postmortem study

PubMed Central

Hasirci, A. Sait; Maldonado-Devincci, Antoniette M.; Beattie, Matthew C.; O'Buckley, Todd K.; Morrow, A. Leslie

2016-01-01

Background The GABAergic neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) enhances GABAergic activity and produces subjective effects similar to ethanol. The effect of chronic alcohol exposure on 3α,5α-THP concentrations has been studied in mouse, rat, and monkey limbic brain areas. Chronic ethanol exposure produced divergent brain region and cell specific changes in 3α,5α-THP concentrations in animal studies. However, 3α,5α-THP levels in similar human brain regions have never been examined in individuals diagnosed with alcohol use disorder (AUD). Therefore, we used immunohistochemistry to examine 3α,5α-THP levels in the ventral tegmental area (VTA), substantia nigra pars medialis (SNM), and amygdala of human postmortem brains of patients diagnosed with AUD compared to social drinkers. The effects of sex and liver disease on 3α,5α-THP concentrations were examined in the aforementioned brain regions. Methods Human postmortem brains of AUD patients and age-matched controls were obtained from the New South Wales Brain Tissue Resource Center. Immunohistochemistry was performed using anti-3α,5α-THP antibody on formalin fixed and paraffin embedded brain sections to detect cellular 3α,5α-THP levels. Immunoreactivity was analyzed by pixel density/mm2 for the comparison between AUD patients and controls. Results 3α,5α-THP immunoreactivity was increased by 23.2±9% in the VTA of AUD patients compared to age matched controls (p= 0.014). Moreover, a 29.6±10% increase in 3α,5α-THP immunoreactivity was observed in the SNM of male AUD patients compared to male controls (p<0.01), but not in female subjects. 3α,5α-THP immunoreactivity in the VTA and SNM regions did not differ between non-cirrhotic and cirrhotic AUD patients. A sex difference in 3α,5α-THP immunoreactivity (female 51±18% greater than male) was observed among control subjects in the SNM, but no other brain region. 3α,5α-THP immunoreactivity in the

Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats.

PubMed

Eppolito, Amy K; Kodeih, Hanna R; Gerak, Lisa R

2014-10-01

Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone. Copyright © 2014 Elsevier Inc. All rights reserved.

Steroid dysregulation and stomatodynia (burning mouth syndrome).

PubMed

Woda, Alain; Dao, Thuan; Gremeau-Richard, Christelle

2009-01-01

Stomatodynia ( burning mouth syndrome) is characterized by a spontaneous, continuous burning pain felt in the oral mucosa typically of anxiodepressive menopausal women. Because there is no obvious organic cause, it is considered a nonspecific pain. This Focus Article proposes a hypothesis based on the following pathophysiological cascade: chronic anxiety or post traumatic stress leads to a dysregulation of the adrenal production of steroids. One consequence is a decreased or modified production of some major precursors for the neuroactive steroid synthesis occurring in the skin, mucosa, and nervous system. At menopause, the drastic fall of the other main precursor supply , the gonadal steroids, leads to a brisk alteration of the production of neuroactive steroids. This results in neurodegenerative alterations of small nerves fibers of the oral mucosa and /or some brain areas involved in oral somatic sensations. These neuropathic changes become irreversible and precipitate the burning pain, dysgeusia, and xerostomia associated with stomatodynia, which all involve thin nerve fibers.

Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade.

PubMed

Crabtree, Gregg W; Park, Alan J; Gordon, Joshua A; Gogos, Joseph A

2016-10-04

Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Circulating steroids negatively correlate with tinnitus.

PubMed

Chrbolka, Pavel; Palúch, Zoltán; Hill, Martin; Alušík, Štefan

2017-07-01

While not a disease entity in itself; symptoms of tinnitus (from Latin tinnio - clink) accompany a number of diseases. Tinnitus prevalence increases with age, deteriorates one's quality of life, and may even result in suicidal behavior. Tinnitus develops in response to a variety of risk factors, otoxic substances, noise exposure, hearing disorders, and psychological alterations. Tinnitus is closely related to mood, depression, and psychological state. In the present study, we focused on alterations of the steroid metabolome and particularly neuroactive, neuroprotective, and immunomodulatory steroids in patients with tinnitus. The study group consisted of 28 patients without evidence of an organic cause of tinnitus as well as without associated diseases or the effect of ototoxic medications. All patients underwent a complete audiological assessment and laboratory tests including routine biochemical markers and quantification of circulating steroids using gas chromatography/mass spectrometry and immunoassays. To rule out a pathology in the cerebellopontine angle area, CT scan or MRI were performed. To diagnose stem lesions, evoked potentials were also measured. Pearson's correlations and multivariate regression were used to assess any links between tinnitus intensity and frequency on the one hand, and steroid levels on the other. Results indicated a significant and consistent negative correlation between tinnitus indices and intensity of adrenal steroidogenesis. The circulating steroid metabolome including hormones and neuroactive, neuroprotective, and immunomodulatory steroids negatively correlates with the degree of tinnitus due to hypothalamo-pituitary-adrenal axis malfunction. Our results may help explain the pathophysiology of tinnitus and improve its diagnosis. However, further studies are needed to verify our postulation. Copyright © 2017 Elsevier Inc. All rights reserved.

Peripartum neuroactive steroid and γ-aminobutyric acid profiles in women at-risk for postpartum depression

PubMed Central

Deligiannidis, Kristina M.; Kroll-Desrosiers, Aimee R.; Mo, Shunyan; Nguyen, Hien P.; Svenson, Abby; Jaitly, Nina; Hall, Janet E.; Barton, Bruce A.; Rothschild, Anthony J.; Shaffer, Scott A.

2016-01-01

Neuroactive steroids (NAS) are allosteric modulators of the γ-aminobutyric acid (GABA) system. NAS and GABA are implicated in depression. The peripartum period involves physiologic changes in NAS which may be associated with peripartum depression and anxiety. We measured peripartum plasma NAS and GABA in healthy comparison subjects (HCS) and those at-risk for postpartum depression (AR-PPD) due to current mild depressive or anxiety symptoms or a history of depression. We evaluated 56 peripartum medication-free subjects. We measured symptoms with the Hamilton Depression Rating Scale (HAM-D17), Hamilton Anxiety Rating Scale (HAM-A) and Spielberger State-Trait Anxiety Inventory-State (STAI-S). Plasma NAS and GABA were quantified by liquid chromatography-mass spectrometry. We examined the associations between longitudinal changes in NAS, GABA and depressive and anxiety symptoms using generalized estimating equation methods. Peripartum GABA concentration was 1.9 ± 0.7 ng/mL (p=0.004) lower and progesterone and pregnanolone were 15.8 ± 7.5 (p=0.04) and 1.5 ± 0.7 ng/mL (p=0.03) higher in AR-PPD versus HCS, respectively. HAM-D17 was negatively associated with GABA (β=−0.14 ± 0.05, p=0.01) and positively associated with pregnanolone (β=0.16 ± 0.06, p=0.01). STAI-S was positively associated with pregnanolone (β=0.11 ± 0.04, p=0.004), allopregnanolone (β=0.13 ± 0.05, p=0.006) and pregnenolone (β=0.02 ± 0.01, p=0.04). HAM-A was negatively associated with GABA (β=−0.12 ± 0.04, p=0.004) and positively associated with pregnanolone (β=0.11 ± 0.05, p=0.05). Altered peripartum NAS and GABA profiles in AR-PPD women suggest that their interaction may play an important role in the pathophysiology of peripartum depression and anxiety. PMID:27209438

Corticotropin-Releasing Factor Modulation of Forebrain GABAergic Transmission has a Pivotal Role in the Expression of Anabolic Steroid-Induced Anxiety in the Female Mouse

PubMed Central

Oberlander, Joseph G; Henderson, Leslie P

2012-01-01

Increased anxiety is commonly observed in individuals who illicitly administer anabolic androgenic steroids (AAS). Behavioral effects of steroid abuse have become an increasing concern in adults and adolescents of both sexes. The dorsolateral bed nucleus of the stria terminalis (dlBnST) has a critical role in the expression of diffuse anxiety and is a key site of action for the anxiogenic neuromodulator, corticotropin releasing factor (CRF). Here we demonstrate that chronic, but not acute, exposure of female mice during adolescence to AAS augments anxiety-like behaviors; effects that were blocked by central infusion of the CRF receptor type 1 antagonist, antalarmin. AAS treatment selectively increased action potential (AP) firing in neurons of the central amygdala (CeA) that project to the dlBnST, increased the frequency of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in dlBnST target neurons, and decreased both c-FOS immunoreactivity (IR) and AP frequency in these postsynaptic cells. Acute application of antalarmin abrogated the enhancement of GABAergic inhibition induced by chronic AAS exposure whereas application of CRF to brain slices of naïve mice mimicked the actions of this treatment. These results, in concert with previous data demonstrating that chronic AAS treatment results in enhanced levels of CRF mRNA in the CeA and increased CRF-IR in the dlBnST neuropil, are consistent with a mechanism in which the enhanced anxiety elicited by chronic AAS exposure involves augmented inhibitory activity of CeA afferents to the dlBnST and CRF-dependent enhancement of GABAergic inhibition in this brain region. PMID:22298120

ANABOLIC ANDROGENIC STEROID ABUSE: MULTIPLE MECHANISMS OF REGULATION OF GABAERGIC SYNAPSES IN NEUROENDOCRINE CONTROL REGIONS OF THE RODENT FOREBRAIN

PubMed Central

Oberlander, Joseph G.; Porter, Donna M.; Penatti, Carlos A. A.; Henderson, Leslie P.

2011-01-01

Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone originally developed for clinical purposes, but now predominantly taken at suprapharmacological levels as drugs of abuse. To date, nearly 100 different AAS compounds that vary in metabolic fate and physiological effects have been designed and synthesised. While administered for their ability to enhance muscle mass and performance, untoward side effects of AAS use include changes in reproductive and sexual behaviours. Specifically, AAS, depending on the type of compound administered, can delay or advance pubertal onset, lead to irregular oestrous cyclicity, diminished male and female sexual behaviours, and accelerate reproductive senescence. Numerous brains regions and neurotransmitter signalling systems are involved in the generation of these behaviours, and are potential targets for both chronic and acute actions of the AAS. However critical to all of these behaviours is neurotransmission mediated by GABAA receptors within a nexus of interconnected forebrain regions that includes the medial preoptic area (mPOA), the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus of the hypothalamus. Here we review how exposure to AAS alters GABAergic transmission and neural activity within these forebrain regions, taking advantage of in vitro systems and both wild-type and genetically altered mouse strains, in order to better understand how these synthetic steroids affect the neural systems that underlie the regulation of reproduction and the expression of sexual behaviours. PMID:21554430

Early post-natal neuroactive steroid manipulation modulates ondansetron effects on initial periods of alcohol consumption in rats.

PubMed

Bartolomé, Iris; Llidó, Anna; Darbra, Sònia; Pallarès, Marc

2018-06-21

Neuroactive steroids (NS) such as allopregnanolone are crucial for brain development and adult behaviour. Early post-natal alterations of NS by administering finasteride induce a decrease in the sensitivity to stimulant effects of low alcohol doses, an increase in alcohol consumption, and a decrease in ventrostriatal dopamine and serotonin levels. The aim of the present study is to observe if the effects of the 5HT3 receptor antagonist ondansetron on initial alcohol consumption are modulated by post-natal NS manipulation. For this purpose, allopregnanolone, finasteride, or vehicle was injected from day 5 to 9. In adulthood, a novel object preference test was carried out in order to detect a possible novelty-seeking pattern in our animals, which has been related to vulnerability to drug abuse. The subjects then had access to two bottles (alcohol or control solutions) one hour daily for two consecutive weeks. Ondansetron (0.01 mg/kg, 0.1 mg/kg or vehicle) was administered before the hour of consumption in the initial phase (days 1, 2, 3) of the procedure, and after prolonged alcohol intake (days 11, 12, 13). Results indicated that finasteride animals showed a higher preference to explore the new object, as well as a higher alcohol consumption than the rest of the groups. Moreover, 0.1 mg/kg of ondansetron decreased alcohol consumption, but only in the post-natal finasteride group, suggesting a possible increase in 5HT3 receptor sensitivity in these animals. In conclusion, NS manipulation in crucial stages of development, such as early post-natal periods, seems to play an important role on the effects of ondansetron on alcohol intake and in the vulnerability to develop drug use or abuse. Copyright © 2018. Published by Elsevier Inc.

The role of steroids in the development of post-partum mental disorders.

PubMed

Paskova, Andrea; Jirak, Roman; Mikesova, Michaela; Adamcova, Karolina; Fartakova, Zdenka; Horakova, Vladimira; Koucky, Michal; Hill, Martin; Hruskovicova, Hana; Starka, Luboslav; Duskova, Michaela; Parizek, Antonin

2014-09-01

Unfavorable post-partum changes to mental well-being affect more than half of all women, and are a risk to the health of both mother and baby. Their effects place strains on health and social systems. Currently, no generally accepted theory exists of the causes and mechanisms of post-partum mental disorders. Literature search up to 2012, using PubMed and search words: neuroactive steroids, post-partum mental disorders, depression, corticotropin-releasing hormone and estrogens. There are several theories for post-partum depression. One is that autoimmune diseases are involved. Others revolve around genes responsible or that lead to increased disposition to the disorder. It is likely however that the process is associated with the separation of the placenta and the fetal zone of fetal adrenal gland, the main sources of corticotropin-releasing hormone and sexual and neuroactive steroids during pregnancy, and the ability of the receptor system to adapt to these changes. The central nervous system is able to produce neurosteroids, but the drop in levels of peripheral steroids likely leads to a sudden deficit in neuroinhibitory steroids modulating ionotropic receptors in the brain. Post-partum depression is a multifactorial disease with unknown etiology. It is probably associated with sudden changes in the production of hormones influencing the nervous system, and on the other hand the ability of the receptor system to adapt to these changes. When the relative changes in concentrations of hormones, rather than their absolute levels, is likely more important.

A new method for determining levels of sedation in dogs: A pilot study with propofol and a novel neuroactive steroid anesthetic.

PubMed

Youngblood, B L; Ueyama, Y; Muir, W W; Belfort, G M; Hammond, R H; Dai, J; Salituro, F G; Robichaud, A J; Doherty, J J

2018-05-22

Different levels of consciousness are required in order to perform different medical procedures. Sedation scales established to objectively define various levels of sedation in humans have not been thoroughly characterized in non-human species. Postural changes in rats or dogs are useful as gross measures of sedation but are inadequate for quantitative assessment since graded levels of sedation are difficult to delineate and obscured by movement abnormalities. A new canine sedation scoring (CSS) method was developed based on the modified observer's assessment of alertness and sedation score (MOAA/S) used in humans. The method employed a combination of physical, auditory and somatosensory stimuli of increasing intensity. Cardiovascular, respiratory, and a neurophysiological measure of sedation (bispectral index: BIS) data were recorded. Validation studies were performed following intravenous loading and constant rate infusion of propofol or a novel synthetic neuroactive steroid (SGE-746). Four levels of consciousness were identified: 1) Awake, 2) Moderate Sedation (MS), 3) Deep Sedation (DS) and 4) General Anesthesia (GA). Cardiorespiratory measurements obtained after bolus administration of propofol and SGE-746 and at the end of each CRI remained within normal limits. Canine sedation scores correlated with BIS for SGE-746. SGE-746 exhibited a more gradual exposure-response relationship than propofol. Larger increases in the plasma concentration from awake values were required to achieve different levels of sedation with SGE-746 compared to propofol. No other canine sedation scoring methods are widely accepted. A CSS method, based on the human MOAA/S scale defined four levels of consciousness in dogs and provided better resolution of sedation depth than BIS alone. Copyright © 2018 Elsevier B.V. All rights reserved.

In-stream attenuation of neuro-active pharmaceuticals and their metabolites

USGS Publications Warehouse

Writer, Jeffrey; Antweiler, Ronald C.; Ferrar, Imma; Ryan, Joseph N.; Thurman, Michael

2013-01-01

In-stream attenuation was determined for 14 neuro-active pharmaceuticals and associated metabolites. Lagrangian sampling, which follows a parcel of water as it moves downstream, was used to link hydrological and chemical transformation processes. Wastewater loading of neuro-active compounds varied considerably over a span of several hours, and thus a sampling regime was used to verify that the Lagrangian parcel was being sampled and a mechanism was developed to correct measured concentrations if it was not. In-stream attenuation over the 5.4-km evaluated reach could be modeled as pseudo-first-order decay for 11 of the 14 evaluated neuro-active pharmaceutical compounds, illustrating the capacity of streams to reduce conveyance of neuro-active compounds downstream. Fluoxetine and N-desmethyl citalopram were the most rapidly attenuated compounds (t1/2 = 3.6 ± 0.3 h, 4.0 ± 0.2 h, respectively). Lamotrigine, 10,11,-dihydro-10,11,-dihydroxy-carbamazepine, and carbamazepine were the most persistent (t1/2 = 12 ± 2.0 h, 12 ± 2.6 h, 21 ± 4.5 h, respectively). Parent compounds (e.g., buproprion, carbamazepine, lamotrigine) generally were more persistent relative to their metabolites. Several compounds (citalopram, venlafaxine, O-desmethyl-venlafaxine) were not attenuated. It was postulated that the primary mechanism of removal for these compounds was interaction with bed sediments and stream biofilms, based on measured concentrations in stream biofilms and a column experiment using stream sediments.

Neuroactive substances in the human vestibular end organs.

PubMed

Usami, S; Matsubara, A; Shinkawa, H; Matsunaga, T; Kanzaki, J

1995-01-01

In order to evaluate the involvement of neuroactive substances in the human vestibular periphery, the immunocytochemical distribution of substance P (SP), calcitonin gene-related peptide (CGRP), and choline acetyltransferase (ChAT) was examined. SP-like immunoreactivity (LI) was present around and beneath sensory hair cells, probably corresponding to their afferent nerve endings. SP-LI was found predominantly in subpopulations of the primary afferents distributed in the peripheral region of the end organs. ChAT-LI and CGRP-LI were found throughout as small puncta below the hair cell layer, probably corresponding to efferent endings. The present results indicate that these neuroactive substances, previously described in animals, are also distributed in the human vestibular periphery, and almost certainly contribute to human vestibular function.

Blunted neuroactive steroid and HPA axis responses to stress are associated with reduced sleep quality and negative affect in pregnancy: a pilot study.

PubMed

Crowley, Shannon K; O'Buckley, Todd K; Schiller, Crystal E; Stuebe, Alison; Morrow, A Leslie; Girdler, Susan S

2016-04-01

Anxiety during pregnancy has been linked to adverse maternal health outcomes, including postpartum depression (PPD). However, there has been limited study of biological mechanisms underlying behavioral predictors of PPD during pregnancy. Considering the shared etiology of chronic stress amongst antenatal behavioral predictors, the primary goal of this pilot study was to examine associations among stress-related physiological factors (including GABA-ergic neurosteroids) and stress-related behavioral indices of anxiety during pregnancy. Fourteen nulliparous women in their second trimester of a singleton pregnancy underwent speech and mental arithmetic stress, following a 2-week subjective and objective recording of sleep-wake behavior. Lower cortisol, progesterone, and a combined measure of ALLO + pregnanolone throughout the entire stressor protocol (area under the curve, AUC) were associated with greater negative emotional responses to stress, and lower cortisol AUC was associated with worse sleep quality. Lower adrenocorticotropic hormone was associated with greater anxious and depressive symptoms. Stress produced paradoxical reductions in cortisol, progesterone, and a combined measure of allopregnanolone + pregnanolone, while tetrahydrodeoxycorticosterone levels were elevated. These data suggest that cortisol, progesterone, and ALLO + pregnanolone levels in the second trimester of pregnancy are inversely related to negative emotional symptoms, and the negative impact of acute stress challenge appears to exert its effects by reducing these steroids to further promote negative emotional responses.

Reduction of circulating and selective limbic brain levels of (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) following forced swim stress in C57BL/6J mice

PubMed Central

Maldonado-Devincci, Antoniette M.; Beattie, Matthew C.; Morrow, Danielle H.; McKinley, Raechel E.; Cook, Jason B.; O’Buckley, Todd K.

2014-01-01

Rationale Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, and GABAergic neuroactive steroids contribute to homeostatic regulation of this circuitry. Acute forced swim stress (FSS) increases plasma, cortical, and hypothalamic (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) levels in rats. However, there have not been systemic investigations of acute stress on changes in plasma and brain levels of 3α,5α-THP in mouse models. Objectives The present experiments aimed to assess circulating and local brain levels of 3α,5α-THP following acute FSS in C57BL/6J mice. Methods Mice were exposed to FSS (10 min), and 50 min later, blood and brains were collected. Circulating pregnenolone and 3α,5α-THP levels were assessed in serum. Free-floating brain sections (40 µm, four to five sections/region) were immunostained and analyzed in cortical and limbic brain structures. Results FSS decreased circulating 3α,5α-THP (−41.6± 10.4 %) and reduced 3α,5α-THP immunolabeling in the paraventricular nucleus of the hypothalamus (−15.2±5.7 %), lateral amygdala (LA, −31.1±13.4 %), and nucleus accumbens (NAcc) shell (−31.9±14.6). Within the LA, vesicular glutamate transporter 1 (VGLUT1) and vesicular GABA transporter were localized in 3α,5α-THP-positively stained cells, while in the NAcc shell, only VGLUT1 was localized in 3α,5α-THP-positively stained cells, suggesting that both glutamatergic and GABAergic cells within the LA are 3α,5α-THP-positive, while in the NAcc shell, 3α,5α-THP only localizes to glutamatergic cells. Conclusions The decrease in circulating and brain levels of 3α,5α-THP may be due to alterations in the biosynthesis/ metabolism or changes in the regulation of the HPA axis following FSS. Changes in GABAergic neuroactive steroids in response to stress likely mediate functional adaptations in neuronal activity. This may provide a potential targeted therapeutic avenue to address maladaptive stress responsivity. PMID:24744202

The role of steroids in the prediction of affective disorders in adult men.

PubMed

Šrámková, Monika; Dušková, Michaela; Hill, Martin; Bičíková, Marie; Řípová, Daniela; Mohr, Pavel; Stárka, Luboslav

2017-05-01

Anxiety and mood disorders (AMD) are the most frequent mental disorders in the human population. They have recently shown increasing prevalence, and commonly disrupt personal and working lives. The aim of our study was to analyze the spectrum of circulating steroids in order to discover differences that could potentially be markers of affective depression or anxiety, and identify which steroids could be a predictive component for these diseases. We studied the steroid metabolome including 47 analytes in 20 men with depression (group D), 20 men with anxiety (group AN) and 30 healthy controls. OPLS and multivariate regression models were used for statistical analysis. Discrimination of group D from controls by the OPLS method was absolute, as was group AN from controls (sensitivity=1.000 (0.839, 1.000), specificity=1.000 (0.887, 1.000)). Relatively good predictivity was also found for discrimination between group D from AN (sensitivity=0.850 (0.640, 0.948), specificity=0.900 (0.699, 0.972)). Selected circulating steroids, including those that are neuroactive and neuroprotective, can be useful tools for discriminating between these affective diseases in adult men. Copyright © 2016. Published by Elsevier Inc.

Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed α1β2γ2L GABAA Receptors

PubMed Central

Chakrabarti, Sampurna; Qian, Mingxing; Krishnan, Kathiresan; Covey, Douglas F.; Mennerick, Steven

2016-01-01

Neuroactive steroids are efficacious modulators of γ-aminobutyric acid type A receptor (GABAA) receptor function. The effects of steroids on the GABAA receptor are typically determined by comparing steady-state single-channel open probability or macroscopic peak responses elicited by GABA in the absence and presence of a steroid. Due to differences in activation conditions (exposure duration, concentration of agonist), it is not obvious whether modulation measured using typical experimental protocols can be used to accurately predict the effect of a modulator on native receptors under physiologic conditions. In the present study, we examined the effects of 14 neuroactive steroids and analogs on the properties of spontaneous inhibitory postsynaptic currents (sIPSCs) in cultured rat hippocampal neurons. The goal was to determine whether the magnitude of modulation of the decay time course of sIPSCs correlates with the extent of modulation and kinetic properties of potentiation as determined in previous single-channel studies. The steroids were selected to cover a wide range of efficacy on heterologously expressed rat α1β2γ2L GABAA receptors, ranging from essentially inert to highly efficacious (strong potentiators of single-channel and macroscopic peak responses). The data indicate a strong correlation between prolongation of the decay time course of sIPSCs and potentiation of single-channel open probability. Furthermore, changes in intracluster closed time distributions were the single best predictor of prolongation of sIPSCs. We infer that the information obtained in steady-state single-channel recordings can be used to forecast modulation of synaptic currents. PMID:26769414

Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat.

PubMed

Qaiser, M Zeeshan; Dolman, Diana E M; Begley, David J; Abbott, N Joan; Cazacu-Davidescu, Mihaela; Corol, Delia I; Fry, Jonathan P

2017-09-01

Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism. Using rat brain perfusion in situ, we have found 3 H-PregS to enter more rapidly than 3 H-DHEAS and both to undergo extensive (> 50%) desulphation within 0.5 min of uptake. Enzyme activity for the steroid sulphatase catalysing this deconjugation was enriched in the capillary fraction of the blood-brain barrier and its mRNA expressed in cultures of rat brain endothelial cells and astrocytes. Although permeability measurements suggested a net efflux, addition of the efflux inhibitors GF120918 and/or MK571 to the perfusate reduced rather than enhanced the uptake of 3 H-DHEAS and 3 H-PregS; a further reduction was seen upon the addition of unlabelled steroid sulphate, suggesting a saturable uptake transporter. Analysis of brain fractions after 0.5 min perfusion with the 3 H-steroid sulphates showed no further metabolism of PregS beyond the liberation of free steroid pregnenolone. By contrast, DHEAS underwent 17-hydroxylation to form androstenediol in both the steroid sulphate and the free steroid fractions, with some additional formation of androstenedione in the latter. Our results indicate a gain of free steroid from circulating steroid sulphates as hormone precursors at the blood-brain barrier, with implications for ageing, neurogenesis, neuronal survival, learning and memory. © 2017 International Society for Neurochemistry.

The hidden side of drug action: Brain temperature changes induced by neuroactive drugs

PubMed Central

Kiyatkin, Eugene A.

2013-01-01

Rationale Most neuroactive drugs affect brain metabolism as well as systemic and cerebral blood flow, thus altering brain temperature. Although this aspect of drug action usually remains in the shadows, drug-induced alterations in brain temperature reflect their metabolic neural effects and affect neural activity and neural functions. Objectives Here, I review brain temperature changes induced by neuroactive drugs, which are used therapeutically (general anesthetics), as a research tool (dopamine agonists and antagonists), and self-administered to induce desired psychic effects (cocaine, methamphetamine, ecstasy). I consider the mechanisms underlying these temperature fluctuations and their influence on neural, physiological, and behavioral effects of these drugs. Results By interacting with neural mechanisms regulating metabolic activity and heat exchange between the brain and the rest of the body, neuroactive drugs either increase or decrease brain temperatures both within (35-39°C) and exceeding the range of physiological fluctuations. These temperature effects differ drastically depending upon the environmental conditions and activity state during drug administration. This state-dependence is especially important for drugs of abuse that are usually taken by humans during psycho-physiological activation and in environments that prevent proper heat dissipation from the brain. Under these conditions, amphetamine-like stimulants induce pathological brain hyperthermia (>40°C) associated with leakage of the blood-brain barrier and structural abnormalities of brain cells. Conclusions The knowledge on brain temperature fluctuations induced by neuroactive drugs provides new information to understand how they influence metabolic neural activity, why their effects depend upon the behavioral context of administration, and the mechanisms underlying adverse drug effects including neurotoxicity PMID:23274506

Live-Cell, Label-Free Identification of GABAergic and Non-GABAergic Neurons in Primary Cortical Cultures Using Micropatterned Surface

PubMed Central

Kono, Sho; Kushida, Takatoshi; Hirano-Iwata, Ayumi; Niwano, Michio; Tanii, Takashi

2016-01-01

Excitatory and inhibitory neurons have distinct roles in cortical dynamics. Here we present a novel method for identifying inhibitory GABAergic neurons from non-GABAergic neurons, which are mostly excitatory glutamatergic neurons, in primary cortical cultures. This was achieved using an asymmetrically designed micropattern that directs an axonal process to the longest pathway. In the current work, we first modified the micropattern geometry to improve cell viability and then studied the axon length from 2 to 7 days in vitro (DIV). The cell types of neurons were evaluated retrospectively based on immunoreactivity against GAD67, a marker for inhibitory GABAergic neurons. We found that axons of non-GABAergic neurons grow significantly longer than those of GABAergic neurons in the early stages of development. The optimal threshold for identifying GABAergic and non-GABAergic neurons was evaluated to be 110 μm at 6 DIV. The method does not require any fluorescence labelling and can be carried out on live cells. The accuracy of identification was 98.2%. We confirmed that the high accuracy was due to the use of a micropattern, which standardized the development of cultured neurons. The method promises to be beneficial both for engineering neuronal networks in vitro and for basic cellular neuroscience research. PMID:27513933

Diversity in GABAergic signaling.

PubMed

Vogt, Kaspar

2015-01-01

GABA(A) receptor-mediated synaptic transmission is responsible for inhibitory control of neural function in the brain. Recent progress has shown that GABA(A) receptors also provide a wide range of additional functions beyond simple inhibition. This diversity of functions is mediated by a large variety of different interneuron classes acting on a diverse population of receptor subtypes. Here, I will focus on an additional source of GABAergic signaling diversity, caused by the highly variable ion signaling mechanism of GABA(A) receptors. In concert with the other two sources of GABAergic heterogeneity, this variability in signaling allows for a wide array of GABAergic effects that are crucial for the development of the brain and its function. © 2015 Elsevier Inc. All rights reserved.

Widespread occurrence of neuro-active pharmaceuticals and metabolites in 24 Minnesota rivers and wastewaters

USGS Publications Warehouse

Writer, Jeffrey; Ferrer, Imma; Barber, Larry B.; Thurman, E. Michael

2013-01-01

Concentrations of 17 neuro-active pharmaceuticals and their major metabolites (bupropion, hydroxy-bupropion, erythro-hydrobupropion, threo-hydrobupropion, carbamazepine, 10,11,-dihydro-10,11,-dihydroxycarbamazepine, 10-hydroxy-carbamazepine, citalopram, N-desmethyl-citalopram, fluoxetine, norfluoxetine, gabapentin, lamotrigine, 2-N-glucuronide-lamotrigine, oxcarbazepine, venlafaxine and O-desmethyl-venlafaxine), were measured in treated wastewater and receiving surface waters from 24 locations across Minnesota, USA. The analysis of upstream and downstream sampling sites indicated that the wastewater treatment plants were the major source of the neuro-active pharmaceuticals and associated metabolites in surface waters of Minnesota. Concentrations of parent compound and the associated metabolite varied substantially between treatment plants (concentrations ± standard deviation of the parent compound relative to its major metabolite) as illustrated by the following examples; bupropion and hydrobupropion 700 ± 1000 ng L−1, 2100 ± 1700 ng L−1, carbamazepine and 10-hydroxy-carbamazepine 480 ± 380 ng L−1, 360 ± 400 ng L−1, venlafaxine and O-desmethyl-venlafaxine 1400 ± 1300 ng L−1, 1800 ± 2300 ng L−1. Metabolites of the neuro-active compounds were commonly found at higher or comparable concentrations to the parent compounds in wastewater effluent and the receiving surface water. Neuro-active pharmaceuticals and associated metabolites were detected only sporadically in samples upstream from the effluent outfall. Metabolite to parent ratios were used to evaluate transformation, and we determined that ratios in wastewater were much lower than those reported in urine, indicating that the metabolites are relatively more labile than the parent compounds in the treatment plants and in receiving waters. The widespread occurrence of neuro-active pharmaceuticals and metabolites in Minnesota effluents and surface waters indicate that

Lipid nanoparticles for administration of poorly water soluble neuroactive drugs.

PubMed

Esposito, Elisabetta; Drechsler, Markus; Mariani, Paolo; Carducci, Federica; Servadio, Michela; Melancia, Francesca; Ratano, Patrizia; Campolongo, Patrizia; Trezza, Viviana; Cortesi, Rita; Nastruzzi, Claudio

2017-09-01

This study describes the potential of solid lipid nanoparticles and nanostructured lipid carriers as nano-formulations to administer to the central nervous system poorly water soluble drugs. Different neuroactive drugs, i.e. dimethylfumarate, retinyl palmitate, progesterone and the endocannabinoid hydrolysis inhibitor URB597 have been studied. Lipid nanoparticles constituted of tristearin or tristearin in association with gliceryl monoolein were produced. The nanoencapsulation strategy allowed to obtain biocompatible and non-toxic vehicles, able to increase the solubility of the considered neuroactive drugs. To improve URB597 targeting to the brain, stealth nanoparticles were produced modifying the SLN surface with polysorbate 80. A behavioural study was conducted in rats to test the ability of SLN containing URB597 given by intranasal administration to alter behaviours relevant to psychiatric disorders. URB597 maintained its activity after nanoencapsulation, suggesting the possibility to propose this kind of vehicle as alternative to unphysiological mixtures usually employed for animal and clinical studies.

The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: Implications for diagnosis and treatment

PubMed Central

Guille, Constance; Spencer, Susan; Cavus, Idil; Epperson, C. Neill

2014-01-01

Despite our understanding of hormonal influences on central nervous system (CNS) function, there is still much to learn about the pathogenesis of menstrual cycle-linked disorders. A growing literature suggests that the influence of sex steroids on neurological and psychiatric disorders is in part mediated by an aberrant CNS response to neuroactive steroids. Although sex steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO) influence numerous neurotransmitter systems, it is their potent effect on the brain's primary inhibitory and excitatory neurotransmitters γ aminobutyric acid (GABA) and glutamate that links the study of premenstrual dysphoric disorder (PMDD) and catamenial epilepsy (CE). After providing an overview of these menstrual cycle-linked disorders, this article focuses on the preclinical and clinical research investigating the role of estradiol and progesterone (via ALLO) in the etiology of PMDD and CE. Through exploration of the phenomenological and neurobiological overlap between CE and PMDD, we aim to highlight areas for future research and development of treatments for menstrual cycle-linked neuropsychiatric disorders. PMID:18346939

Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms

PubMed Central

Penatti, Carlos A A; Porter, Donna M; Henderson, Leslie P

2009-01-01

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which γ-aminobutyric acid type A (GABAA) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABAA receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, sIPSC amplitude and frequency and the expression of selective GABAA receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- vs. ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu. PMID:19812324

Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets

PubMed Central

Giordano, Carmela; Marchiò, Maddalena; Timofeeva, Elena; Biagini, Giuseppe

2014-01-01

Various ketogenic diet (KD) therapies, including classic KD, medium chain triglyceride administration, low glycemic index treatment, and a modified Atkins diet, have been suggested as useful in patients affected by pharmacoresistant epilepsy. A common goal of these approaches is to achieve an adequate decrease in the plasma glucose level combined with ketogenesis, in order to mimic the metabolic state of fasting. Although several metabolic hypotheses have been advanced to explain the anticonvulsant effect of KDs, including changes in the plasma levels of ketone bodies, polyunsaturated fatty acids, and brain pH, direct modulation of neurotransmitter release, especially purinergic (i.e., adenosine) and γ-aminobutyric acidergic neurotransmission, was also postulated. Neuropeptides and peptide hormones are potent modulators of synaptic activity, and their levels are regulated by metabolic states. This is the case for neuroactive peptides such as neuropeptide Y, galanin, cholecystokinin, and peptide hormones such as leptin, adiponectin, and growth hormone-releasing peptides (GHRPs). In particular, the GHRP ghrelin and its related peptide des-acyl ghrelin are well-known controllers of energy homeostasis, food intake, and lipid metabolism. Notably, ghrelin has also been shown to regulate the neuronal excitability and epileptic activation of neuronal networks. Several lines of evidence suggest that GHRPs are upregulated in response to starvation and, particularly, in patients affected by anorexia and cachexia, all conditions in which also ketone bodies are upregulated. Moreover, starvation and anorexia nervosa are accompanied by changes in other peptide hormones such as adiponectin, which has received less attention. Adipocytokines such as adiponectin have also been involved in modulating epileptic activity. Thus, neuroactive peptides whose plasma levels and activity change in the presence of ketogenesis might be potential candidates for elucidating the neurohormonal

Genetic dissection of GABAergic neural circuits in mouse neocortex

PubMed Central

Taniguchi, Hiroki

2014-01-01

Diverse and flexible cortical functions rely on the ability of neural circuits to perform multiple types of neuronal computations. GABAergic inhibitory interneurons significantly contribute to this task by regulating the balance of activity, synaptic integration, spiking, synchrony, and oscillation in a neural ensemble. GABAergic interneurons display a high degree of cellular diversity in morphology, physiology, connectivity, and gene expression. A considerable number of subtypes of GABAergic interneurons diversify modes of cortical inhibition, enabling various types of information processing in the cortex. Thus, comprehensively understanding fate specification, circuit assembly, and physiological function of GABAergic interneurons is a key to elucidate the principles of cortical wiring and function. Recent advances in genetically encoded molecular tools have made a breakthrough to systematically study cortical circuitry at the molecular, cellular, circuit, and whole animal levels. However, the biggest obstacle to fully applying the power of these to analysis of GABAergic circuits was that there were no efficient and reliable methods to express them in subtypes of GABAergic interneurons. Here, I first summarize cortical interneuron diversity and current understanding of mechanisms, by which distinct classes of GABAergic interneurons are generated. I then review recent development in genetically encoded molecular tools for neural circuit research, and genetic targeting of GABAergic interneuron subtypes, particularly focusing on our recent effort to develop and characterize Cre/CreER knockin lines. Finally, I highlight recent success in genetic targeting of chandelier cells, the most unique and distinct GABAergic interneuron subtype, and discuss what kind of questions need to be addressed to understand development and function of cortical inhibitory circuits. PMID:24478631

Neurosteroid Influences on Sensitivity to Ethanol

PubMed Central

Helms, Christa M.; Rossi, David J.; Grant, Kathleen A.

2011-01-01

This review will highlight a variety of mechanisms by which neurosteroids affect sensitivity to ethanol, including physiological states associated with activity of the hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–gonadal (HPG) axes, and the effects of chronic exposure to ethanol, in addition to behavioral implications. To date, γ-aminobutyric acid (GABAA) receptor mechanisms are a major focus of the modulation of ethanol effects by neuroactive steroids. While NMDA receptor mechanisms are gaining prominence in the literature, these complex data would be best discussed separately. Accordingly, GABAA receptor mechanisms are emphasized in this review with brief mention of some NMDA receptor mechanisms to point out contrasting neuroactive steroid pharmacology. Overall, the data suggest that neurosteroids are virtually ubiquitous modulators of inhibitory neurotransmission. Neurosteroids appear to affect sensitivity to ethanol in specific brain regions and, consequently, specific behavioral tests, possibly related to the efficacy and potency of ethanol to potentiate the release of GABA and increase neurosteroid concentrations. Although direct interaction of ethanol and neuroactive steroids at common receptor binding sites has been suggested in some studies, this proposition is still controversial. It is currently difficult to assign a specific mechanism by which neuroactive steroids could modulate the effects of ethanol in particular behavioral tasks. PMID:22654852

Protective Actions of 17β-Estradiol and Progesterone on Oxidative Neuronal Injury Induced by Organometallic Compounds

PubMed Central

Ishihara, Yasuhiro; Takemoto, Takuya; Yamazaki, Takeshi

2015-01-01

Steroid hormones synthesized in and secreted from peripheral endocrine glands pass through the blood-brain barrier and play a role in the central nervous system. In addition, the brain possesses an inherent endocrine system and synthesizes steroid hormones known as neurosteroids. Increasing evidence shows that neuroactive steroids protect the central nervous system from various harmful stimuli. Reports show that the neuroprotective actions of steroid hormones attenuate oxidative stress. In this review, we summarize the antioxidative effects of neuroactive steroids, especially 17β-estradiol and progesterone, on neuronal injury in the central nervous system under various pathological conditions, and then describe our recent findings concerning the neuroprotective actions of 17β-estradiol and progesterone on oxidative neuronal injury induced by organometallic compounds, tributyltin, and methylmercury. PMID:25815107

Acidosis-Induced Dysfunction of Cortical GABAergic Neurons through Astrocyte-Related Excitotoxicity

PubMed Central

Guan, Sudong; Zhu, Yan; Wang, Jin-Hui

2015-01-01

Background Acidosis impairs cognitions and behaviors presumably by acidification-induced changes in neuronal metabolism. Cortical GABAergic neurons are vulnerable to pathological factors and their injury leads to brain dysfunction. How acidosis induces GABAergic neuron injury remains elusive. As the glia cells and neurons interact each other, we intend to examine the role of the astrocytes in acidosis-induced GABAergic neuron injury. Results Experiments were done at GABAergic cells and astrocytes in mouse cortical slices. To identify astrocytic involvement in acidosis-induced impairment, we induced the acidification in single GABAergic neuron by infusing proton intracellularly or in both neurons and astrocytes by using proton extracellularly. Compared the effects of intracellular acidification and extracellular acidification on GABAergic neurons, we found that their active intrinsic properties and synaptic outputs appeared more severely impaired in extracellular acidosis than intracellular acidosis. Meanwhile, extracellular acidosis deteriorated glutamate transporter currents on the astrocytes and upregulated excitatory synaptic transmission on the GABAergic neurons. Moreover, the antagonists of glutamate NMDA-/AMPA-receptors partially reverse extracellular acidosis-induced injury in the GABAergic neurons. Conclusion Our studies suggest that acidosis leads to the dysfunction of cortical GABAergic neurons by astrocyte-mediated excitotoxicity, in addition to their metabolic changes as indicated previously. PMID:26474076

[Dissociated learning with GABAergic drugs].

PubMed

Azarashvili, A A; Kaĭmachnikova, I E

2008-01-01

The possibility of dissociated learning was investigated using drugs which act directly on GABAB receptors of the brain. The earlier proposed suggestion that the cholinergic system plays a key role in the mechanisms of dissociated learning was tested. It was shown in male Wistar rats that dissociated learning was possible with GABAergic drugs. The dissociated state was induced by injecting the animals with both GABA agonist Baclofen and GABA antagonist 5-aminovaleric acid. Thus, dissociated learning is possible with drugs which act on either cholinergic or GABAergic transmitter systems.

Hilar GABAergic Interneuron Activity Controls Spatial Learning and Memory Retrieval

PubMed Central

Andrews-Zwilling, Yaisa; Gillespie, Anna K.; Kravitz, Alexxai V.; Nelson, Alexandra B.; Devidze, Nino; Lo, Iris; Yoon, Seo Yeon; Bien-Ly, Nga; Ring, Karen; Zwilling, Daniel; Potter, Gregory B.; Rubenstein, John L. R.; Kreitzer, Anatol C.; Huang, Yadong

2012-01-01

Background Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear. Methodology and Principal Findings We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0)—a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity. Conclusions and Significance Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD. PMID:22792368

A novel GABAergic afferent input to the pontine reticular formation: the mesopontine GABAergic column.

PubMed

Liang, Chang-Lin; Marks, Gerald A

2009-11-10

Pharmacological manipulations of gamma-aminobutyric acid (GABA) neurotransmission in the nucleus pontis oralis (PnO) of the rat brainstem produce alterations in sleep/wake behavior. Local applications of GABA(A) receptor antagonists and agonists increase REM sleep and wake, respectively. These findings support a role for GABAergic mechanisms of the PnO in the control of arousal state. We have been investigating sources of GABA innervation of the PnO that may interact with local GABA(A) receptors in the control of state. Utilizing a retrograde tracer, cholera toxin-B subunit (CTb), injected into the PnO and dual-label immunohistochemistry with an antibody against glutamic acid decarboxalase-67 (GAD67), we report on a previously unidentified GABAergic neuronal population projecting to the contralateral PnO appearing as a column of cells, with long-axis in the sagittal plane, extending through the midbrain and pons. We refer to these neurons as the mesopontine GABAergic column (MPGC). The contiguous, columnar, anatomical distribution suggests operation as a functional neural system, which may influence expression of REM sleep, wake and other behaviors subserved by the PnO.

The GABAergic System and the Gastrointestinal Physiopathology.

PubMed

Auteri, Michelangelo; Zizzo, Maria Grazia; Serio, Rosa

2015-01-01

Since the first report about the presence of γ-aminobutyric acid (GABA) within the gastrointestinal (GI) tract, accumulating evidence strongly supports the widespread representation of the GABAergic system in the enteric milieu, underlining its potential multifunctional role in the regulation of GI functions in health and disease. GABA and GABA receptors are widely distributed throughout the GI tract, constituting a complex network likely regulating the diverse GI behaviour patterns, cooperating with other major neurotransmitters and mediators for maintaining GI homeostasis in physiologic and pathologic conditions. GABA is involved in the circuitry of the enteric nervous system, controlling GI secretion and motility, as well as in the GI endocrine system, possibly acting as a autocrine/paracrine or hormonal agent. Furthermore, a series of investigations addresses the GABAergic system as a potential powerful modulator of GI visceral pain processing, enteric immune system and carcinogenesis. Although overall such actions may imply the consideration of the GABAergic system as a novel therapeutic target in different GI pathologic states, including GI motor and secretory diseases and different enteric inflammatory- and pain-related pathologies, current clinical applications of GABAergic drugs are scarce. Thus, in an attempt to propel novel scientific efforts addressing the detailed characterization of the GABAergic signaling in the GI tract, and consequently the development of novel strategies for the treatment of different GI disorders, we reviewed and discussed the current evidence about GABA actions in the enteric environment, with a particular focus on their possible therapeutic implications.

Developmental neurotoxicity and autism: A potential link between indoor neuroactive pollutants and the curious birth order risk factor.

PubMed

Gray, Wesley A; Billock, Vincent A

2017-11-01

Epidemiological and demographic studies find an increased risk of autism among first-borns. Toxicological studies show that some semi-volatile substances found in infant products produce adverse effects in neural and endocrine systems of animals, including behavioral and developmental effects. Several factors elevate the exposure of human infants to these chemicals. The highest exposures found in infants are comparable to the exposures that induce neural toxicity in animals. A review of these literatures suggests a linking hypothesis that could bridge the epidemiological and toxicological lines of evidence: an infant's exposure to neuroactive compounds emitted by infant products is increased by product newness and abundance; exposure is likely maximized for first-born children in families that can afford new products. Exposure is reduced for subsequently-born children who reuse these now neuroactive-depleted products. The presence of neuroactive chemical emissions from infant products has implications for birth-order effects and for other curious risk factors in autism, including gender, socioeconomic status, and season-of-birth risk factors. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Role of GABAergic inhibition in hippocampal network oscillations.

PubMed

Mann, Edward O; Paulsen, Ole

2007-07-01

Physiological rhythmic activity in cortical circuits relies on GABAergic inhibition to balance excitation and control spike timing. With a focus on recent experimental progress in the hippocampus, here we review the mechanisms by which synaptic inhibition can control the precise timing of spike generation, by way of effects of GABAergic events on membrane conductance ('shunting' inhibition) and membrane potential ('hyperpolarizing' inhibition). Synaptic inhibition itself can be synchronized by way of interactions within networks of GABAergic neurons, and by excitatory neurons. The importance of GABAergic mechanisms for generation of cortical rhythms is now well established. What remains to be resolved is how such inhibitory control of spike timing can be harnessed for long-range fast synchronization, and the relevance of these mechanisms to network function. This review is part of the INMED/TINS special issue Physiogenic and pathogenic oscillations: the beauty and the beast, based on presentations at the annual INMED/TINS symposium (http://inmednet.com).

Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

PubMed Central

Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

2014-01-01

The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically

GABAergic circuit dysfunction in the Drosophila Fragile X syndrome model.

PubMed

Gatto, Cheryl L; Pereira, Daniel; Broadie, Kendal

2014-05-01

Fragile X syndrome (FXS), caused by loss of FMR1 gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 protein (FMRP) translational regulator mediates activity-dependent control of synapses. In addition to the metabotropic glutamate receptor (mGluR) hyperexcitation FXS theory, the GABA theory postulates that hypoinhibition is causative for disease state symptoms. Here, we use the Drosophila FXS model to assay central brain GABAergic circuitry, especially within the Mushroom Body (MB) learning center. All 3 GABAA receptor (GABAAR) subunits are reportedly downregulated in dfmr1 null brains. We demonstrate parallel downregulation of glutamic acid decarboxylase (GAD), the rate-limiting GABA synthesis enzyme, although GABAergic cell numbers appear unaffected. Mosaic analysis with a repressible cell marker (MARCM) single-cell clonal studies show that dfmr1 null GABAergic neurons innervating the MB calyx display altered architectural development, with early underdevelopment followed by later overelaboration. In addition, a new class of extra-calyx terminating GABAergic neurons is shown to include MB intrinsic α/β Kenyon Cells (KCs), revealing a novel level of MB inhibitory regulation. Functionally, dfmr1 null GABAergic neurons exhibit elevated calcium signaling and altered kinetics in response to acute depolarization. To test the role of these GABAergic changes, we attempted to pharmacologically restore GABAergic signaling and assay effects on the compromised MB-dependent olfactory learning in dfmr1 mutants, but found no improvement. Our results show that GABAergic circuit structure and function are impaired in the FXS disease state, but that correction of hypoinhibition alone is not sufficient to rescue a behavioral learning impairment. Copyright © 2014 Elsevier Inc. All rights reserved.

Dissociated learning using GABAergic drugs.

PubMed

Azarashvili, A A; Kaimachnikova, I E

2009-02-01

Experiments on Wistar rats addressed the possibility of dissociated learning using drugs acting directly on brain GABA(B) receptors. A previously suggested hypothesis was tested: that the cholinergic system of the brain plays the decisive role in the mechanisms of dissociative learning. The data obtained here provided evidence that dissociated learning an occur with compounds acting on the GABAergic transmitter system of the brain. Dissociated states arose on treatment of animals with both the GABA-mimetic baclofen and the GABA receptor antagonist 5-aminovaleric acid. Thus, these results show that dissociated learning can occur using drugs acting on both the cholinergic and the GABAergic transmitter systems of the brain.

Distinct Translaminar Glutamatergic Circuits to GABAergic Interneurons in the Neonatal Auditory Cortex.

PubMed

Deng, Rongkang; Kao, Joseph P Y; Kanold, Patrick O

2017-05-09

GABAergic activity is important in neocortical development and plasticity. Because the maturation of GABAergic interneurons is regulated by neural activity, the source of excitatory inputs to GABAergic interneurons plays a key role in development. We show, by laser-scanning photostimulation, that layer 4 and layer 5 GABAergic interneurons in the auditory cortex in neonatal mice (GABAergic interneurons showed two spatial patterns of translaminar connection: inputs originating predominantly from supragranular or from supragranular and infragranular layers, including the subplate, which relays early thalamocortical activity. Sensory deprivation altered the development of translaminar inputs. Thus, distinct translaminar circuits to GABAergic interneurons exist throughout development, and the maturation of excitatory synapses is input-specific. Glutamatergic signaling from subplate and intracortical sources likely plays a role in the maturation of GABAergic interneurons. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Neuronal Diversity in GABAergic Long-Range Projections from the Hippocampus

PubMed Central

Jinno, Shozo; Klausberger, Thomas; Marton, Laszlo F.; Dalezios, Yannis; Roberts, J. David B.; Fuentealba, Pablo; Bushong, Eric A.; Henze, Darrell; Buzsáki, György; Somogyi, Peter

2008-01-01

The formation and recall of sensory, motor, and cognitive representations require coordinated fast communication among multiple cortical areas. Interareal projections are mainly mediated by glutamatergic pyramidal cell projections; only few long-range GABAergic connections have been reported. Using in vivo recording and labeling of single cells and retrograde axonal tracing, we demonstrate novel long-range GABAergic projection neurons in the rat hippocampus: (1) somatostatin- and predominantly mGluR1α-positive neurons in stratum oriens project to the subiculum, other cortical areas, and the medial septum; (2) neurons in stratum oriens, including somatostatin-negative ones; and (3) trilaminar cells project to the subiculum and/or other cortical areas but not the septum. These three populations strongly increase their firing during sharp wave-associated ripple oscillations, communicating this network state to the septotemporal system. Finally, a large population of somatostatin-negative GABAergic cells in stratum radiatum project to the molecular layers of the subiculum, presubiculum, retrosplenial cortex, and indusium griseum and fire rhythmically at high rates during theta oscillations but do not increase their firing during ripples. The GABAergic projection axons have a larger diameter and thicker myelin sheet than those of CA1 pyramidal cells. Therefore, rhythmic IPSCs are likely to precede the arrival of excitation in cortical areas (e.g., subiculum) that receive both glutamatergic and GABAergic projections from the CA1 area. Other areas, including the retrosplenial cortex, receive only rhythmic GABAergic CA1 input. We conclude that direct GABAergic projections from the hippocampus to other cortical areas and the septum contribute to coordinating oscillatory timing across structures. PMID:17699661

Impaired Excitatory Drive to Spinal Gabaergic Neurons of Neuropathic Mice

PubMed Central

Leitner, Jörg; Westerholz, Sören; Heinke, Bernhard; Forsthuber, Liesbeth; Wunderbaldinger, Gabriele; Jäger, Tino; Gruber-Schoffnegger, Doris; Braun, Katharina; Sandkühler, Jürgen

2013-01-01

Adequate pain sensitivity requires a delicate balance between excitation and inhibition in the dorsal horn of the spinal cord. This balance is severely impaired in neuropathy leading to enhanced pain sensations (hyperalgesia). The underlying mechanisms remain elusive. Here we explored the hypothesis that the excitatory drive to spinal GABAergic neurons might be impaired in neuropathic animals. Transgenic adult mice expressing EGFP under the promoter for GAD67 underwent either chronic constriction injury of the sciatic nerve or sham surgery. In transverse slices from lumbar spinal cord we performed whole-cell patch-clamp recordings from identified GABAergic neurons in lamina II. In neuropathic animals rates of mEPSC were reduced indicating diminished global excitatory input. This downregulation of excitatory drive required a rise in postsynaptic Ca2+. Neither the density and morphology of dendritic spines on GABAergic neurons nor the number of excitatory synapses contacting GABAergic neurons were affected by neuropathy. In contrast, paired-pulse ratio of Aδ- or C-fiber-evoked monosynaptic EPSCs following dorsal root stimulation was increased in neuropathic animals suggesting reduced neurotransmitter release from primary afferents. Our data indicate that peripheral neuropathy triggers Ca2+-dependent signaling pathways in spinal GABAergic neurons. This leads to a global downregulation of the excitatory drive to GABAergic neurons. The downregulation involves a presynaptic mechanism and also applies to the excitation of GABAergic neurons by presumably nociceptive Aδ- and C-fibers. This then leads to an inadequately low recruitment of inhibitory interneurons during nociception. We suggest that this previously unrecognized mechanism of impaired spinal inhibition contributes to hyperalgesia in neuropathy. PMID:24009748

Identification of marine neuroactive molecules in behaviour-based screens in the larval zebrafish.

PubMed

Long, Si-Mei; Liang, Feng-Yin; Wu, Qi; Lu, Xi-Lin; Yao, Xiao-Li; Li, Shi-Chang; Li, Jing; Su, Huanxing; Pang, Ji-Yan; Pei, Zhong

2014-05-30

High-throughput behavior-based screen in zebrafish is a powerful approach for the discovery of novel neuroactive small molecules for treatment of nervous system diseases such as epilepsy. To identify neuroactive small molecules, we first screened 36 compounds (1-36) derived from marine natural products xyloketals and marine isoprenyl phenyl ether obtained from the mangrove fungus. Compound 1 demonstrated the most potent inhibition on the locomotor activity in larval zebrafish. Compounds 37-42 were further synthesized and their potential anti-epilepsy action was then examined in a PTZ-induced epilepsy model in zebrafish. Compound 1 and compounds 39, 40 and 41 could significantly attenuate PTZ-induced locomotor hyperactivity and elevation of c-fos mRNA in larval zebrafish. Compound 40 showed the most potent inhibitory action against PTZ-induced hyperactivity. The structure-activity analysis showed that the OH group at 12-position played a critical role and the substituents at the 13-position were well tolerated in the inhibitory activity of xyloketal derivatives. Thus, these derivatives may provide some novel drug candidates for the treatment of epilepsy.

Exposure to bisphenol A affects GABAergic neuron differentiation in neurosphere cultures.

PubMed

Fukushima, Nobuyuki; Nagao, Tetsuji

2018-06-13

Endocrine-disrupting chemicals (EDCs) influence not only endocrine functions but also neuronal development and functions. In-vivo studies have suggested the relationship of EDC-induced neurobehavioral disorders with dysfunctions of neurotransmitter mechanisms including γ-aminobutyric acid (GABA)ergic mechanisms. However, whether EDCs affect GABAergic neuron differentiation remains unclear. In the present study, we show that a representative EDC, bisphenol A (BPA), affects GABAergic neuron differentiation. Cortical neurospheres prepared from embryonic mice were exposed to BPA for 7 days, and then neuronal differentiation was induced. We found that BPA exposure resulted in a decrease in the ratio of GABAergic neurons to total neurons. However, the same exposure stimulated the differentiation of neurons expressing calbindin, a calcium-binding protein observed in a subpopulation of GABAergic neurons. These findings suggested that BPA might influence the formation of an inhibitory neuronal network in developing cerebral cortex involved in the occurrence of neurobehavioral disorders.

Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection.

PubMed

Buzhdygan, Tetyana; Lisinicchia, Joshua; Patel, Vipulkumar; Johnson, Kenneth; Neugebauer, Volker; Paessler, Slobodan; Jennings, Kristofer; Gelman, Benjamin

2016-06-01

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients with effective suppression of virus replication by combination antiretroviral therapy (cART). Several neurotransmitter systems were reported to be abnormal in HIV-infected patients, including the inhibitory GABAergic system, which mediates fine-tuning of neuronal processing and plays an essential role in cognitive functioning. To elucidate the role of abnormal GABAergic transmission in HAND, the expression of GABAergic markers was measured in 449 human brain specimens from HIV-infected patients with and without HAND. Using real-time polymerase chain reaction, immunoblotting and immunohistochemistry we found that the GABAergic markers were significantly decreased in most sectors of cerebral neocortex, the neostriatum, and the cerebellum of HIV-infected subjects. Low GABAergic expression in frontal neocortex was correlated significantly with high expression of endothelial cell markers, dopamine receptor type 2 (DRD2L), and preproenkephalin (PENK) mRNAs, and with worse performance on tasks of verbal fluency. Significant associations were not found between low GABAergic mRNAs and HIV-1 RNA concentration in the brain, the history of cART, or HIV encephalitis. Pathological evidence of neurodegeneration of the affected GABAergic neurons was not present. We conclude that abnormally low expression of GABAergic markers is prevalent in HIV-1 infected patients. Interrelationships with other neurotransmitter systems including dopaminergic transmission and with endothelial cell markers lend added support to suggestions that synaptic plasticity and cerebrovascular anomalies are involved with HAND in virally suppressed patients.

Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease

PubMed Central

Govindpani, Karan; Calvo-Flores Guzmán, Beatriz; Vinnakota, Chitra; Waldvogel, Henry J.; Kwakowsky, Andrea

2017-01-01

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the vertebrate brain. In the past, there has been a major research drive focused on the dysfunction of the glutamatergic and cholinergic neurotransmitter systems in Alzheimer’s disease (AD). However, there is now growing evidence in support of a GABAergic contribution to the pathogenesis of this neurodegenerative disease. Previous studies paint a complex, convoluted and often inconsistent picture of AD-associated GABAergic remodeling. Given the importance of the GABAergic system in neuronal function and homeostasis, in the maintenance of the excitatory/inhibitory balance, and in the processes of learning and memory, such changes in GABAergic function could be an important factor in both early and later stages of AD pathogenesis. Given the limited scope of currently available therapies in modifying the course of the disease, a better understanding of GABAergic remodeling in AD could open up innovative and novel therapeutic opportunities. PMID:28825683

Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network.

PubMed

Frank, Julie G; Mendelowitz, David

2012-01-01

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+) currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for

GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies

PubMed Central

de Jonge, Jeroen C.; Vinkers, Christiaan H.; Hulshoff Pol, Hilleke E.; Marsman, Anouk

2017-01-01

Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical γ-aminobutyric acid (GABAergic) neurons contribute to the clinical features of schizophrenia. In vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS) offers the possibility to provide more insight into the relationship between problems in GABAergic neurotransmission and clinical symptoms of schizophrenia patients. This study reviews and links alterations in the GABA system in postmortem studies, animal models, and human studies in schizophrenia. Converging evidence implicates alterations in both presynaptic and postsynaptic components of GABAergic neurotransmission in schizophrenia, and GABA may thus play an important role in the pathophysiology of schizophrenia. MRS studies can provide direct insight into the GABAergic mechanisms underlying the development of schizophrenia as well as changes during its course. PMID:28848455

Investigation of synapse formation and function in a glutamatergic-GABAergic two-neuron microcircuit.

PubMed

Chang, Chia-Ling; Trimbuch, Thorsten; Chao, Hsiao-Tuan; Jordan, Julia-Christine; Herman, Melissa A; Rosenmund, Christian

2014-01-15

Neural circuits are composed of mainly glutamatergic and GABAergic neurons, which communicate through synaptic connections. Many factors instruct the formation and function of these synapses; however, it is difficult to dissect the contribution of intrinsic cell programs from that of extrinsic environmental effects in an intact network. Here, we perform paired recordings from two-neuron microculture preparations of mouse hippocampal glutamatergic and GABAergic neurons to investigate how synaptic input and output of these two principal cells develop. In our reduced preparation, we found that glutamatergic neurons showed no change in synaptic output or input regardless of partner neuron cell type or neuronal activity level. In contrast, we found that glutamatergic input caused the GABAergic neuron to modify its output by way of an increase in synapse formation and a decrease in synaptic release efficiency. These findings are consistent with aspects of GABAergic synapse maturation observed in many brain regions. In addition, changes in GABAergic output are cell wide and not target-cell specific. We also found that glutamatergic neuronal activity determined the AMPA receptor properties of synapses on the partner GABAergic neuron. All modifications of GABAergic input and output required activity of the glutamatergic neuron. Because our system has reduced extrinsic factors, the changes we saw in the GABAergic neuron due to glutamatergic input may reflect initiation of maturation programs that underlie the formation and function of in vivo neural circuits.

Effects of chronic exposure to an anabolic androgenic steroid cocktail on alpha5-receptor-mediated GABAergic transmission and neural signaling in the forebrain of female mice.

PubMed

Penatti, C A A; Costine, B A; Porter, D M; Henderson, L P

2009-06-30

Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone that are illicitly self-administered for enhancement of performance and body image, but which also have significant effects on the brain and on behavior. While the stereotypical AAS user is an adult male, AAS abuse in women is rapidly increasing, yet few studies have examined AAS effects in female subjects. We have assessed the effects in female mice of a combination of commonly abused AAS on neuronal activity and neurotransmission mediated by GABA type A (GABA(A)) receptors in the medial preoptic nucleus (MPN); a nexus in the circuits of the hypothalamus and forebrain that are critical for the expression of social behaviors known to be altered in AAS abuse. Our data indicate that chronic exposure to AAS resulted in androgen receptor (AR)-dependent upregulation of alpha(5), beta(3) and delta subunit mRNAs. Acute application of the alpha(5) subunit-selective inverse agonist, L-655,708 (L6), indicated that a significant fraction of the synaptic current is carried by alpha(5)-containing receptors and that AAS treatment may enhance expression of alpha(5)-containing receptors contributing to synaptic, but not tonic, currents in the MPN. AAS treatment also resulted in a significant decrease in action potential frequency in MPN neurons that was also correlated with an increased sensitivity to L-655,708. Our data demonstrate that chronic exposure to multiple AAS elicits significant changes in GABAergic transmission and neuronal activity that are likely to reflect changes in the expression of alpha(5)-containing synaptic receptors within the MPN.

Effects of Chronic Exposure to an Anabolic Androgenic Steroid Cocktail on α5-Receptor Mediated GABAergic Transmission and Neural Signaling in the Forebrain of Female Mice

PubMed Central

Penatti, Carlos A. A.; Costine, Beth A.; Porter, Donna M.; Henderson, Leslie P.

2009-01-01

Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone that are illicitly self-administered for enhancement of performance and body image, but which also have significant effects on the brain and on behavior. While the stereotypical AAS user is an adult male, AAS abuse in women is rapidly increasing, yet few studies have examined AAS effects in female subjects. We have assessed the effects in female mice of a combination of commonly abused AAS on neuronal activity and neurotransmission mediated by γ-aminobutyric acid type A (GABAA) receptors in the medial preoptic nucleus (MPN); a nexus in the circuits of the hypothalamus and forebrain that are critical for the expression of social behaviors known to be altered in AAS abuse. Our data indicate that chronic exposure to AAS resulted in androgen receptor (AR)-dependent upregulation of α5, β3 and δ subunit mRNA. Acute application of the α5 subunit-selective inverse agonist, L-655,708, indicated that a significant fraction of the synaptic current is carried by α5-containing receptors and that AAS treatment may enhance expression of α5-containing receptors contributing to synaptic, but not tonic, currents in the MPN. AAS treatment also resulted in a significant decrease in action potential frequency in MPN neurons that was also correlated with an increased sensitivity to L655,708. Our data demonstrate that chronic exposure to multiple AAS elicits significant changes in GABAergic transmission and neuronal activity that are likely to reflect changes in the expression of α5-containing synaptic receptors within the MPN. PMID:19324077

Cortical parvalbumin GABAergic deficits with α7 nicotinic acetylcholine receptor deletion: Implications for schizophrenia

PubMed Central

Lin, Hong; Hsu, Fu-Chun; Baumann, Bailey H.; Coulter, Douglas A.; Anderson, Stewart A.; Lynch, David R.

2014-01-01

Dysfunction of cortical parvalbumin (PV)-containing GABAergic interneurons has been implicated in cognitive deficits of schizophrenia. In humans microdeletion of the CHRNA7 (α7 nicotinic acetylcholine receptor, nAChR) gene is associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia while in mice similar deletion causes analogous abnormalities including impaired attention, working-memory and learning. However, the pathophysiological roles of α7 nAChRs in cortical PV GABAergic development remain largely uncharacterized. In both in vivo and in vitro models, we identify here that deletion of the α7 nAChR gene in mice impairs cortical PV GABAergic development and recapitulates many of the characteristic neurochemical deficits in PV-positive GABAergic interneurons found in schizophrenia. α7 nAChR null mice had decreased cortical levels of GABAergic markers including PV, Glutamic Acid Decarboxylase 65/67 (GAD65/67) and the α1 subunit of GABAA receptors, particularly reductions of PV and GAD67 levels in cortical PV-positive interneurons during late postnatal life and adulthood. Cortical GABAergic synaptic deficits were identified in the prefrontal cortex of α7 nAChR null mice and α7 nAChR null cortical cultures. Similar disruptions in development of PV-positive GABAergic interneurons and perisomatic synapses were found in cortical cultures lacking α7 nAChRs. Moreover, NMDA receptor expression was reduced in GABAergic interneurons, implicating NMDA receptor hypofunction in GABAergic deficits in α7 nAChR null mice. Our findings thus demonstrate impaired cortical PV GABAergic development and multiple characteristic neurochemical deficits reminiscent of schizophrenia in cortical PV-positive interneurons in α7 nAChR gene deletion models. This implicates crucial roles of α7 nAChRs in cortical PV GABAergic development and dysfunction in schizophrenia and other neuropsychiatric disorders. PMID

Caenorhabditis elegans flamingo cadherin fmi-1 regulates GABAergic neuronal development.

PubMed

Najarro, Elvis Huarcaya; Wong, Lianna; Zhen, Mei; Carpio, Edgar Pinedo; Goncharov, Alexandr; Garriga, Gian; Lundquist, Erik A; Jin, Yishi; Ackley, Brian D

2012-03-21

In a genetic screen for regulators of synaptic morphology, we identified the single Caenorhabditis elegans flamingo-like cadherin fmi-1. The fmi-1 mutants exhibit defective axon pathfinding, reduced synapse number, aberrant synapse size and morphology, as well as an abnormal accumulation of synaptic vesicles at nonsynaptic regions. Although FMI-1 is primarily expressed in the nervous system, it is not expressed in the ventral D-type (VD) GABAergic motorneurons, which are defective in fmi-1 mutants. The axon and synaptic defects of VD neurons could be rescued when fmi-1 was expressed exclusively in non-VD neighboring neurons, suggesting a cell nonautonomous action of FMI-1. FMI-1 protein that lacked its intracellular domain still retained its ability to rescue the vesicle accumulation defects of GABAergic motorneurons, indicating that the extracellular domain was sufficient for this function of FMI-1 in GABAergic neuromuscular junction development. Mutations in cdh-4, a Fat-like cadherin, cause similar defects in GABAergic motorneurons. The cdh-4 is expressed by the VD neurons and seems to function in the same genetic pathway as fmi-1 to regulate GABAergic neuron development. Thus, fmi-1 and cdh-4 cadherins might act together to regulate synapse development and axon pathfinding.

Lack of Intrinsic GABAergic Connections in the Thalamic Reticular Nucleus of the Mouse.

PubMed

Hou, Guoqiang; Smith, Alison G; Zhang, Zhong-Wei

2016-07-06

It is generally thought that neurons in the thalamic reticular nucleus (TRN) form GABAergic synapses with other TRN neurons and that these interconnections are important for the function of the TRN. However, the existence of such intrinsic connections is controversial. We combine two complementary approaches to examine intrinsic GABAergic connections in the TRN of the mouse. We find that optogenetic stimulation of TRN neurons and their axons evokes GABAergic IPSCs in TRN neurons in mice younger than 2 weeks of age but fails to do so after that age. Blocking synaptic release from TRN neurons through conditional deletion of vesicular GABA transporter has no effect on spontaneous IPSCs recorded in TRN neurons aged 2 weeks or older while dramatically reducing GABAergic transmission in thalamic relay neurons. These results demonstrate that except for a short period after birth, the TRN of the mouse lacks intrinsic GABAergic connections. The thalamic reticular nucleus has a critical role in modulating information transfer from the thalamus to the cortex. It has been proposed that neurons in the thalamic reticular nucleus are interconnected through GABAergic synapses and that these connections serve important functions. Our results show that except for the first 2 weeks after birth, the thalamic reticular nucleus of the mouse lacks intrinsic GABAergic connections. Copyright © 2016 the authors 0270-6474/16/367246-07$15.00/0.

Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum

PubMed Central

Salib, Minas; Joshi, Abhilasha; Unal, Gunes; Berry, Naomi

2018-01-01

Rhythmic theta frequency (~5–12 Hz) oscillations coordinate neuronal synchrony and higher frequency oscillations across the cortex. Spatial navigation and context-dependent episodic memories are represented in several interconnected regions including the hippocampal and entorhinal cortices, but the cellular mechanisms for their dynamic coupling remain to be defined. Using monosynaptically-restricted retrograde viral tracing in mice, we identified a subcortical GABAergic input from the medial septum that terminated in the entorhinal cortex, with collaterals innervating the dorsal presubiculum. Extracellularly recording and labeling GABAergic entorhinal-projecting neurons in awake behaving mice show that these subcortical neurons, named orchid cells, fire in long rhythmic bursts during immobility and locomotion. Orchid cells discharge near the peak of hippocampal and entorhinal theta oscillations, couple to entorhinal gamma oscillations, and target subpopulations of extra-hippocampal GABAergic interneurons. Thus, orchid cells are a specialized source of rhythmic subcortical GABAergic modulation of ‘upstream’ and ‘downstream’ cortico-cortical circuits involved in mnemonic functions. PMID:29620525

Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum.

PubMed

Viney, Tim James; Salib, Minas; Joshi, Abhilasha; Unal, Gunes; Berry, Naomi; Somogyi, Peter

2018-04-05

Rhythmic theta frequency (~5-12 Hz) oscillations coordinate neuronal synchrony and higher frequency oscillations across the cortex. Spatial navigation and context-dependent episodic memories are represented in several interconnected regions including the hippocampal and entorhinal cortices, but the cellular mechanisms for their dynamic coupling remain to be defined. Using monosynaptically-restricted retrograde viral tracing in mice, we identified a subcortical GABAergic input from the medial septum that terminated in the entorhinal cortex, with collaterals innervating the dorsal presubiculum. Extracellularly recording and labeling GABAergic entorhinal-projecting neurons in awake behaving mice show that these subcortical neurons, named orchid cells, fire in long rhythmic bursts during immobility and locomotion. Orchid cells discharge near the peak of hippocampal and entorhinal theta oscillations, couple to entorhinal gamma oscillations, and target subpopulations of extra-hippocampal GABAergic interneurons. Thus, orchid cells are a specialized source of rhythmic subcortical GABAergic modulation of 'upstream' and 'downstream' cortico-cortical circuits involved in mnemonic functions. © 2018, Viney et al.

Nicotine recruits a local glutamatergic circuit to excite septohippocampal GABAergic neurons.

PubMed

Wu, Min; Hajszan, Tibor; Leranth, Csaba; Alreja, Meenakshi

2003-09-01

Tonic impulse flow in the septohippocampal GABAergic pathway is essential for normal cognitive functioning and is sustained, in part, by acetylcholine (ACh) that is released locally via axon collaterals of septohippocampal cholinergic neurons. Septohippocampal cholinergic neurons degenerate in Alzheimer's disease and other neurodegenerative disorders. While the importance of the muscarinic effects of ACh on septohippocampal GABAergic neurons is well recognized, the nicotinic effects of ACh remain unstudied despite the reported benefits of nicotine on cognitive functioning. In the present study, using electrophysiological recordings in a rat brain slice preparation, rapid applications of nicotine excited 90% of retrogradely labelled septohippocampal GABA-type neurons with an EC50 of 17 microm and increased the frequency of spontaneously occurring, impulse-dependent fast GABAergic and glutamatergic synaptic currents via the alpha4beta2-nicotinic receptor. Interestingly, tetrodotoxin blocked all effects of nicotine on septohippocampal GABAergic type neurons, suggesting involvement of indirect mechanisms. We demonstrate that the effects of nicotine on septohippocampal GABA-type neurons involve recruitment of a novel, local glutamatergic circuitry as (i). Group I metabotropic glutamatergic receptor antagonists reduced the effects of nicotine; (ii). the number of nicotine responsive neurons was significantly reduced in recordings from slices that had been trimmed so as to reduce the number of glutamate-containing neurons within the slice preparation; (iii). in light and ultrastructural double immunocytochemical labelling studies vesicular glutamate 2 transporter immunoreactive terminals made synaptic contacts with parvalbumin-immunoreactive septohippocampal GABAergic neurons. The discovery of a local glutamatergic circuit within the septum may provide another avenue for restoring septohippocampal GABAergic functions in neurodegenerative disorders associated with a loss

Altered GABAA receptor-mediated synaptic transmission disrupts the firing of gonadotropin-releasing hormone neurons in male mice under conditions that mimic steroid abuse

PubMed Central

Penatti, Carlos A A; Davis, Matthew C; Porter, Donna M; Henderson, Leslie P

2010-01-01

Gonadotropin–releasing hormone (GnRH) neurons are the central regulators of reproduction. GABAergic transmission plays a critical role in pubertal activation of pulsatile GnRH secretion. Self-administration of excessive doses of anabolic androgenic steroids (AAS) disrupts reproductive function and may have critical repercussions for pubertal onset in adolescent users. Here, we demonstrate that chronic treatment of adolescent male mice with the AAS, 17α-methyltestosterone (17αMT), significantly decreased action potential frequency in GnRH neurons, reduced the serum gonadotropin levels, and decreased testes mass. AAS treatment did not induce significant changes in GABAA receptor subunit mRNA levels or alter the amplitude or decay kinetics of GABAA receptor-mediated spontaneous postsynaptic currents (sPSC) or tonic currents in GnRH neurons. However, AAS treatment significantly increased action potential frequency in neighboring medial preoptic area (mPOA) neurons and GABAA receptor-mediated sPSC frequency in GnRH neurons. In addition, physical isolation of the more lateral aspects of the mPOA from the medially-localized GnRH neurons abrogated the AAS-induced increase in GABAA receptor-mediated sPSC frequency and the decrease in action potential firing in the GnRH cells. Our results indicate that AAS act predominantly on steroid-sensitive presynaptic neurons within the mPOA to impart significant increases in GABAA receptor-mediated inhibitory tone onto downstream GnRH neurons resulting in diminished activity of these pivotal mediators of reproductive function. These AAS-induced changes in central GABAergic circuits of the forebrain may significantly contribute to the disruptive actions of these drugs on pubertal maturation and the development of reproductive competence in male steroid abusers. PMID:20463213

Chronic Exposure to Anabolic Androgenic Steroids Alters Activity and Synaptic Function in Neuroendocrine Control Regions of the Female Mouse

PubMed Central

Penatti, Carlos A.A.; Oberlander, Joseph G.; Davis, Matthew C.; Porter, Donna M.; Henderson, Leslie P.

2011-01-01

Summary Disruption of reproductive function is a hallmark of abuse of anabolic androgenic steroids (AAS) in female subjects. To understand the central actions of AAS, patch clamp recordings were made in estrous, diestrous and AAS-treated mice from gonadotropin releasing hormone (GnRH) neurons, neurons in the medial preoptic area (mPOA) and neurons in the anteroventroperiventricular nucleus (AVPV); regions known to provide GABAergic and kisspeptin inputs to the GnRH cells. Action potential (AP) frequency was significantly higher in GnRH neurons of estrous mice than in AAS-treated or diestrous animals. No significant differences in AAS-treated, estrous or diestrous mice were evident in the amplitude or kinetics of spontaneous postsynaptic currents (sPCSs), miniature PSCs or tonic currents mediated by GABAA receptors or in GABAA receptor subunit expression in GnRH neurons. In contrast, the frequency of GABAA receptor-mediated sPSCs in GnRH neurons showed an inverse correlation with AP frequency across the three hormonal states. Surprisingly, AP activity in the medial preoptic area (mPOA), a likely source of GABAergic afferents to GnRH cells, did not vary in concert with the sPSCs in the GnRH neurons. Furthermore, pharmacological blockade of GABAA receptors did not alter the pattern in which there was lower AP frequency in GnRH neurons of AAS-treated and diestrous versus estrous mice. These data suggest that AAS do not impose their effects either directly on GnRH neurons or on putative GABAergic afferents in the mPOA. AP activity recorded from neurons in kisspeptin-rich regions of the anteroventroperiventricular nucleus (AVPV) and the expression of kisspeptin mRNA and peptide did vary coordinately with AP activity in GnRH neurons. Our data demonstrate that AAS treatment imposes a “diestrous-like” pattern of activity in GnRH neurons and suggest that this effect may arise from suppression of presynaptic kisspeptin-mediated excitatory drive arising from the AVPV. The

A GABAergic nigrotectal pathway for coordination of drinking behavior

PubMed Central

Rossi, Mark A.; Li, Haofang E.; Lu, Dongye; Kim, Il Hwan; Bartholomew, Ryan A.; Gaidis, Erin; Barter, Joseph W.; Kim, Namsoo; Cai, Min Tong; Soderling, Scott H.; Yin, Henry H.

2016-01-01

The contribution of basal ganglia outputs to consummatory behavior remains poorly understood. We recorded from the substantia nigra pars reticulata (SNR), the major basal ganglia output nucleus, during self-initiated drinking. The firing rates of many lateral SNR neurons were time-locked to individual licks. These neurons send GABAergic projections to the deep layers of the orofacial region of the lateral tectum (superior colliculus, SC). Many tectal neurons are also time-locked to licking, but their activity is usually antiphase to that of SNR neurons, suggesting inhibitory nigrotectal projections. We used optogenetics to selectively activate the GABAergic nigrotectal afferents in the deep layers of the SC. Photo-stimulation of the nigrotectal projections transiently inhibited the activity of the lick-related tectal neurons, disrupted their licking-related oscillatory pattern, and suppressed self-initiated drinking. These results demonstrate that GABAergic nigrotectal projections play a crucial role in coordinating drinking behavior. PMID:27043290

Fluoxetine disrupts motivation and GABAergic signaling in adolescent female hamsters.

PubMed

Shannonhouse, John L; DuBois, Dustin W; Fincher, Annette S; Vela, Alejandra M; Henry, Morgan M; Wellman, Paul J; Frye, Gerald D; Morgan, Caurnel

2016-08-01

Initial antidepressant treatment can paradoxically worsen symptoms in depressed adolescents by undetermined mechanisms. Interestingly, antidepressants modulate GABAA receptors, which mediate paradoxical effects of other therapeutic drugs, particularly in females. Although the neuroanatomic site of action for this paradox is unknown, elevated GABAA receptor signaling in the nucleus accumbens can disrupt motivation. We assessed fluoxetine's effects on motivated behaviors in pubescent female hamsters - anhedonia in the reward investigational preference (RIP) test as well as anxiety in the anxiety-related feeding/exploration conflict (AFEC) test. We also assessed accumbal signaling by RT-PCR and electrophysiology. Fluoxetine initially worsened motivated behaviors at puberty, relative to adulthood. It also failed to improve these behaviors as pubescent hamsters transitioned into adulthood. Low accumbal mRNA levels of multiple GABAA receptor subunits and GABA-synthesizing enzyme, GAD67, assessed by RT-PCR, suggested low GABAergic tone at puberty. Nonetheless, rapid fluoxetine-induced reductions of α5GABAA receptor and BDNF mRNA levels at puberty were consistent with age-related differences in GABAergic responses to fluoxetine and disruption of the motivational state. Whole-cell patch clamping of accumbal slices also suggested low GABAergic tone by the low amplitude of miniature inhibitory postsynaptic currents (mIPSCs) at puberty. It also confirmed age-related differences in GABAergic responses to fluoxetine. Specifically, fluoxetine potentiated mIPSC amplitude and frequency at puberty, but attenuated the amplitude during adulthood. These results implicate GABAergic tone and GABAA receptor plasticity in adverse motivational responses and resistance to fluoxetine during adolescence. Copyright © 2016 Elsevier Inc. All rights reserved.

Overexpression of the Steroidogenic Enzyme Cytochrome P450 Side Chain Cleavage in the Ventral Tegmental Area Increases 3α,5α-THP and Reduces Long-Term Operant Ethanol Self-Administration

PubMed Central

Cook, Jason B.; Werner, David F.; Maldonado-Devincci, Antoniette M.; Leonard, Maggie N.; Fisher, Kristen R.; O'Buckley, Todd K.; Porcu, Patrizia; McCown, Thomas J.; Besheer, Joyce; Hodge, Clyde W.

2014-01-01

Neuroactive steroids are endogenous neuromodulators capable of altering neuronal activity and behavior. In rodents, systemic administration of endogenous or synthetic neuroactive steroids reduces ethanol self-administration. We hypothesized this effect arises from actions within mesolimbic brain regions that we targeted by viral gene delivery. Cytochrome P450 side chain cleavage (P450scc) converts cholesterol to pregnenolone, the rate-limiting enzymatic reaction in neurosteroidogenesis. Therefore, we constructed a recombinant adeno-associated serotype 2 viral vector (rAAV2), which drives P450scc expression and neuroactive steroid synthesis. The P450scc-expressing vector (rAAV2-P450scc) or control GFP-expressing vector (rAAV2-GFP) were injected bilaterally into the ventral tegmental area (VTA) or nucleus accumbens (NAc) of alcohol preferring (P) rats trained to self-administer ethanol. P450scc overexpression in the VTA significantly reduced ethanol self-administration by 20% over the 3 week test period. P450scc overexpression in the NAc, however, did not alter ethanol self-administration. Locomotor activity was unaltered by vector administration to either region. P450scc overexpression produced a 36% increase in (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone)-positive cells in the VTA, but did not increase 3α,5α-THP immunoreactivity in NAc. These results suggest that P450scc overexpression and the resultant increase of 3α,5α-THP-positive cells in the VTA reduces ethanol reinforcement. 3α,5α-THP is localized to neurons in the VTA, including tyrosine hydroxylase neurons, but not astrocytes. Overall, the results demonstrate that using gene delivery to modulate neuroactive steroids shows promise for examining the neuronal mechanisms of moderate ethanol drinking, which could be extended to other behavioral paradigms and neuropsychiatric pathology. PMID:24760842

Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3α,5α-THP and reduces long-term operant ethanol self-administration.

PubMed

Cook, Jason B; Werner, David F; Maldonado-Devincci, Antoniette M; Leonard, Maggie N; Fisher, Kristen R; O'Buckley, Todd K; Porcu, Patrizia; McCown, Thomas J; Besheer, Joyce; Hodge, Clyde W; Morrow, A Leslie

2014-04-23

Neuroactive steroids are endogenous neuromodulators capable of altering neuronal activity and behavior. In rodents, systemic administration of endogenous or synthetic neuroactive steroids reduces ethanol self-administration. We hypothesized this effect arises from actions within mesolimbic brain regions that we targeted by viral gene delivery. Cytochrome P450 side chain cleavage (P450scc) converts cholesterol to pregnenolone, the rate-limiting enzymatic reaction in neurosteroidogenesis. Therefore, we constructed a recombinant adeno-associated serotype 2 viral vector (rAAV2), which drives P450scc expression and neuroactive steroid synthesis. The P450scc-expressing vector (rAAV2-P450scc) or control GFP-expressing vector (rAAV2-GFP) were injected bilaterally into the ventral tegmental area (VTA) or nucleus accumbens (NAc) of alcohol preferring (P) rats trained to self-administer ethanol. P450scc overexpression in the VTA significantly reduced ethanol self-administration by 20% over the 3 week test period. P450scc overexpression in the NAc, however, did not alter ethanol self-administration. Locomotor activity was unaltered by vector administration to either region. P450scc overexpression produced a 36% increase in (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone)-positive cells in the VTA, but did not increase 3α,5α-THP immunoreactivity in NAc. These results suggest that P450scc overexpression and the resultant increase of 3α,5α-THP-positive cells in the VTA reduces ethanol reinforcement. 3α,5α-THP is localized to neurons in the VTA, including tyrosine hydroxylase neurons, but not astrocytes. Overall, the results demonstrate that using gene delivery to modulate neuroactive steroids shows promise for examining the neuronal mechanisms of moderate ethanol drinking, which could be extended to other behavioral paradigms and neuropsychiatric pathology.

Emotions and Steroid Secretion in Aging Men: A Multi—Study Report

PubMed Central

Walther, Andreas; Waldvogel, Patricia; Noser, Emilou; Ruppen, Jessica; Ehlert, Ulrike

2017-01-01

Although aging increases the risk of cognitive and socioemotional deterioration, it has also been shown to be accompanied by an increase in experienced positive emotions and a decrease in negative emotions. Steroid hormones and age-related alterations in secretion patterns have been suggested to play a crucial role in these age-related changes in emotional experience. Importantly, previous studies identified effects of neuroactive hormones on age-related alterations in emotional experience, which vary by sex and depression levels. Therefore, in three independent cross-sectional studies including a total of 776 men, we examined age-related differences in emotional experience and subsequently the moderation effect of steroid hormones. Sample one consisted of 271 self-reporting healthy (SRH) men aged between 40 and 75 years, while sample two comprised 121 men in the identical age range but only including vitally exhausted (VE) men. Sample three included 384 men aged between 25 and 78 years who reported having fathered (FA) at least one child. For the SRH men, age was negatively associated with anxiety symptoms and aggression, while negative trends emerged for depressive symptoms. In VE men, age was negatively associated with depressive symptoms and positively associated with aggression and positive emotions. For FA men, anxiety symptoms and aggression were negatively associated with age. Age trends of steroid hormones and identified moderation effects are reported. However, with adjustment for multiple comparisons, most of the significant associations fade and the reported associations need to be regarded as exploratory starting points for the further investigation of age-related alterations in emotional experience and their relation to steroid secretion. Overall, the results indicate that salivary cortisol might be a moderator of the association between age and symptoms of anxiety for SRH and VE men, while salivary testosterone seems to moderate the association

Steroids

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... Staying Safe Videos for Educators Search English Español Steroids KidsHealth / For Kids / Steroids What's in this article? ... a good idea to avoid them. What Are Steroids? "Steroids" has more than one meaning. Your body ...

Cortical GABAergic neurons are more severely impaired by alkalosis than acidosis

PubMed Central

2013-01-01

Background Acid–base imbalance in various metabolic disturbances leads to human brain dysfunction. Compared with acidosis, the patients suffered from alkalosis demonstrate more severe neurological signs that are difficultly corrected. We hypothesize a causative process that the nerve cells in the brain are more vulnerable to alkalosis than acidosis. Methods The vulnerability of GABAergic neurons to alkalosis versus acidosis was compared by analyzing their functional changes in response to the extracellular high pH and low pH. The neuronal and synaptic functions were recorded by whole-cell recordings in the cortical slices. Results The elevation or attenuation of extracellular pH impaired these GABAergic neurons in terms of their capability to produce spikes, their responsiveness to excitatory synaptic inputs and their outputs via inhibitory synapses. Importantly, the dysfunction of these active properties appeared severer in alkalosis than acidosis. Conclusions The severer impairment of cortical GABAergic neurons in alkalosis patients leads to more critical neural excitotoxicity, so that alkalosis-induced brain dysfunction is difficultly corrected, compared to acidosis. The vulnerability of cortical GABAergic neurons to high pH is likely a basis of severe clinical outcomes in alkalosis versus acidosis. PMID:24314112

Septo-hippocampal GABAergic signaling across multiple modalities in awake mice.

PubMed

Kaifosh, Patrick; Lovett-Barron, Matthew; Turi, Gergely F; Reardon, Thomas R; Losonczy, Attila

2013-09-01

Hippocampal interneurons receive GABAergic input from the medial septum. Using two-photon Ca(2+) imaging of axonal boutons in hippocampal CA1 of behaving mice, we found that populations of septo-hippocampal GABAergic boutons were activated during locomotion and salient sensory events; sensory responses scaled with stimulus intensity and were abolished by anesthesia. We found similar activity patterns among boutons with common putative postsynaptic targets, with low-dimensional bouton population dynamics being driven primarily by presynaptic spiking.

Concentrating mixtures of neuroactive pharmaceuticals and altered neurotransmitter levels in the brain of fish exposed to a wastewater effluent.

PubMed

David, Arthur; Lange, Anke; Tyler, Charles R; Hill, Elizabeth M

2018-04-15

Fish can be exposed to a variety of neuroactive pharmaceuticals via the effluent discharges from wastewater treatment plants and concerns have arisen regarding their potential impacts on fish behaviour and ecology. In this study, we investigated the uptake of 14 neuroactive pharmaceuticals from a treated wastewater effluent into blood plasma and brain regions of roach (Rutilus rutilus) after exposure for 15days. We show that a complex mixture of pharmaceuticals including, 6 selective serotonin reuptake inhibitors, a serotonin-noradrenaline reuptake inhibitor, 3 atypical antipsychotics, 2 tricyclic antidepressants and a benzodiazepine, concentrate in different regions of the brain including the telencephalon, hypothalamus, optic tectum and hindbrain of effluent-exposed fish. Pharmaceuticals, with the exception of nordiazepam, were between 3-40 fold higher in brain compared with blood plasma, showing these neuroactive drugs are readily uptaken, into brain tissues in fish. To assess for the potential for any adverse ecotoxicological effects, the effect ratio was calculated from human therapeutic plasma concentrations (HtPCs) and the measured or predicted fish plasma concentrations of pharmaceuticals. After accounting for a safety factor of 1000, the effect ratios indicated that fluoxetine, norfluoxetine, sertraline, and amitriptyline warrant prioritisation for risk assessment studies. Furthermore, although plasma concentrations of all the pharmaceuticals were between 33 and 5714-fold below HtPCs, alterations in serotonin, glutamate, acetylcholine and tryptophan concentrations were observed in different brain regions of effluent-exposed fish. This study highlights the importance of determining the potential health effects arising from the concentration of complex environmental mixtures in risk assessment studies. Copyright © 2017 Elsevier B.V. All rights reserved.

The space where aging acts: focus on the GABAergic synapse.

PubMed

Rozycka, Aleksandra; Liguz-Lecznar, Monika

2017-08-01

As it was established that aging is not associated with massive neuronal loss, as was believed in the mid-20th Century, scientific interest has addressed the influence of aging on particular neuronal subpopulations and their synaptic contacts, which constitute the substrate for neural plasticity. Inhibitory neurons represent the most complex and diverse group of neurons, showing distinct molecular and physiological characteristics and possessing a compelling ability to control the physiology of neural circuits. This review focuses on the aging of GABAergic neurons and synapses. Understanding how aging affects synapses of particular neuronal subpopulations may help explain the heterogeneity of aging-related effects. We reviewed the literature concerning the effects of aging on the numbers of GABAergic neurons and synapses as well as aging-related alterations in their presynaptic and postsynaptic components. Finally, we discussed the influence of those changes on the plasticity of the GABAergic system, highlighting our results concerning aging in mouse somatosensory cortex and linking them to plasticity impairments and brain disorders. We posit that aging-induced impairments of the GABAergic system lead to an inhibitory/excitatory imbalance, thereby decreasing neuron's ability to respond with plastic changes to environmental and cellular challenges, leaving the brain more vulnerable to cognitive decline and damage by synaptopathic diseases. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Behavior-dependent activity patterns of GABAergic long-range projecting neurons in the rat hippocampus.

PubMed

Katona, Linda; Micklem, Ben; Borhegyi, Zsolt; Swiejkowski, Daniel A; Valenti, Ornella; Viney, Tim J; Kotzadimitriou, Dimitrios; Klausberger, Thomas; Somogyi, Peter

2017-04-01

Long-range glutamatergic and GABAergic projections participate in temporal coordination of neuronal activity in distributed cortical areas. In the hippocampus, GABAergic neurons project to the medial septum and retrohippocampal areas. Many GABAergic projection cells express somatostatin (SOM+) and, together with locally terminating SOM+ bistratified and O-LM cells, contribute to dendritic inhibition of pyramidal cells. We tested the hypothesis that diversity in SOM+ cells reflects temporal specialization during behavior using extracellular single cell recording and juxtacellular neurobiotin-labeling in freely moving rats. We have demonstrated that rare GABAergic projection neurons discharge rhythmically and are remarkably diverse. During sharp wave-ripples, most projection cells, including a novel SOM+ GABAergic back-projecting cell, increased their activity similar to bistratified cells, but unlike O-LM cells. During movement, most projection cells discharged along the descending slope of theta cycles, but some fired at the trough jointly with bistratified and O-LM cells. The specialization of hippocampal SOM+ projection neurons complements the action of local interneurons in differentially phasing inputs from the CA3 area to CA1 pyramidal cell dendrites during sleep and wakefulness. Our observations suggest that GABAergic projection cells mediate the behavior- and network state-dependent binding of neuronal assemblies amongst functionally-related brain regions by transmitting local rhythmic entrainment of neurons in CA1 to neuronal populations in other areas. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Behavior‐dependent activity patterns of GABAergic long‐range projecting neurons in the rat hippocampus

PubMed Central

Micklem, Ben; Borhegyi, Zsolt; Swiejkowski, Daniel A.; Valenti, Ornella; Viney, Tim J.; Kotzadimitriou, Dimitrios; Klausberger, Thomas

2017-01-01

ABSTRACT Long‐range glutamatergic and GABAergic projections participate in temporal coordination of neuronal activity in distributed cortical areas. In the hippocampus, GABAergic neurons project to the medial septum and retrohippocampal areas. Many GABAergic projection cells express somatostatin (SOM+) and, together with locally terminating SOM+ bistratified and O‐LM cells, contribute to dendritic inhibition of pyramidal cells. We tested the hypothesis that diversity in SOM+ cells reflects temporal specialization during behavior using extracellular single cell recording and juxtacellular neurobiotin‐labeling in freely moving rats. We have demonstrated that rare GABAergic projection neurons discharge rhythmically and are remarkably diverse. During sharp wave‐ripples, most projection cells, including a novel SOM+ GABAergic back‐projecting cell, increased their activity similar to bistratified cells, but unlike O‐LM cells. During movement, most projection cells discharged along the descending slope of theta cycles, but some fired at the trough jointly with bistratified and O‐LM cells. The specialization of hippocampal SOM+ projection neurons complements the action of local interneurons in differentially phasing inputs from the CA3 area to CA1 pyramidal cell dendrites during sleep and wakefulness. Our observations suggest that GABAergic projection cells mediate the behavior‐ and network state‐dependent binding of neuronal assemblies amongst functionally‐related brain regions by transmitting local rhythmic entrainment of neurons in CA1 to neuronal populations in other areas. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:27997999

GABAergic Inhibition in Visual Cortical Plasticity

PubMed Central

Sale, Alessandro; Berardi, Nicoletta; Spolidoro, Maria; Baroncelli, Laura; Maffei, Lamberto

2010-01-01

Experience is required for the shaping and refinement of developing neural circuits during well defined periods of early postnatal development called critical periods. Many studies in the visual cortex have shown that intracortical GABAergic circuitry plays a crucial role in defining the time course of the critical period for ocular dominance plasticity. With the end of the critical period, neural plasticity wanes and recovery from the effects of visual defects on visual acuity (amblyopia) or binocularity is much reduced or absent. Recent results pointed out that intracortical inhibition is a fundamental limiting factor for adult cortical plasticity and that its reduction by means of different pharmacological and environmental strategies makes it possible to greatly enhance plasticity in the adult visual cortex, promoting ocular dominance plasticity and recovery from amblyopia. Here we focus on the role of intracortical GABAergic circuitry in controlling both developmental and adult cortical plasticity. We shall also discuss the potential clinical application of these findings to neurological disorders in which synaptic plasticity is compromised because of excessive intracortical inhibition. PMID:20407586

Steroids

MedlinePlus

... or sometimes with chemotherapy. Steroids are used for short-term symptom control although they may occasionally be continued ... even in lymphoma steroids are not typically a long-term cure for this tumor. HOW ARE STEROIDS TAKEN? ...

Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons

EPA Science Inventory

Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons P Valdivia1, M Martin2, WR LeFew3, D Hall3, J Ross1, K Houck2 and TJ Shafer3 1Axion Biosystems, Atlanta GA and 2NCCT, 3ISTD, NHEERL, ORD, US EPA, RT...

Cracking Down on Inhibition: Selective Removal of GABAergic Interneurons from Hippocampal Networks

PubMed Central

Antonucci, Flavia; Alpár, Alán; Kacza, Johannes; Caleo, Matteo; Verderio, Claudia; Giani, Alice; Martens, Henrik; Chaudhry, Farrukh A.; Allegra, Manuela; Grosche, Jens; Michalski, Dominik; Erck, Christian; Hoffmann, Anke; Härtig, Wolfgang

2012-01-01

Inhibitory (GABAergic) interneurons entrain assemblies of excitatory principal neurons to orchestrate information processing in the hippocampus. Disrupting the dynamic recruitment as well as the temporally precise activity of interneurons in hippocampal circuitries can manifest in epileptiform seizures, and impact specific behavioral traits. Despite the importance of GABAergic interneurons during information encoding in the brain, experimental tools to selectively manipulate GABAergic neurotransmission are limited. Here, we report the selective elimination of GABAergic interneurons by a ribosome inactivation approach through delivery of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro as well as in the mouse and rat hippocampus in vivo. We demonstrate the selective loss of GABAergic—but not glutamatergic—synapses, reduced GABA release, and a shift in excitation/inhibition balance in mixed cultures of hippocampal neurons exposed to SAVAs. We also show the focal and indiscriminate loss of calbindin+, calretinin+, parvalbumin/system A transporter 1+, somatostatin+, vesicular glutamate transporter 3 (VGLUT3)/cholecystokinin/CB1 cannabinoid receptor+ and neuropeptide Y+ local-circuit interneurons upon SAVA microlesions to the CA1 subfield of the rodent hippocampus, with interneuron debris phagocytosed by infiltrating microglia. SAVA microlesions did not affect VGLUT1+ excitatory afferents. Yet SAVA-induced rearrangement of the hippocampal circuitry triggered network hyperexcitability associated with the progressive loss of CA1 pyramidal cells and the dispersion of dentate granule cells. Overall, our data identify SAVAs as an effective tool to eliminate GABAergic neurons from neuronal circuits underpinning high-order behaviors and cognition, and whose manipulation can recapitulate pathogenic cascades of epilepsy and other neuropsychiatric illnesses. PMID:22323713

Modulation of the GABAergic pathway for the treatment of fragile X syndrome.

PubMed

Lozano, Reymundo; Hare, Emma B; Hagerman, Randi J

2014-01-01

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further

Regulation of GABAergic Inputs to CA1 Pyramidal Neurons by Nicotinic Receptors and Kynurenic Acid

PubMed Central

Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Pereira, Edna F. R.

2012-01-01

Impaired α7 nicotinic acetylcholine receptor (nAChR) function and GABAergic transmission in the hippocampus and elevated brain levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway, are key features of schizophrenia. KYNA acts as a noncompetitive antagonist with respect to agonists at both α7 nAChRs and N-methyl-d-aspartate receptors. Here, we tested the hypothesis that in hippocampal slices tonically active α7 nAChRs control GABAergic transmission to CA1 pyramidal neurons and are sensitive to inhibition by rising levels of KYNA. The α7 nAChR-selective antagonist α-bungarotoxin (α-BGT; 100 nM) and methyllycaconitine (MLA; 10 nM), an antagonist at α7 and other nAChRs, reduced by 51.3 ± 1.3 and 65.2 ± 1.5%, respectively, the frequency of GABAergic postsynaptic currents (PSCs) recorded from CA1 pyramidal neurons. MLA had no effect on miniature GABAergic PSCs. Thus, GABAergic synaptic activity in CA1 pyramidal neurons is maintained, in part, by tonically active α7 nAChRs located on the preterminal region of axons and/or the somatodendritic region of interneurons that synapse onto the neurons under study. l-Kynurenine (20 or 200 μM) or KYNA (20–200 μM) suppressed concentration-dependently the frequency of GABAergic PSCs; the inhibitory effect of 20 μM l-kynurenine had an onset time of approximately 35 min and could not be detected in the presence of 100 nM α-BGT. These results suggest that KYNA levels generated from 20 μM kynurenine inhibit tonically active α7 nAChR-dependent GABAergic transmission to the pyramidal neurons. Disruption of nAChR-dependent GABAergic transmission by mildly elevated levels of KYNA can be an important determinant of the cognitive deficits presented by patients with schizophrenia. PMID:22344459

Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function

PubMed Central

Berryer, Martin H.; Chattopadhyaya, Bidisha; Xing, Paul; Riebe, Ilse; Bosoi, Ciprian; Sanon, Nathalie; Antoine-Bertrand, Judith; Lévesque, Maxime; Avoli, Massimo; Hamdan, Fadi F.; Carmant, Lionel; Lamarche-Vane, Nathalie; Lacaille, Jean-Claude; Michaud, Jacques L.; Di Cristo, Graziella

2016-01-01

Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice. Decrease of Syngap1 in mice has been previously shown to cause cognitive deficits at least in part by inducing alterations in glutamatergic neurotransmission and premature maturation of excitatory connections. Whether Syngap1 plays a role in the development of cortical GABAergic connectivity and function remains unclear. Here, we show that Syngap1 haploinsufficiency significantly reduces the formation of perisomatic innervations by parvalbumin-positive basket cells, a major population of GABAergic neurons, in a cell-autonomous manner. We further show that Syngap1 haploinsufficiency in GABAergic cells derived from the medial ganglionic eminence impairs their connectivity, reduces inhibitory synaptic activity and cortical gamma oscillation power, and causes cognitive deficits. Our results indicate that Syngap1 plays a critical role in GABAergic circuit function and further suggest that Syngap1 haploinsufficiency in GABAergic circuits may contribute to cognitive deficits. PMID:27827368

Regulation of the Hippocampal Network by VGLUT3-Positive CCK- GABAergic Basket Cells

PubMed Central

Fasano, Caroline; Rocchetti, Jill; Pietrajtis, Katarzyna; Zander, Johannes-Friedrich; Manseau, Frédéric; Sakae, Diana Y.; Marcus-Sells, Maya; Ramet, Lauriane; Morel, Lydie J.; Carrel, Damien; Dumas, Sylvie; Bolte, Susanne; Bernard, Véronique; Vigneault, Erika; Goutagny, Romain; Ahnert-Hilger, Gudrun; Giros, Bruno; Daumas, Stéphanie; Williams, Sylvain; El Mestikawy, Salah

2017-01-01

Hippocampal interneurons release the inhibitory transmitter GABA to regulate excitation, rhythm generation and synaptic plasticity. A subpopulation of GABAergic basket cells co-expresses the GABA/glycine vesicular transporters (VIAAT) and the atypical type III vesicular glutamate transporter (VGLUT3); therefore, these cells have the ability to signal with both GABA and glutamate. GABAergic transmission by basket cells has been extensively characterized but nothing is known about the functional implications of VGLUT3-dependent glutamate released by these cells. Here, using VGLUT3-null mice we observed that the loss of VGLUT3 results in a metaplastic shift in synaptic plasticity at Shaeffer’s collaterals – CA1 synapses and an altered theta oscillation. These changes were paralleled by the loss of a VGLUT3-dependent inhibition of GABAergic current in CA1 pyramidal layer. Therefore presynaptic type III metabotropic could be activated by glutamate released from VGLUT3-positive interneurons. This putative presynaptic heterologous feedback mechanism inhibits local GABAergic tone and regulates the hippocampal neuronal network. PMID:28559797

Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons.

PubMed

Tepper, James M; Wilson, Charles J; Koós, Tibor

2008-08-01

There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of

The Wnt receptor Ryk controls specification of GABAergic neurons versus oligodendrocytes during telencephalon development

PubMed Central

Zhong, Jingyang; Kim, Hyoung-Tai; Lyu, Jungmook; Yoshikawa, Kazuaki; Nakafuku, Masato; Lu, Wange

2011-01-01

GABAergic neurons and oligodendrocytes originate from progenitors within the ventral telencephalon. However, the molecular mechanisms that control neuron-glial cell-fate segregation, especially how extrinsic factors regulate cell-fate changes, are poorly understood. We have discovered that the Wnt receptor Ryk promotes GABAergic neuron production while repressing oligodendrocyte formation in the ventral telencephalon. We demonstrate that Ryk controls the cell-fate switch by negatively regulating expression of the intrinsic oligodendrogenic factor Olig2 while inducing expression of the interneuron fate determinant Dlx2. In addition, we demonstrate that Ryk is required for GABAergic neuron induction and oligodendrogenesis inhibition caused by Wnt3a stimulation. Furthermore, we showed that the cleaved intracellular domain of Ryk is sufficient to regulate the cell-fate switch by regulating the expression of intrinsic cell-fate determinants. These results identify Ryk as a multi-functional receptor that is able to transduce extrinsic cues into progenitor cells, promote GABAergic neuron formation, and inhibit oligodendrogenesis during ventral embryonic brain development. PMID:21205786

Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons

PubMed Central

Vong, Linh; Ye, Chianping; Yang, Zongfang; Choi, Brian; Chua, Streamson; Lowell, Bradford B.

2011-01-01

SUMMARY Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part due to incomplete knowledge regarding first order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first order neurons. While functionally relevant neurons have been identified, the observed effects have been small suggesting that most first order neurons remain unidentified. Here we take an alternative approach and test whether first order neurons are inhibitory (GABAergic, VGAT+) or excitatory (glutamatergic, VGLUT2+). Remarkably, the vast majority of leptin’s anti-obesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons likely mediates, at least in part, leptin’s anti-obesity effects. PMID:21745644

Cryopreservation of GABAergic Neuronal Precursors for Cell-Based Therapy

PubMed Central

2017-01-01

Cryopreservation protocols are essential for stem cells storage in order to apply them in the clinic. Here we describe a new standardized cryopreservation protocol for GABAergic neural precursors derived from the medial glanglionic eminence (MGE), a promising source of GABAergic neuronal progenitors for cell therapy against interneuron-related pathologies. We used 10% Me2SO as cryoprotectant and assessed the effects of cell culture amplification and cellular organization, as in toto explants, neurospheres, or individualized cells, on post-thaw cell viability and retrieval. We confirmed that in toto cryopreservation of MGE explants is an optimal preservation system to keep intact the interneuron precursor properties for cell transplantation, together with a high cell viability (>80%) and yield (>70%). Post-thaw proliferation and self-renewal of the cryopreserved precursors were tested in vitro. In addition, their migration capacity, acquisition of mature neuronal morphology, and potency to differentiate into multiple interneuron subtypes were also confirmed in vivo after transplantation. The results show that the cryopreserved precursor features remained intact and were similar to those immediately transplanted after their dissection from the MGE. We hope this protocol will facilitate the generation of biobanks to obtain a permanent and reliable source of GABAergic precursors for clinical application in cell-based therapies against interneuronopathies. PMID:28122047

Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP)-treated rats.

PubMed

Kjaerby, Celia; Broberg, Brian V; Kristiansen, Uffe; Dalby, Nils Ole

2014-09-01

A compromised γ-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-D-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmission in adulthood. The present study examines prefrontal GABAergic transmission in adult rats administered with the NMDA receptor channel blocker, phencyclidine (PCP), for 3 days during the second postnatal week. Whole-cell patch-clamp recordings from pyramidal cells in PCP-treated rats showed a 22% reduction in the frequency of miniature inhibitory postsynaptic currents in layer II/III, but not in layer V pyramidal neurons of the prefrontal cortex. Furthermore, early postnatal PCP treatment caused insensitivity toward effects of the GABA transporter 1 (GAT-1) inhibitor, 1,2,5,6-tetrahydro-1-[2-[[(diphenyl-methylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid, and also diminished currents passed by δ-subunit-containing GABAA receptors in layer II/III pyramidal neurons. The observed impairments in GABAergic function are compatible with the alteration of GABAergic markers as well as cognitive dysfunction observed in early postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Similar GABAergic inputs in dentate granule cells born during embryonic and adult neurogenesis.

PubMed

Laplagne, Diego A; Kamienkowski, Juan E; Espósito, M Soledad; Piatti, Verónica C; Zhao, Chunmei; Gage, Fred H; Schinder, Alejandro F

2007-05-01

Neurogenesis in the dentate gyrus of the hippocampus follows a unique temporal pattern that begins during embryonic development, peaks during the early postnatal stages and persists through adult life. We have recently shown that dentate granule cells born in early postnatal and adult mice acquire a remarkably similar afferent connectivity and firing behavior, suggesting that they constitute a homogeneous functional population [Laplagne et al. (2006)PLoS Biol., 4, e409]. Here we extend our previous study by comparing mature neurons born in the embryonic and adult hippocampus, with a focus on intrinsic membrane properties and gamma-aminobutyric acid (GABA)ergic synaptic inputs. For this purpose, dividing neuroblasts of the ventricular wall were retrovirally labeled with green fluorescent protein at embryonic day 15 (E15), and progenitor cells of the subgranular zone were labeled with red fluorescent protein in the same mice at postnatal day 42 (P42, adulthood). Electrophysiological properties of mature neurons born at either stage were then compared in the same brain slices. Evoked and spontaneous GABAergic postsynaptic responses of perisomatic and dendritic origin displayed similar characteristics in both neuronal populations. Miniature GABAergic inputs also showed similar functional properties and pharmacological profile. A comparative analysis of the present data with our previous observations rendered no significant differences among GABAergic inputs recorded from neurons born in the embryonic, early postnatal and adult mice. Yet, embryo-born neurons showed a reduced membrane excitability, suggesting a lower engagement in network activity. Our results demonstrate that granule cells of different age, location and degree of excitability receive GABAergic inputs of equivalent functional characteristics.

Hypothalamic GABAergic influences on treadmill exercise responses in rats.

PubMed

Overton, J M; Redding, M W; Yancey, S L; Stremel, R W

1994-01-01

Microinjection of GABAergic antagonists in the posterior hypothalamus (PH) produces exercise-like adjustments in cardiovascular function. To test the hypothesis that a hypothalamic GABAergic mechanism within the PH modulates the cardiovascular adjustments to dynamic exercise in conscious animals, Sprague-Dawley rats (n = 10) were instrumented with bilateral guide cannula directed at the pH, an arterial cannula, and Doppler flow probes on the iliac and mesenteric arteries. Saline (100 nl) or the GABAA receptor agonist muscimol (125 ng.100 nl-1) was bilaterally injected into the PH during treadmill exercise (20 m.min-1). Microinjection of saline had no effect on mean arterial pressure (MAP), heart rate (HR), mesenteric vascular resistance (MR), or iliac vascular resistance (IR) during exercise. Microinjection of muscimol during exercise produced no significant changes in MAP (mean change +/- SE; +0 +/- 1 mmHg), HR (+17 +/- 12 b.min-1), or MR (+7 +/- 13%). However, microinjection of muscimol produced a significant increase in IR during exercise (16 +/- 6%). In addition, muscimol significantly decreased treadmill run time (saline = 19.6 +/- 0.4 min; muscimol = 17.8 +/- 0.6 min) and produced behavioral effects (including mild sedation) that were most evident after exercise. The results of these experiments suggest that while the posterior hypothalamic GABAergic system may modulate iliac blood flow during exercise in rats, this system does not modulate HR and MR responses to dynamic exercise.

The Memory-Impairing Effects of Septal GABA Receptor Activation Involve GABAergic Septo-Hippocampal Projection Neurons

ERIC Educational Resources Information Center

Krebs-Kraft, Desiree L.; Wheeler, Marina G.; Parent, Marise B.

2007-01-01

Septal infusions of the [gamma]-aminobutyric acid (GABA)[subscript A] agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA[subscript A] receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are…

Alcohol Exposure During Late Adolescence Increases Drinking in Adult Wistar Rats, an Effect that is not Reduced by Finasteride

PubMed Central

Milivojevic, Verica; Covault, Jonathan

2013-01-01

Aims: We tested whether an exposure to alcohol in late adolescence, an age of rapid increase in neuroactive steroid precursors, would increase voluntary alcohol consumption in adult rats and whether this effect would be modulated by finasteride, an inhibitor of neuroactive steroid synthesis. Methods: In Experiment 1, we exposed male Wistar rats to 8% alcohol during the dark cycle for 1 week during late adolescence [postnatal days (PNDs) 51–58], and then measured voluntary alcohol consumption 1 month later in adulthood (PNDs 91–104). In Experiment 2, finasteride was administered during the forced alcohol exposure in late adolescence and, in Experiment 3, during voluntary alcohol consumption in adulthood. Plasma was collected at the end of each finasteride treatment to confirm the reduction of plasma neuroactive steroid levels. Results: We found that a daily 12-h exposure to alcohol for 7 days in late adolescence significantly increased voluntary alcohol consumption (4-fold) a month later during adulthood. Finasteride administration in late adolescence increased group alcohol intake in late adolescence but did not block the effect of adolescent alcohol exposure on increasing alcohol preference in adulthood. There was no effect of finasteride treatment in adulthood on alcohol preference. Conclusions: A daily 12-h exposure to alcohol for 7 days in late adolescence was sufficient to induce chronically increased alcohol preference in adulthood, indicating that this age may be sensitive to the effects of alcohol. PMID:22997410

Anesthetic effects changeable in habitual drinkers: Mechanistic drug interactions with neuro-active indoleamine-aldehyde condensation products associated with alcoholic beverage consumption.

PubMed

Tsuchiya, Hironori

2016-07-01

Clinicians often experience the reduced efficacy of general and local anesthetics and anesthesia-related drugs in habitual drinkers and chronic alcoholics. However, the mechanistic background underlying such anesthetic tolerance remains unclear. Biogenic indoleamines condense with alcohol-derived aldehydes during fermentation processes and under physiological conditions to produce neuro-active tetrahydro-β-carbolines and β-carbolines, many of which are contained not only in various alcoholic beverages but also in human tissues and body fluids. These indoleamine-aldehyde condensation products are increased in the human body because of their exogenous and endogenous supply enhanced by alcoholic beverage consumption. Since tetrahydro-β-carbolines and β-carbolines target receptors, ion channels and neuronal membranes which are common to anesthetic agents, we propose a hypothesis that they may pharmacodynamically interact at GABAA receptors, NMDA receptors, voltage-gated Na(+) channels and membrane lipid bilayers to attenuate anesthetics-induced positive allosteric GABAA receptor modulation, NMDA receptor antagonism, ion channel blockade and neuronal membrane modification, thereby affecting anesthetic efficacy. The condensation products may also cooperatively interact with ethanol that induces adaptive changes and cross-tolerance to anesthetics and with dopamine-aldehyde adducts that act on GABAA receptors and membrane lipids. Because tetrahydro-β-carbolines and β-carbolines are metabolized to lose or decrease their neuro-activities, induction of the relevant enzymes by habitual drinking could produce an inter-individual difference of drinkers in susceptibility to anesthetic agents. The present hypothesis would also provide a unified framework for different modes of anesthetic action, which are inhibited by neuro-active indoleamine-aldehyde condensation products associated with alcoholic beverage consumption. Copyright © 2016 Elsevier Ltd. All rights reserved.

Steroidal Saponins

NASA Astrophysics Data System (ADS)

Sahu, N. P.; Banerjee, S.; Mondal, N. B.; Mandal, D.

The medicinal activities of plants are generally due to the secondary metabolites (1) which often occur as glycosides of steroids, terpenoids, phenols etc. Saponins are a group of naturally occurring plant glycosides, characterized by their strong foam-forming properties in aqueous solution. The cardiac glycosides also possess this, property but are classified separately because of their specific biological activity. Unlike the cardiac glycosides, saponins generally do not affect the heart. These are classified as steroid or triterpenoid saponins depending on the nature of the aglycone. Steroidal glycosides are naturally occurring sugar conjugates of C27 steroidal compounds. The aglycone of a steroid saponin is usually a spirostanol or a furostanol. The glycone parts of these compounds are mostly oligosaccharides, arranged either in a linear or branched fashion, attached to hydroxyl groups through an acetal linkage (2, 3). Another class of saponins, the basic steroid saponins, contain nitrogen analogues of steroid sapogenins as aglycones.

Deficient GABAergic gliotransmission may cause broader sensory tuning in schizophrenia.

PubMed

Hoshino, Osamu

2013-12-01

We examined how the depression of intracortical inhibition due to a reduction in ambient GABA concentration impairs perceptual information processing in schizophrenia. A neural network model with a gliotransmission-mediated ambient GABA regulatory mechanism was simulated. In the network, interneuron-to-glial-cell and principal-cell-to-glial-cell synaptic contacts were made. The former hyperpolarized glial cells and let their transporters import (remove) GABA from the extracellular space, thereby lowering ambient GABA concentration, reducing extrasynaptic GABAa receptor-mediated tonic inhibitory current, and thus exciting principal cells. In contrast, the latter depolarized the glial cells and let the transporters export GABA into the extracellular space, thereby elevating the ambient GABA concentration and thus inhibiting the principal cells. A reduction in ambient GABA concentration was assumed for a schizophrenia network. Multiple dynamic cell assemblies were organized as sensory feature columns. Each cell assembly responded to one specific feature stimulus. The tuning performance of the network to an applied feature stimulus was evaluated in relation to the level of ambient GABA. Transporter-deficient glial cells caused a deficit in GABAergic gliotransmission and reduced ambient GABA concentration, which markedly deteriorated the tuning performance of the network, broadening the sensory tuning. Interestingly, the GABAergic gliotransmission mechanism could regulate local ambient GABA levels: it augmented ambient GABA around stimulus-irrelevant principal cells, while reducing ambient GABA around stimulus-relevant principal cells, thereby ensuring their selective responsiveness to the applied stimulus. We suggest that a deficit in GABAergic gliotransmission may cause a reduction in ambient GABA concentration, leading to a broadening of sensory tuning in schizophrenia. The GABAergic gliotransmission mechanism proposed here may have an important role in the

Interactions between ethanol and the endocannabinoid system at GABAergic synapses on basolateral amygdala principal neurons

PubMed Central

Talani, Giuseppe; Lovinger, David M.

2015-01-01

The basolateral amygdala (BLA) plays crucial roles in stimulus value coding, as well as drug and alcohol dependence. Ethanol alters synaptic transmission in the BLA, while endocannabinoids (eCBs) produce presynaptic depression at BLA synapses. Recent studies suggest interactions between ethanol and eCBs that have important consequences for alcohol drinking behavior. To determine how ethanol and eCBs interact in the BLA, we examined the physiology and pharmacology of GABAergic synapses onto BLA pyramidal neurons in neurons from young rats. Application of ethanol at concentrations relevant to intoxication increased, in both young and adult animals, the frequency of spontaneous and miniature GABAergic inhibitory postsynaptic currents, indicating a presynaptic site of ethanol action. The potentiation by ethanol was prevented by inhibition by adenylyl cyclase, and reduced by inhibition by protein kinase A. Activation of type 1 cannabinoid receptors (CB1) in the BLA inhibited GABAergic transmission via an apparent presynaptic mechanism, and prevented ethanol potentiation. Surprisingly, ethanol potentiation was also prevented by CB1 antagonists/inverse agonists. Brief depolarization of BLA pyramidal neurons suppressed GABAergic transmission (depolarization-induced suppression of inhibition [DSI]), an effect previously shown to be mediated by postsynaptic eCB release and presynaptic CB1 activation. A CB1-mediated suppression of GABAergic transmission was also produced by combined afferent stimulation at 0.1 Hz (LFS), and postsynaptic loading with the eCB arachidonoyl ethanolamide (AEA). Both DSI and LFS-induced synaptic depression were prevented by ethanol. Our findings indicate antagonistic interactions between ethanol and eCB/CB1 modulation at GABAergic BLA synapses that may contribute to eCB roles in ethanol seeking and drinking. PMID:26603632

Whole-Brain Mapping of Direct Inputs to and Axonal Projections from GABAergic Neurons in the Parafacial Zone.

PubMed

Su, Yun-Ting; Gu, Meng-Yang; Chu, Xi; Feng, Xiang; Yu, Yan-Qin

2018-06-01

The GABAergic neurons in the parafacial zone (PZ) play an important role in sleep-wake regulation and have been identified as part of a sleep-promoting center in the brainstem, but the long-range connections mediating this function remain poorly characterized. Here, we performed whole-brain mapping of both the inputs and outputs of the GABAergic neurons in the PZ of the mouse brain. We used the modified rabies virus EnvA-ΔG-DsRed combined with a Cre/loxP gene-expression strategy to map the direct monosynaptic inputs to the GABAergic neurons in the PZ, and found that they receive inputs mainly from the hypothalamic area, zona incerta, and parasubthalamic nucleus in the hypothalamus; the substantia nigra, pars reticulata and deep mesencephalic nucleus in the midbrain; and the intermediate reticular nucleus and medial vestibular nucleus (parvocellular part) in the pons and medulla. We also mapped the axonal projections of the PZ GABAergic neurons with adeno-associated virus, and defined the reciprocal connections of the PZ GABAergic neurons with their input and output nuclei. The newly-found inputs and outputs of the PZ were also listed compared with the literature. This cell-type-specific neuronal whole-brain mapping of the PZ GABAergic neurons may reveal the circuits underlying various functions such as sleep-wake regulation.

Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli.

PubMed

Navarro, Montserrat; Olney, Jeffrey J; Burnham, Nathan W; Mazzone, Christopher M; Lowery-Gionta, Emily G; Pleil, Kristen E; Kash, Thomas L; Thiele, Todd E

2016-05-01

It was recently reported that activation of a subset of lateral hypothalamus (LH) GABAergic neurons induced both appetitive (food-seeking) and consummatory (eating) behaviors in vGat-ires-cre mice, while inhibition or deletion of GABAergic neurons blunted these behaviors. As food and caloric-dense liquid solutions were used, the data reported suggest that these LH GABAergic neurons may modulate behaviors that function to maintain homeostatic caloric balance. Here we report that chemogenetic activation of this GABAergic population in vGat-ires-cre mice increased consummatory behavior directed at any available stimulus, including those entailing calories (food, sucrose, and ethanol), those that do not (saccharin and water), and those lacking biological relevance (wood). Chemogenetic inhibition of these neurons attenuated consummatory behaviors. These data indicate that LH GABAergic neurons modulate consummatory behaviors regardless of the caloric content or biological relevance of the consumed stimuli.

Steroid osteopathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Conway, J.J.; Weiss, S.C.

1984-01-01

Patients receiving steroids or having disease processes which increase natural steroid production often demonstrate ''the classic x-ray changes'' of avascular necrosis of bone. Bone scintigraphy in these patients most frequently demonstrates an increased radionuclide localization. The literature suggests that the increased activity is related to healing of the avascular process. In a recent study of Legg-Calve-Perthes Disease (LCPD), 37 of the children had multiple studies and increased activity within the epiphysis during revascularization was extremely rare. Not only are the scintigraphic findings in steroid osteopathy dissimilar to that in healing LCPD, but the time interval for healing is much tomore » short for that of a vascular necrosis and no patients demonstrated an avascular phase on bone scintigraphy. Of 15 children with renal transplants on steroid therapy, 9 demonstrated x-ray and clinical findings of osteopathy. In 8 of 9 instances, bone scintigraphy showed increased localization of radionuclide in the affected bone. Improvement or a return to normal occurred in those patients in whom steroids were discontinued. The following is a proposed mechanism for steroid osteopathy. Steroids affect the osteoblastic and osteoclastic activity of bone and weaken its internal structure. Ordinary stress produces microtrabecular fractures. Fractures characteristically stimulate reactive hyperemia and increase bone metabolism. The result is increased bone radiopharmaceutical localization. The importance of recognizing this concept is that steroid osteopathy is preventable by reducing the administered steroid dose. As opposed to avascular necrosis, bone changes are reversible.« less

Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy.

PubMed

Llansola, Marta; Montoliu, Carmina; Agusti, Ana; Hernandez-Rabaza, Vicente; Cabrera-Pastor, Andrea; Gomez-Gimenez, Belen; Malaguarnera, Michele; Dadsetan, Sherry; Belghiti, Majedeline; Garcia-Garcia, Raquel; Balzano, Tiziano; Taoro, Lucas; Felipo, Vicente

2015-09-01

The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia-thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy. Copyright © 2014 Elsevier Ltd. All rights reserved.

A single-run liquid chromatography mass spectrometry method to quantify neuroactive kynurenine pathway metabolites in rat plasma.

PubMed

Orsatti, Laura; Speziale, Roberto; Orsale, Maria Vittoria; Caretti, Fulvia; Veneziano, Maria; Zini, Matteo; Monteagudo, Edith; Lyons, Kathryn; Beconi, Maria; Chan, Kelvin; Herbst, Todd; Toledo-Sherman, Leticia; Munoz-Sanjuan, Ignacio; Bonelli, Fabio; Dominguez, Celia

2015-03-25

Neuroactive metabolites in the kynurenine pathway of tryptophan catabolism are associated with neurodegenerative disorders. Tryptophan is transported across the blood-brain barrier and converted via the kynurenine pathway to N-formyl-L-kynurenine, which is further degraded to L-kynurenine. This metabolite can then generate a group of metabolites called kynurenines, most of which have neuroactive properties. The association of tryptophan catabolic pathway alterations with various central nervous system (CNS) pathologies has raised interest in analytical methods to accurately quantify kynurenines in body fluids. We here describe a rapid and sensitive reverse-phase HPLC-MS/MS method to quantify L-kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxy-L-kynurenine (3HK) and anthranilic acid (AA) in rat plasma. Our goal was to quantify these metabolites in a single run; given their different physico-chemical properties, major efforts were devoted to develop a chromatography suitable for all metabolites that involves plasma protein precipitation with acetonitrile followed by chromatographic separation by C18 RP chromatography, detected by electrospray mass spectrometry. Quantitation range was 0.098-100 ng/ml for 3HK, 9.8-20,000 ng/ml for KYN, 0.49-1000 ng/ml for KYNA and AA. The method was linear (r>0.9963) and validation parameters were within acceptance range (calibration standards and QC accuracy within ±30%). Copyright © 2015 Elsevier B.V. All rights reserved.

Organization of GABAergic synaptic circuits in the rat ventral tegmental area.

PubMed

Ciccarelli, Alessandro; Calza, Arianna; Panzanelli, Patrizia; Concas, Alessandra; Giustetto, Maurizio; Sassoè-Pognetto, Marco

2012-01-01

The ventral tegmental area (VTA) is widely implicated in drug addiction and other psychiatric disorders. This brain region is densely populated by dopaminergic (DA) neurons and also contains a sparse population of γ-aminobutyric acid (GABA)ergic cells that regulate the activity of the principal neurons. Therefore, an in-depth knowledge of the organization of VTA GABAergic circuits and of the plasticity induced by drug consumption is essential for understanding the mechanisms by which drugs induce stable changes in brain reward circuits. Using immunohistochemistry, we provide a detailed description of the localization of major GABA(A) and GABA(B) receptor subunits in the rat VTA. We show that DA and GABAergic cells express both GABA(A) and GABA(B) receptors. However VTA neurons differ considerably in the expression of GABA(A) receptor subunits, as the α1 subunit is associated predominantly with non-DA cells, whereas the α3 subunit is present at low levels in both types of VTA neurons. Using an unbiased stereological method, we then demonstrate that α1-positive elements represent only a fraction of non-DA neurons and that the ratio of DA and non-DA cells is quite variable throughout the rostro-caudal extent of the VTA. Interestingly, DA and non-DA cells receive a similar density of perisomatic synapses, whereas axo-dendritic synapses are significantly more abundant in non-DA cells, indicating that local interneurons receive prominent GABAergic inhibition. These findings reveal a differential expression of GABA receptor subtypes in the two major categories of VTA neurons and provide an anatomical basis for interpreting the plasticity of inhibitory circuits induced by drug exposure.

New insights into the classification and nomenclature of cortical GABAergic interneurons.

PubMed

DeFelipe, Javier; López-Cruz, Pedro L; Benavides-Piccione, Ruth; Bielza, Concha; Larrañaga, Pedro; Anderson, Stewart; Burkhalter, Andreas; Cauli, Bruno; Fairén, Alfonso; Feldmeyer, Dirk; Fishell, Gord; Fitzpatrick, David; Freund, Tamás F; González-Burgos, Guillermo; Hestrin, Shaul; Hill, Sean; Hof, Patrick R; Huang, Josh; Jones, Edward G; Kawaguchi, Yasuo; Kisvárday, Zoltán; Kubota, Yoshiyuki; Lewis, David A; Marín, Oscar; Markram, Henry; McBain, Chris J; Meyer, Hanno S; Monyer, Hannah; Nelson, Sacha B; Rockland, Kathleen; Rossier, Jean; Rubenstein, John L R; Rudy, Bernardo; Scanziani, Massimo; Shepherd, Gordon M; Sherwood, Chet C; Staiger, Jochen F; Tamás, Gábor; Thomson, Alex; Wang, Yun; Yuste, Rafael; Ascoli, Giorgio A

2013-03-01

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus.

GABAergic Neurons of the Central Amygdala Promote Cataplexy

PubMed Central

Agostinelli, Lindsay J.; Lowell, Bradford B.

2017-01-01

Narcolepsy is characterized by chronic sleepiness and cataplexy—sudden muscle paralysis triggered by strong, positive emotions. This condition is caused by a lack of orexin (hypocretin) signaling, but little is known about the neural mechanisms that mediate cataplexy. The amygdala regulates responses to rewarding stimuli and contains neurons active during cataplexy. In addition, lesions of the amygdala reduce cataplexy. Because GABAergic neurons of the central nucleus of the amygdala (CeA) target brainstem regions known to regulate muscle tone, we hypothesized that these cells promote emotion-triggered cataplexy. We injected adeno-associated viral vectors coding for Cre-dependent DREADDs or a control vector into the CeA of orexin knock-out mice crossed with vGAT-Cre mice, resulting in selective expression of the excitatory hM3 receptor or the inhibitory hM4 receptor in GABAergic neurons of the CeA. We measured sleep/wake behavior and cataplexy after injection of saline or the hM3/hM4 ligand clozapine-N-oxide (CNO) under baseline conditions and under conditions that should elicit positive emotions. In mice expressing hM3, CNO approximately doubled the amount of cataplexy in the first 3 h after dosing under baseline conditions. Rewarding stimuli (chocolate or running wheels) also increased cataplexy, but CNO produced no further increase. In mice expressing hM4, CNO reduced cataplexy in the presence of chocolate or running wheels. These results demonstrate that GABAergic neurons of the CeA are sufficient and necessary for the production of cataplexy in mice, and they likely are a key part of the mechanism through which positive emotions trigger cataplexy. SIGNIFICANCE STATEMENT Cataplexy is one of the major symptoms of narcolepsy, but little is known about how strong, positive emotions trigger these episodes of muscle paralysis. Prior research shows that amygdala neurons are active during cataplexy and cataplexy is reduced by lesions of the amygdala. We found that

GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility.

PubMed

Judson, Matthew C; Wallace, Michael L; Sidorov, Michael S; Burette, Alain C; Gu, Bin; van Woerden, Geeske M; King, Ian F; Han, Ji Eun; Zylka, Mark J; Elgersma, Ype; Weinberg, Richard J; Philpot, Benjamin D

2016-04-06

Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS. Copyright © 2016 Elsevier Inc. All rights reserved.

GABAergic neuron-specific loss of Ube3a causes Angelman syndrome-like EEG abnormalities and enhances seizure susceptibility

PubMed Central

Judson, Matthew C.; Wallace, Michael L.; Sidorov, Michael S.; Burette, Alain C.; Gu, Bin; van Woerden, Geeske M.; King, Ian F.; Han, Ji Eun; Zylka, Mark J.; Elgersma, Ype; Weinberg, Richard J.; Philpot, Benjamin D.

2016-01-01

SUMMARY Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs) – all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS. PMID:27021170

Simultaneous quantification of neuroactive dopamine serotonin and kynurenine pathway metabolites in gender-specific youth urine by ultra performance liquid chromatography tandem high resolution mass spectrometry.

PubMed

Lu, Haihua; Yu, Jing; Wang, Jun; Wu, Linlin; Xiao, Hang; Gao, Rong

2016-04-15

Neuroactive metabolites in dopamine, serotonin and kynurenine metabolic pathways play key roles in several physiological processes and their imbalances have been implicated in the pathophysiology of a wide range of disorders. The association of these metabolites' alterations with various pathologies has raised interest in analytical methods for accurate quantification in biological fluids. However, simultaneous measurement of various neuroactive metabolites represents great challenges due to their trace level, high polarity and instability. In this study, an analytical method was developed and validated for accurately quantifying 12 neuroactive metabolites covering three metabolic pathways in youth urine by ultra performance liquid chromatography coupled to electrospray tandem high resolution mass spectrometry (UPLC-ESI-HRMS/MS). The strategy of dansyl chloride derivatization followed by solid phase extraction on C18 cartridges were employed to reduce matrix interference and improve the extraction efficiency. The reverse phase chromatographic separation was achieved with a gradient elution program in 20 min. The high resolution mass spectrometer (Q Exactive) was employed, with confirmation and quantification by Target-MS/MS scan mode. Youth urine samples collected from 100 healthy volunteers (Female:Male=1:1) were analyzed to explore the differences in metabolite profile and their turnover between genders. The results demonstrated that the UPLC-ESI-HRMS/MS method is sensitive and robust, suitable for monitoring a large panel of metabolites and for discovering new biomarkers in the medical fields. Copyright © 2016 Elsevier B.V. All rights reserved.

Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats

PubMed Central

Nagaya, Naomi; Acca, Gillian M.; Maren, Stephen

2015-01-01

Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry. PMID:26300750

Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats.

PubMed

Nagaya, Naomi; Acca, Gillian M; Maren, Stephen

2015-01-01

Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry.

Spatio-temporal specialization of GABAergic septo-hippocampal neurons for rhythmic network activity.

PubMed

Unal, Gunes; Crump, Michael G; Viney, Tim J; Éltes, Tímea; Katona, Linda; Klausberger, Thomas; Somogyi, Peter

2018-03-03

Medial septal GABAergic neurons of the basal forebrain innervate the hippocampus and related cortical areas, contributing to the coordination of network activity, such as theta oscillations and sharp wave-ripple events, via a preferential innervation of GABAergic interneurons. Individual medial septal neurons display diverse activity patterns, which may be related to their termination in different cortical areas and/or to the different types of innervated interneurons. To test these hypotheses, we extracellularly recorded and juxtacellularly labeled single medial septal neurons in anesthetized rats in vivo during hippocampal theta and ripple oscillations, traced their axons to distant cortical target areas, and analyzed their postsynaptic interneurons. Medial septal GABAergic neurons exhibiting different hippocampal theta phase preferences and/or sharp wave-ripple related activity terminated in restricted hippocampal regions, and selectively targeted a limited number of interneuron types, as established on the basis of molecular markers. We demonstrate the preferential innervation of bistratified cells in CA1 and of basket cells in CA3 by individual axons. One group of septal neurons was suppressed during sharp wave-ripples, maintained their firing rate across theta and non-theta network states and mainly fired along the descending phase of CA1 theta oscillations. In contrast, neurons that were active during sharp wave-ripples increased their firing significantly during "theta" compared to "non-theta" states, with most firing during the ascending phase of theta oscillations. These results demonstrate that specialized septal GABAergic neurons contribute to the coordination of network activity through parallel, target area- and cell type-selective projections to the hippocampus.

The role of spinal GABAergic circuits in the control of phrenic nerve motor output

PubMed Central

Ghali, Michael G. Z.; Rogers, Robert F.

2015-01-01

While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti-GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus. The number of GAD65/67-positive cells was drastically reduced on the side of siRNA microinjections, especially in the lateral aspects of Rexed's laminae VII and IX in the ventral horn of cervical segment C4, but not contralateral to microinjections. We hypothesize that intraspinal GABAergic control of phrenic output is primarily phasic, but also plays an important role in tonic regulation of phrenic discharge. Also, we identified respiration-modulated GABAergic interneurons (both inspiratory and expiratory) located slightly dorsal to the phrenic nucleus. Our data provide the first direct evidence for the existence of intraspinal GABAergic circuits contributing to the formation of phrenic output. The physiological role of local intraspinal inhibition, independent of descending direct bulbospinal control, is discussed. PMID:25833937

Synaptic plasticity in glutamatergic and GABAergic neurotransmission following chronic memantine treatment in an in vitro model of limbic epileptogenesis

PubMed Central

He, Shuijin; Bausch, Suzanne B.

2013-01-01

Chronic N-methyl-D-aspartate receptor (NMDAR) blockade with high affinity competitive and uncompetitive antagonists can lead to seizure exacerbation, presumably due to an imbalance in glutamatergic and GABAergic transmission. Acute administration of the moderate affinity NMDAR antagonist memantine in vivo has been associated with pro- and anticonvulsive properties. Chronic treatment with memantine can exacerbate seizures. Therefore, we hypothesized that chronic memantine treatment would increase glutamatergic and decrease GABAergic transmission, similar to high affinity competitive and uncompetitive antagonists. To test this hypothesis, organotypic hippocampal slice culture were treated for 17–21 days with memantine and then subjected to electrophysiological recordings. Whole-cell recordings from dentate granule cells revealed that chronic memantine treatment slightly, but significantly increased sEPSC frequency, mEPSC amplitude and mEPSC charge transfer, consistent with minimally increased glutamatergic transmission. Chronic memantine treatment also increased both sIPSC and mIPSC frequency and amplitude, suggestive of increased GABAergic transmission. Results suggest that a simple imbalance between glutamatergic and GABAergic neurotransmission may not underlie memantine’s ictogenic properties. That said, glutamatergic and GABAergic transmission were assayed independently of one another in the current study. More complex interactions between glutamatergic and GABAergic transmission may prevail under conditions of intact circuitry. PMID:24184417

Adolescent Steroid Use.

ERIC Educational Resources Information Center

Office of Inspector General (DHHS), Washington, DC.

The study focused on non-medical steroid use by adolescents according to data obtained from the National Institute on Drug Abuse, professional literature, 30 key informants knowledgeable in steroid issues, and 72 current or former steroid users. The findings indicated: (1) over 250,000 adolescents, primarily males, used or have used steroids, and…

Nucleus accumbens GABAergic inhibition generates intense eating and fear that resists environmental retuning and needs no dopamine

PubMed Central

Richard, Jocelyn M.; Plawecki, Andrea M.; Berridge, Kent C.

2013-01-01

Intense fearful behavior and/or intense appetitive eating behavior can be generated by localized amino acid inhibitions along a rostrocaudal anatomical gradient within medial shell of nucleus accumbens of the rat. This can be produced by microinjections in medial shell of either the GABAA agonist muscimol (mimicking intrinsic GABAergic inputs) or the AMPA antagonist DNQX (disrupting corticolimbic glutamate inputs). At rostral sites in medial shell, each drug robustly stimulates appetitive eating and food intake, whereas at more caudal sites the same drugs instead produce increasingly fearful behaviors such as escape, distress vocalizations, and defensive treading (an antipredator behavior rodents emit to snakes and scorpions). Previously we showed that intense motivated behaviors generated by glutamate blockade require local endogenous dopamine and can be modulated in valence by environmental ambience. Here we investigated whether GABAergic generation of intense appetitive and fearful motivations similarly depends on local dopamine signals, and whether the valence of motivations generated by GABAergic inhibition can also be retuned by changes in environmental ambience. We report that the answer to both questions is ‘no’. Eating and fear generated by GABAergic inhibition of accumbens shell does not need endogenous dopamine. Also, the appetitive/fearful valence generated by GABAergic muscimol microinjections resists environmental retuning and is determined almost purely by rostrocaudal anatomical placement. These results suggest that NAc GABAergic release of fear and eating are relatively independent of modulatory dopamine signals, and more anatomically pre-determined in valence balance than release of the same intense behaviors by glutamate disruptions. PMID:23551138

GABAergic neurons in nucleus accumbens are correlated to resilience and vulnerability to chronic stress for major depression

PubMed Central

Cui, Shan; Wang, Jin-Hui

2017-01-01

Background Major depression, persistent low mood, is one of common psychiatric diseases. Chronic stressful life is believed to be a major risk factor that leads to dysfunctions of the limbic system. However, a large number of the individuals with experiencing chronic stress do not suffer from major depression, called as resilience. Endogenous mechanisms underlying neuronal invulnerability to chronic stress versus major depression are largely unknown. As GABAergic neurons are vulnerable to chronic stress and their impairments is associated with major depression, we have examined whether the invulnerability of GABAergic neurons in the limbic system is involved in resilience. Results GABAergic neurons in the nucleus accumbens from depression-like mice induced by chronic unpredictable mild stress appear the decreases in their GABA release, spiking capability and excitatory input reception, compared with those in resilience mice. The levels of decarboxylase and vesicular GABA transporters decrease in depression-like mice, but not resilience. Materials and Methods Mice were treated by chronic unpredictable mild stress for three weeks. Depression-like behaviors or resilience was confirmed by seeing whether their behaviors change significantly in sucrose preference, Y-maze and forced swimming tests. Mice from controls as well as depression and resilience in response to chronic unpredictable mild stress were studied in terms of GABAergic neuron activity in the nucleus accumbens by cell electrophysiology and protein chemistry. Conclusions The impairment of GABAergic neurons in the nucleus accumbens is associated with major depression. The invulnerability of GABAergic neurons to chronic stress may be one of cellular mechanisms for the resilience to chronic stress. PMID:28415589

Homeostatic Changes in GABA and Acetylcholine Muscarinic Receptors on GABAergic Neurons in the Mesencephalic Reticular Formation following Sleep Deprivation

PubMed Central

2017-01-01

Abstract We have examined whether GABAergic neurons in the mesencephalic reticular formation (RFMes), which are believed to inhibit the neurons in the pons that generate paradoxical sleep (PS or REMS), are submitted to homeostatic regulation under conditions of sleep deprivation (SD) by enforced waking during the day in mice. Using immunofluorescence, we investigated first, by staining for c-Fos, whether GABAergic RFMes neurons are active during SD and then, by staining for receptors, whether their activity is associated with homeostatic changes in GABAA or acetylcholine muscarinic type 2 (AChM2) receptors (Rs), which evoke inhibition. We found that a significantly greater proportion of the GABAergic neurons were positively stained for c-Fos after SD (∼27%) as compared to sleep control (SC; ∼1%) and sleep recovery (SR; ∼6%), suggesting that they were more active during waking with SD and less active or inactive during sleep with SC and SR. The density of GABAARs and AChM2Rs on the plasma membrane of the GABAergic neurons was significantly increased after SD and restored to control levels after SR. We conclude that the density of these receptors is increased on RFMes GABAergic neurons during presumed enhanced activity with SD and is restored to control levels during presumed lesser or inactivity with SR. Such increases in GABAAR and AChM2R with sleep deficits would be associated with increased susceptibility of the wake-active GABAergic neurons to inhibition from GABAergic and cholinergic sleep-active neurons and to thus permitting the onset of sleep and PS with muscle atonia. PMID:29302615

New insights into the classification and nomenclature of cortical GABAergic interneurons

PubMed Central

DeFelipe, Javier; López-Cruz, Pedro L.; Benavides-Piccione, Ruth; Bielza, Concha; Larrañaga, Pedro; Anderson, Stewart; Burkhalter, Andreas; Cauli, Bruno; Fairén, Alfonso; Feldmeyer, Dirk; Fishell, Gord; Fitzpatrick, David; Freund, Tamás F.; González-Burgos, Guillermo; Hestrin, Shaul; Hill, Sean; Hof, Patrick R.; Huang, Josh; Jones, Edward G.; Kawaguchi, Yasuo; Kisvárday, Zoltán; Kubota, Yoshiyuki; Lewis, David A.; Marín, Oscar; Markram, Henry; McBain, Chris J.; Meyer, Hanno S.; Monyer, Hannah; Nelson, Sacha B.; Rockland, Kathleen; Rossier, Jean; Rubenstein, John L. R.; Rudy, Bernardo; Scanziani, Massimo; Shepherd, Gordon M.; Sherwood, Chet C.; Staiger, Jochen F.; Tamás, Gábor; Thomson, Alex; Wang, Yun; Yuste, Rafael; Ascoli, Giorgio A.

2013-01-01

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts’ assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus. PMID:23385869

Midazolam: An Improved Anticonvulsant Treatment for Nerve Agent-Induced Seizures

DTIC Science & Technology

2002-01-01

variety of compounds that different authors had championed as being capable of stopping or moderating nerve agent seizures (e.g., memantine , clonidine...e.g., memantine , neuroactive steroids; EEG seizures were still evident) or required such a narrow dose range or specific treatment conditions that

Steroids

NASA Astrophysics Data System (ADS)

Frey, Felix J.; Frey, Brigitte M.; Benet, Leslie Z.

If a radioimmunoassay, a protein binding method, or a colorimetric assay for the assessment of a steroid level is replaced by high performance liquid chromatography (HPLC), the cost for the determination of a steroid level increases at least initially because one must acquire the new HPLC equipment. Therefore, if an older method provides the same results as the new, "advanced" HPLC method, the only advantage resulting from the introduction of a high performance chromatographic assay is that gained by the manufacturer in terms of greater sales. Thus, justification for the assessment of steroids by HPLC is only obtained if the quality and/or quantity of information gained is significantly increased as compared to that provided by the conventional methods. But this evidential relation, that more and better information justifies a higher price in any case, is no longer true in health care, with the birth some years ago of the categoric imperative for the reduction of costs in the medical sector. That is, each new technology introduced for health maintenance should demonstrate at least a stabilizing impact on total medical expenditures. Therefore, after reviewing the presently available HPLC methods for the clinically important steroids, we will consider whether HPLC analyses for these steroids can be recommended without violating this vox populi.

Prenatal betamethasone does not affect glutamatergic or GABAergic neurogenesis in preterm newborns

PubMed Central

Vose, Linnea R.; Vinukonda, Govindaiah; Diamond, Daniel; Korumilli, Ritesh; Hu, Furong; Zia, Muhammad TK; Hevner, Robert; Ballabh, Praveen

2014-01-01

Prenatal glucocorticoids (GCs) are routinely used for pregnant women in preterm labor to prevent respiratory distress syndrome and intraventricular hemorrhage in premature infants. However, the effect of antenatal GCs on neurogenesis in preterm neonates remains elusive. Herein, we hypothesized that prenatal GCs might suppress both glutamatergic and GABAergic neurogenesis in preterm rabbits and that this treatment would induce distinct changes in the expression of transcription factors regulating these developmental events. To test our hypotheses, we treated pregnant rabbits with betamethasone at E27 and E28, delivered the pups at E29 (term=32d), and assessed neurogenesis at birth and postnatal day 3. We quantified radial glia (Sox2+) and intermediate progenitor cells (Tbr2+) in the dorsal cortical subventricular zone to assess glutamatergic neuronal progenitors, and counted Nkx2.1+ and Dlx2+ cells in the ganglionic eminence to evaluate GABAergic neurogenesis. In addition, we assayed transcription factors regulating neurogenesis. We found that prenatal GCs did not affect the densities of radial glia and intermediate progenitors of glutamatergic or GABAergic neurons. The number of GABA+ interneurons in the ganglionic eminence was similar between the prenatal GC treated pups compared to untreated controls. Moreover, the mRNA expression of transcription factors, including Pax6, Ngn1/2, Emx1/2, Insm1, Dlx1, Nkx2.1, and Gsh2, were comparable between the two groups. However, there was a transient elevation in Mash1 protein in betamethasone treated pups relative to controls at birth. This data suggests that prenatal GC treatment does not significantly impact the balance of glutamatergic and GABAergic neurogenesis in premature infants. PMID:24735821

GABAergic Neurons of the Central Amygdala Promote Cataplexy.

PubMed

Mahoney, Carrie E; Agostinelli, Lindsay J; Brooks, Jessica N K; Lowell, Bradford B; Scammell, Thomas E

2017-04-12

Narcolepsy is characterized by chronic sleepiness and cataplexy-sudden muscle paralysis triggered by strong, positive emotions. This condition is caused by a lack of orexin (hypocretin) signaling, but little is known about the neural mechanisms that mediate cataplexy. The amygdala regulates responses to rewarding stimuli and contains neurons active during cataplexy. In addition, lesions of the amygdala reduce cataplexy. Because GABAergic neurons of the central nucleus of the amygdala (CeA) target brainstem regions known to regulate muscle tone, we hypothesized that these cells promote emotion-triggered cataplexy. We injected adeno-associated viral vectors coding for Cre-dependent DREADDs or a control vector into the CeA of orexin knock-out mice crossed with vGAT-Cre mice, resulting in selective expression of the excitatory hM3 receptor or the inhibitory hM4 receptor in GABAergic neurons of the CeA. We measured sleep/wake behavior and cataplexy after injection of saline or the hM3/hM4 ligand clozapine -N- oxide (CNO) under baseline conditions and under conditions that should elicit positive emotions. In mice expressing hM3, CNO approximately doubled the amount of cataplexy in the first 3 h after dosing under baseline conditions. Rewarding stimuli (chocolate or running wheels) also increased cataplexy, but CNO produced no further increase. In mice expressing hM4, CNO reduced cataplexy in the presence of chocolate or running wheels. These results demonstrate that GABAergic neurons of the CeA are sufficient and necessary for the production of cataplexy in mice, and they likely are a key part of the mechanism through which positive emotions trigger cataplexy. SIGNIFICANCE STATEMENT Cataplexy is one of the major symptoms of narcolepsy, but little is known about how strong, positive emotions trigger these episodes of muscle paralysis. Prior research shows that amygdala neurons are active during cataplexy and cataplexy is reduced by lesions of the amygdala. We found that

Homeostatic Changes in GABA and Acetylcholine Muscarinic Receptors on GABAergic Neurons in the Mesencephalic Reticular Formation following Sleep Deprivation.

PubMed

Toossi, Hanieh; Del Cid-Pellitero, Esther; Jones, Barbara E

2017-01-01

We have examined whether GABAergic neurons in the mesencephalic reticular formation (RFMes), which are believed to inhibit the neurons in the pons that generate paradoxical sleep (PS or REMS), are submitted to homeostatic regulation under conditions of sleep deprivation (SD) by enforced waking during the day in mice. Using immunofluorescence, we investigated first, by staining for c-Fos, whether GABAergic RFMes neurons are active during SD and then, by staining for receptors, whether their activity is associated with homeostatic changes in GABA A or acetylcholine muscarinic type 2 (AChM2) receptors (Rs), which evoke inhibition. We found that a significantly greater proportion of the GABAergic neurons were positively stained for c-Fos after SD (∼27%) as compared to sleep control (SC; ∼1%) and sleep recovery (SR; ∼6%), suggesting that they were more active during waking with SD and less active or inactive during sleep with SC and SR. The density of GABA A Rs and AChM2Rs on the plasma membrane of the GABAergic neurons was significantly increased after SD and restored to control levels after SR. We conclude that the density of these receptors is increased on RFMes GABAergic neurons during presumed enhanced activity with SD and is restored to control levels during presumed lesser or inactivity with SR. Such increases in GABA A R and AChM2R with sleep deficits would be associated with increased susceptibility of the wake-active GABAergic neurons to inhibition from GABAergic and cholinergic sleep-active neurons and to thus permitting the onset of sleep and PS with muscle atonia.

The role of spinal GABAergic circuits in the control of phrenic nerve motor output.

PubMed

Marchenko, Vitaliy; Ghali, Michael G Z; Rogers, Robert F

2015-06-01

While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti-GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus. The number of GAD65/67-positive cells was drastically reduced on the side of siRNA microinjections, especially in the lateral aspects of Rexed's laminae VII and IX in the ventral horn of cervical segment C4, but not contralateral to microinjections. We hypothesize that intraspinal GABAergic control of phrenic output is primarily phasic, but also plays an important role in tonic regulation of phrenic discharge. Also, we identified respiration-modulated GABAergic interneurons (both inspiratory and expiratory) located slightly dorsal to the phrenic nucleus. Our data provide the first direct evidence for the existence of intraspinal GABAergic circuits contributing to the formation of phrenic output. The physiological role of local intraspinal inhibition, independent of descending direct bulbospinal control, is discussed. Copyright © 2015 the American Physiological Society.

GABAergic Projections from the Medial Septum Selectively Inhibit Interneurons in the Medial Entorhinal Cortex

PubMed Central

Gonzalez-Sulser, Alfredo; Parthier, Daniel; Candela, Antonio; McClure, Christina; Pastoll, Hugh; Garden, Derek; Sürmeli, Gülşen

2014-01-01

The medial septum (MS) is required for theta rhythmic oscillations and grid cell firing in the medial entorhinal cortex (MEC). While GABAergic, glutamatergic, and cholinergic neurons project from the MS to the MEC, their synaptic targets are unknown. To investigate whether MS neurons innervate specific layers and cell types in the MEC, we expressed channelrhodopsin-2 in mouse MS neurons and used patch-clamp recording in brain slices to determine the response to light activation of identified cells in the MEC. Following activation of MS axons, we observed fast monosynaptic GABAergic IPSPs in the majority (>60%) of fast-spiking (FS) and low-threshold-spiking (LTS) interneurons in all layers of the MEC, but in only 1.5% of nonstellate principal cells (NSPCs) and in no stellate cells. We also observed fast glutamatergic responses to MS activation in a minority (<5%) of NSPCs, FS, and LTS interneurons. During stimulation of MS inputs at theta frequency (10 Hz), the amplitude of GABAergic IPSPs was maintained, and spike output from LTS and FS interneurons was entrained at low (25–60 Hz) and high (60–180 Hz) gamma frequencies, respectively. By demonstrating cell type-specific targeting of the GABAergic projection from the MS to the MEC, our results support the idea that the MS controls theta frequency activity in the MEC through coordination of inhibitory circuits. PMID:25505326

Impact of perinatal asphyxia on the GABAergic and locomotor system.

PubMed

Van de Berg, W D J; Kwaijtaal, M; de Louw, A J A; Lissone, N P A; Schmitz, C; Faull, R L M; Blokland, A; Blanco, C E; Steinbusch, H W M

2003-01-01

Perinatal asphyxia can cause neuronal loss and depletion of neurotransmitters within the striatum. The striatum plays an important role in motor control, sensorimotor integration and learning. In the present study we investigated whether perinatal asphyxia leads to motor deficits related to striatal damage, and in particular to the loss of GABAergic neurons. Perinatal asphyxia was induced in time-pregnant Wistar rats on the day of delivery by placing the uterus horns, containing the pups, in a 37 degrees C water bath for 20 min. Three motor performance tasks (open field, grip test and walking pattern) were performed at 3 and 6 weeks of age. Antibodies against calbindin and parvalbumin were used to stain GABAergic striatal projection neurons and interneurons, respectively. The motor tests revealed subtle effects of perinatal asphyxia, i.e. small decrease in motor activity. Analysis of the walking pattern revealed an increase in stride width at 6 weeks of age after perinatal asphyxia. Furthermore, a substantial loss of calbindin-immunoreactive (-22%) and parvalbumin-immunoreactive (-43%) cells was found in the striatum following perinatal asphyxia at two months of age. GABA(A) receptor autoradiography revealed no changes in GABA binding activity within the striatum, globus pallidus or substantia nigra. We conclude that perinatal asphyxia resulted in a loss of GABAergic projection neurons and interneurons in the striatum without alteration of GABA(A) receptor affinity. Despite a considerable loss of striatal neurons, only minor deficits in motor performance were found after perinatal asphyxia.

Pax2/8 act redundantly to specify glycinergic and GABAergic fates of multiple spinal interneurons.

PubMed

Batista, Manuel F; Lewis, Katharine E

2008-11-01

The spinal cord contains several distinct classes of neurons but it is still unclear how many of the functional characteristics of these cells are specified. One of the most crucial functional characteristics of a neuron is its neurotransmitter fate. In this paper, we show that in zebrafish most glycinergic and many GABAergic spinal interneurons express Pax2a, Pax2b and Pax8 and that these transcription factors are redundantly required for the neurotransmitter fates of many of these cells. We also demonstrate that the function of these Pax2/8 transcription factors is very specific: in embryos in which Pax2a, Pax2b and Pax8 are simultaneously knocked-down, many neurons lose their glycinergic and/or GABAergic characteristics, but they do not become glutamatergic or cholinergic and their soma morphologies and axon trajectories are unchanged. In mouse, Pax2 is required for correct specification of GABAergic interneurons in the dorsal horn, but it is not required for the neurotransmitter fates of other Pax2-expressing spinal neurons. Our results suggest that this is probably due to redundancy with Pax8 and that the function of Pax2/8 in specifying GABAergic and glycinergic neuronal fates is much broader than was previously appreciated and is highly conserved between different vertebrates.

GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction.

PubMed

Saha, Rinki; Knapp, Stephanie; Chakraborty, Darpan; Horovitz, Omer; Albrecht, Anne; Kriebel, Martin; Kaphzan, Hanoch; Ehrlich, Ingrid; Volkmer, Hansjürgen; Richter-Levin, Gal

2017-01-01

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum-BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum-BLA-LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

PubMed Central

Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

2016-01-01

Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

[Effect of stimulation of GABA-ergic structures of the substantia nigra and caudate nucleus on food-getting behavior in the cat].

PubMed

Shugalev, N P

1983-01-01

A study was made of the functional significance of GABA-ergic structures of the substantia nigra (SN) and the caudate nucleus (CN) and their role in food-procuring behaviour of cats. Analysis was made of behavioral and EEG-effects of local GABA and the GABA antagonist, picrotoxin, microinjections into the studied brain structures. Stimulation of the GABA-ergic structures of the SN produced a sedative effect and depression of the cat food-procuring behaviour. Effects of stimulation of the CN GABA-ergic structures were to a great degree reverse. The conclusion has been made that GABA-ergic structures of the SN and the CN play different roles in controlling the CN inhibitory influence upon food-procuring behaviour.

GABAergic Local Interneurons Shape Female Fruit Fly Response to Mating Songs.

PubMed

Yamada, Daichi; Ishimoto, Hiroshi; Li, Xiaodong; Kohashi, Tsunehiko; Ishikawa, Yuki; Kamikouchi, Azusa

2018-05-02

Many animals use acoustic signals to attract a potential mating partner. In fruit flies ( Drosophila melanogaster ), the courtship pulse song has a species-specific interpulse interval (IPI) that activates mating. Although a series of auditory neurons in the fly brain exhibit different tuning patterns to IPIs, it is unclear how the response of each neuron is tuned. Here, we studied the neural circuitry regulating the activity of antennal mechanosensory and motor center (AMMC)-B1 neurons, key secondary auditory neurons in the excitatory neural pathway that relay song information. By performing Ca 2+ imaging in female flies, we found that the IPI selectivity observed in AMMC-B1 neurons differs from that of upstream auditory sensory neurons [Johnston's organ (JO)-B]. Selective knock-down of a GABA A receptor subunit in AMMC-B1 neurons increased their response to short IPIs, suggesting that GABA suppresses AMMC-B1 activity at these IPIs. Connection mapping identified two GABAergic local interneurons that synapse with AMMC-B1 and JO-B. Ca 2+ imaging combined with neuronal silencing revealed that these local interneurons, AMMC-LN and AMMC-B2, shape the response pattern of AMMC-B1 neurons at a 15 ms IPI. Neuronal silencing studies further suggested that both GABAergic local interneurons suppress the behavioral response to artificial pulse songs in flies, particularly those with a 15 ms IPI. Altogether, we identified a circuit containing two GABAergic local interneurons that affects the temporal tuning of AMMC-B1 neurons in the song relay pathway and the behavioral response to the courtship song. Our findings suggest that feedforward inhibitory pathways adjust the behavioral response to courtship pulse songs in female flies. SIGNIFICANCE STATEMENT To understand how the brain detects time intervals between sound elements, we studied the neural pathway that relays species-specific courtship song information in female Drosophila melanogaster We demonstrate that the signal

Cell Type-specific Intrinsic Perithreshold Oscillations in Hippocampal GABAergic Interneurons.

PubMed

Kang, Young-Jin; Lewis, Hannah Elisabeth Smashey; Young, Mason William; Govindaiah, Gubbi; Greenfield, Lazar John; Garcia-Rill, Edgar; Lee, Sang-Hun

2018-04-15

The hippocampus plays a critical role in learning, memory, and spatial processing through coordinated network activity including theta and gamma oscillations. Recent evidence suggests that hippocampal subregions (e.g., CA1) can generate these oscillations at the network level, at least in part, through GABAergic interneurons. However, it is unclear whether specific GABAergic interneurons generate intrinsic theta and/or gamma oscillations at the single-cell level. Since major types of CA1 interneurons (i.e., parvalbumin-positive basket cells (PVBCs), cannabinoid type 1 receptor-positive basket cells (CB 1 BCs), Schaffer collateral-associated cells (SCAs), neurogliaform cells and ivy cells) are thought to play key roles in network theta and gamma oscillations in the hippocampus, we tested the hypothesis that these cells generate intrinsic perithreshold oscillations at the single-cell level. We performed whole-cell patch-clamp recordings from GABAergic interneurons in the CA1 region of the mouse hippocampus in the presence of synaptic blockers to identify intrinsic perithreshold membrane potential oscillations. The majority of PVBCs (83%), but not the other interneuron subtypes, produced intrinsic perithreshold gamma oscillations if the membrane potential remained above -45 mV. In contrast, CB 1 BCs, SCAs, neurogliaform cells, ivy cells, and the remaining PVBCs (17%) produced intrinsic theta, but not gamma, oscillations. These oscillations were prevented by blockers of persistent sodium current. These data demonstrate that the major types of hippocampal interneurons produce distinct frequency bands of intrinsic perithreshold membrane oscillations. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Kappa Opioid Receptor-Mediated Dysregulation of GABAergic Transmission in the Central Amygdala in Cocaine Addiction

PubMed Central

Kallupi, Marsida; Wee, Sunmee; Edwards, Scott; Whitfield, Tim W.; Oleata, Christopher S.; Luu, George; Schmeichel, Brooke E.; Koob, George F.; Roberto, Marisa

2013-01-01

Background Studies have demonstrated an enhanced dynorphin/kappa-opioid receptor (KOR) system following repeated cocaine exposure, but few reports have focused on neuroadaptations within the central amygdala (CeA). Methods We identified KOR-related physiological changes in the CeA following escalation of cocaine self-administration in rats. We used in vitro slice electrophysiological (intracellular and whole-cell recordings) methods to assess whether differential cocaine access in either 1h (short access, ShA) or 6h (long access, LgA) sessions induced plasticity at CeA GABAergic synapses, or altered the sensitivity of these synapses to KOR agonism (U50488) or antagonism (nor-BNI). We then determined the functional effects of CeA KOR blockade in cocaine-related behaviors. Results Baseline evoked GABAergic transmission was enhanced in the CeA from ShA and LgA rats compared to cocaine-naïve rats. Acute cocaine (1 uM) application significantly decreased GABA release in all groups (naïve, ShA, and LgA rats). Application of U50488 (1 uM) significantly decreased GABAergic transmission in the CeA from naïve rats, but increased it in LgA rats. Conversely, nor-BNI (200 nM) significantly increased GABAergic transmission in the CeA from naïve rats, but decreased it in LgA rats. Nor-BNI did not alter the acute cocaine-induced inhibition of GABAergic responses. Finally, CeA microinfusion of nor-BNI blocked cocaine-induced locomotor sensitization and attenuated the heightened anxiety-like behavior observed during withdrawal from chronic cocaine exposure in the defensive burying paradigm. Conclusion Together these data demonstrate that CeA dynorphin/KOR systems are dysregulated following excessive cocaine exposure and suggest KOR antagonism as a viable therapeutic strategy for cocaine addiction. PMID:23751206

Anabolic Steroids...What's the Hype?...

ERIC Educational Resources Information Center

Landry, Gregory L.; Wagner, Lauris L.

This pamphlet uses a question-and-answer format to examine the use and abuse of anabolic steroids. It begins by explaining that all steroids are not anabolic steroids and that anabolic steroids are those used specifically to build muscles quickly. Medical uses of anabolic steroids are reviewed; how people get steroids, how they take them, and…

Transcriptional Architecture of Synaptic Communication Delineates GABAergic Neuron Identity.

PubMed

Paul, Anirban; Crow, Megan; Raudales, Ricardo; He, Miao; Gillis, Jesse; Huang, Z Josh

2017-10-19

Understanding the organizational logic of neural circuits requires deciphering the biological basis of neuronal diversity and identity, but there is no consensus on how neuron types should be defined. We analyzed single-cell transcriptomes of a set of anatomically and physiologically characterized cortical GABAergic neurons and conducted a computational genomic screen for transcriptional profiles that distinguish them from one another. We discovered that cardinal GABAergic neuron types are delineated by a transcriptional architecture that encodes their synaptic communication patterns. This architecture comprises 6 categories of ∼40 gene families, including cell-adhesion molecules, transmitter-modulator receptors, ion channels, signaling proteins, neuropeptides and vesicular release components, and transcription factors. Combinatorial expression of select members across families shapes a multi-layered molecular scaffold along the cell membrane that may customize synaptic connectivity patterns and input-output signaling properties. This molecular genetic framework of neuronal identity integrates cell phenotypes along multiple axes and provides a foundation for discovering and classifying neuron types. Copyright © 2017 Elsevier Inc. All rights reserved.

Pax2/8 act redundantly to specify glycinergic and GABAergic fates of multiple spinal interneurons

PubMed Central

Batista, Manuel F.; Lewis, Katharine E.

2008-01-01

The spinal cord contains several distinct classes of neurons but it is still unclear how many of the functional characteristics of these cells are specified. One of the most crucial functional characteristics of a neuron is its neurotransmitter fate. In this paper, we show that in zebrafish most glycinergic and many GABAergic spinal interneurons express Pax2a, Pax2b and Pax8 and that these transcription factors are redundantly required for the neurotransmitter fates of many of these cells. We also demonstrate that the function of these Pax2/8 transcription factors is very specific: in embryos in which Pax2a, Pax2b and Pax8 are simultaneously knocked-down, many neurons lose their glycinergic and/or GABAergic characteristics, but they do not become glutamatergic or cholinergic and their soma morphologies and axon trajectories are unchanged. In mouse, Pax2 is required for correct specification of GABAergic interneurons in the dorsal horn, but it is not required for the neurotransmitter fates of other Pax2-expressing spinal neurons. Our results suggest that this is probably due to redundancy with Pax8 and that the function of Pax2/8 in specifying GABAergic and glycinergic neuronal fates is much broader than was previously appreciated and is highly conserved between different vertebrates. PMID:18761336

Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex.

PubMed

Toriumi, Kazuya; Oki, Mika; Muto, Eriko; Tanaka, Junko; Mouri, Akihiro; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

2016-06-01

We previously reported that prenatal treatment with phencyclidine (PCP) induces glutamatergic dysfunction in the prefrontal cortex (PFC), leading to schizophrenia-like behavioral deficits in adult mice. However, little is known about the prenatal effect of PCP treatment on other types of neurons. We focused on γ-aminobutyric acid (GABA)-ergic interneurons and evaluated the effect of prenatal PCP exposure on the neurodevelopment of GABAergic interneurons in the PFC. PCP was administered at the dose of 10 mg/kg/day to pregnant dams from embryonic day 6.5 to 18.5. After the pups were reared to adult, we analyzed their GABAergic system in the PFC using immunohistological, biochemical, and behavioral analyses in adulthood. The prenatal PCP treatment decreased the density of parvalbumin-positive cells and reduced the expression level of glutamic acid decarboxylase 67 (GAD67) and GABA content of the PFC in adults. Additionally, prenatal PCP treatment induced behavioral deficits in adult mice, such as hypersensitivity to PCP and prepulse inhibition (PPI) deficits. These behavioral deficits were ameliorated by pretreatment with the GABAB receptor agonist baclofen. Furthermore, the density of c-Fos-positive cells was decreased after the PPI test in the PFC of mice treated with PCP prenatally, and this effect was ameliorated by pretreatment with baclofen. These findings suggest that prenatal treatment with PCP induced GABAergic dysfunction in the PFC, which caused behavioral deficits.

P-Glycoprotein Activity in Steroid-Responsive vs. Steroid-Resistant Nephrotic Syndrome.

PubMed

Badr, Hassan S; El-Hawy, Mahmoud A; Helwa, Mohammed A

2016-11-01

To explore the expression of P-glycoprotein (P-gp) in the peripheral blood nucleated cells (PBNCs) of children with nephrotic syndrome in relation to their clinical response to glucocorticoid treatment. Thirty-six children with nephrotic syndrome (20 cases of steroid-responsive and 16 cases of steroid-resistant) were examined. All the participants were subjected to complete history taking, thorough clinical examination, laboratory investigations (24-h urinary protein, serum albumin, complete blood count with differential white blood cell count, serum cholesterol, serum urea, serum creatinine) and functional assay of P-gp using FACS Calibur flowcytometry. P-gp assay was done in both groups during remission. P-gp activity was significantly higher in steroid-resistant than steroid-sensitive cases. P-gp can be used as a predictor of outcome, as a part of laboratory evaluation of the cases before starting steroid therapy, so as to determine whether to use alternative line of therapy or use one of the P-gp inhibitors with steroid therapy.

Neurotoxic and neuroactive compounds from Cnidaria: five decades of research….and more.

PubMed

Mariottini, Gian L; Bonello, Gaido; Giacco, Elisabetta; Pane, Luigi

2015-01-01

Cnidarians are numbered among the most venomous organisms. Their venoms are contained in intracellular capsules, nematocysts, which inject the content into preys/attackers through an eversion system resembling a syringe needle. Several cnidarian venoms have activity against the nervous system, being neurotoxic, or affect other systems whose functioning is under nerve control. Besides direct damage to nerve cells, the activity on ionic conductance, blockade of neuromuscular junctions, and influence on action potentials and on voltage-gated channels have been described. Therefore, cnidarians can be a useful source of nervous system-targeted compounds which could have, in perspective, a role in the therapy of some nervous system diseases. Following this idea, this article aims to review the existing data about the neuroactive properties of cnidarian venoms and their possible usefulness in tackling some neurological diseases as well as neurodegenerative age-related diseases whose incidence is expected to raise in the next decades owing to the increase of life expectancy.

Cortical GABAergic Interneurons in Cross-Modal Plasticity following Early Blindness

PubMed Central

Desgent, Sébastien; Ptito, Maurice

2012-01-01

Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA) play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field. PMID:22720175

GABAergic transmission facilitates ictogenesis and synchrony between CA3, hilus, and dentate gyrus in slices from epileptic rats

PubMed Central

Gafurov, Boris

2013-01-01

The impact of regional hippocampal interactions and GABAergic transmission on ictogenesis remain unclear. Cortico-hippocampal slices from pilocarpine-treated epileptic rats were compared with controls to investigate associations between seizurelike events (SLE), GABAergic transmission, and neuronal synchrony within and between cortico-hippocampal regions. Multielectrode array recordings revealed more prevalent hippocampal SLE in epileptic tissue when excitatory transmission was enhanced and GABAergic transmission was intact [removal of Mg2+ (0Mg)] than when GABAergic transmission was blocked [removal of Mg2+ + bicuculline methiodide (0Mg+BMI)]. When activity within individual regions was analyzed, spectral and temporal slow oscillation/SLE correlations and cross-correlations were highest within the hilus of epileptic tissue during SLE but were similar in 0Mg and 0Mg+BMI. GABAergic facilitation of spectral “slow” oscillation and ripple correlations was most prominent within CA3 of epileptic tissue during SLE. When activity between regions was analyzed, slow oscillation and ripple coherence was highest between the hilus and dentate gyrus as well as between the hilus and CA3 of epileptic tissue during SLE and was significantly higher in 0Mg than 0Mg+BMI. High 0Mg-induced SLE cross-correlations between the hilus and dentate gyrus as well as between the hilus and CA3 were reduced or abolished in 0Mg+BMI. SLE cross-correlation lag measurements provided evidence for a monosynaptic connection from the hilus to the dentate gyrus during SLE. Findings implicate the hilus as an oscillation generator, whose impact on other cortico-hippocampal regions is mediated by GABAergic transmission. Data also suggest that GABAA receptor-mediated transmission facilitates back-propagation from CA3/hilus to the dentate gyrus and that this back-propagation augments SLE in epileptic hippocampus. PMID:23615549

VAMP-2, SNAP-25A/B and syntaxin-1 in glutamatergic and GABAergic synapses of the rat cerebellar cortex

PubMed Central

2011-01-01

Background The aim of this study was to assess the distribution of key SNARE proteins in glutamatergic and GABAergic synapses of the adult rat cerebellar cortex using light microscopy immunohistochemical techniques. Analysis was made of co-localizations of vGluT-1 and vGluT-2, vesicular transporters of glutamate and markers of glutamatergic synapses, or GAD, the GABA synthetic enzyme and marker of GABAergic synapses, with VAMP-2, SNAP-25A/B and syntaxin-1. Results The examined SNARE proteins were found to be diffusely expressed in glutamatergic synapses, whereas they were rarely observed in GABAergic synapses. However, among glutamatergic synapses, subpopulations which did not contain VAMP-2, SNAP-25A/B and syntaxin-1 were detected. They included virtually all the synapses established by terminals of climbing fibres (immunoreactive for vGluT-2) and some synapses established by terminals of parallel and mossy fibres (immunoreactive for vGluT-1, and for vGluT-1 and 2, respectively). The only GABA synapses expressing the SNARE proteins studied were the synapses established by axon terminals of basket neurons. Conclusion The present study supplies a detailed morphological description of VAMP-2, SNAP-25A/B and syntaxin-1 in the different types of glutamatergic and GABAergic synapses of the rat cerebellar cortex. The examined SNARE proteins characterize most of glutamatergic synapses and only one type of GABAergic synapses. In the subpopulations of glutamatergic and GABAergic synapses lacking the SNARE protein isoforms examined, alternative mechanisms for regulating trafficking of synaptic vesicles may be hypothesized, possibly mediated by different isoforms or homologous proteins. PMID:22094010

Specific rescue by ortho-hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB.

PubMed

Guirao, Verónica; Martí-Sistac, Octavi; DeGregorio-Rocasolano, Núria; Ponce, Jovita; Dávalos, Antoni; Gasull, Teresa

2017-11-01

The statin atorvastatin (ATV) given as a post-treatment has been reported beneficial in stroke, although the mechanisms involved are not well understood so far. Here, we investigated in vitro the effect of post-treatment with ATV and its main bioactive metabolite ortho-hydroxy ATV (o-ATV) on neuroprotection after oxygen and glucose deprivation (OGD), and the role of the pro-survival cAMP response element-binding protein (CREB). Post-OGD treatment of primary cultures of rat cortical neurons with o-ATV, but not ATV, provided neuroprotection to a specific subset of cortical neurons that were large and positive for glutamic acid decarboxylase (large-GAD (+) neurons, GABAergic). Significantly, only these GABAergic neurons showed an increase in phosphorylated CREB (pCREB) early after neuronal cultures were treated post-OGD with o-ATV. We found that o-ATV, but not ATV, increased the neuronal uptake of glutamate from the medium; this provides a rationale for the specific effect of o-ATV on pCREB in large-GABAergic neurons, which have a higher ratio of synaptic (pCREB-promoting) vs extrasynaptic (pCREB-reducing) N-methyl-D-aspartate (NMDA) receptors (NMDAR) than that of small-non-GABAergic neurons. When we pharmacologically increased pCREB levels post-OGD in non-GABAergic neurons, through the selective activation of synaptic NMDAR, we observed as well long-lasting neuronal survival. We propose that the statin metabolite o-ATV given post-OGD boosts the intrinsic pro-survival factor pCREB in large-GABAergic cortical neurons in vitro, this contributing to protect them from OGD. © 2017 International Society for Neurochemistry.

Signaling mechanisms mediating muscarinic enhancement of GABAergic synaptic transmission in the spinal cord.

PubMed

Zhang, H-M; Chen, S-R; Cai, Y-Q; Richardson, T E; Driver, L C; Lopez-Berestein, G; Pan, H-L

2009-02-18

Activation of muscarinic acetylcholine receptors (mAChRs) inhibits spinal nociceptive transmission by potentiation of GABAergic tone through M(2), M(3), and M(4) subtypes. To study the signaling mechanisms involved in this unique mAChR action, GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of lamina II neurons were recorded using whole-cell patch clamp techniques in rat spinal cord slices. The mAChR agonist oxotremorine-M caused a profound increase in the frequency of GABAergic sIPSCs, which was abolished in the Ca(2+)-free solution. Inhibition of voltage-gated Ca(2+) channels with Cd(2+) and Ni(2+) largely reduced the effect of oxotremorine-M on sIPSCs. Blocking nonselective cation channels (NSCCs) with SKF96365 or 2-APB also largely attenuated the effect of oxotremorine-M. However, the KCNQ channel blocker XE991 and the adenylyl cyclase inhibitor MDL12330A had no significant effect on oxotremorine-M-induced increases in sIPSCs. Furthermore, the phosphoinositide-3-kinase (PI3K) inhibitor wortmannin or LY294002 significantly reduced the potentiating effect of oxotremorine-M on sIPSCs. In the spinal cord in which the M(3) subtype was specifically knocked down by intrathecal small interfering RNA (siRNA) treatment, SKF96365 and wortmannin still significantly attenuated the effect of oxotremorine-M. In contrast, SKF96365 and wortmannin both failed to alter the effect of oxotremorine-M on sIPSCs when the M(2)/M(4) mAChRs were blocked. Therefore, our study provides new evidence that activation of mAChRs increases synaptic GABA release through Ca(2+) influx and voltage-gated Ca(2+) channels. The PI3K-NSCC signaling cascade is primarily involved in the excitation of GABAergic interneurons by the M(2)/M(4) mAChRs in the spinal dorsal horn.

Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression

PubMed Central

Banasr, Mounira; Lepack, Ashley; Fee, Corey; Duric, Vanja; Maldonado-Aviles, Jaime; DiLeone, Ralph; Sibille, Etienne; Duman, Ronald S.; Sanacora, Gerard

2017-01-01

Evidence continues to build suggesting that the GABAergic neurotransmitter system is altered in brains of patients with major depressive disorder. However, there is little information available related to the extent of these changes or the potential mechanisms associated with these alterations. As stress is a well-established precipitant to depressive episodes, we sought to explore the impact of chronic stress on GABAergic interneurons. Using western blot analyses and quantitative real-time PCR (qPCR) we assessed the effects of five-weeks of chronic unpredictable stress (CUS) exposure on the expression of GABA-synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin (CB), parvalbumin (PV) and calretinin (CR)), and neuropeptides co-expressed in GABAergic neurons (somatostatin (SST), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and cholecystokinin (CCK)) in the prefrontal cortex (PFC) and hippocampus (HPC) of rats. We also investigated the effects of corticosterone (CORT) and dexamethasone (DEX) exposure on these markers in vitro in primary cortical and hippocampal cultures. We found that CUS induced significant reductions of GAD67 protein levels in both the PFC and HPC of CUS-exposed rats, but did not detect changes in GAD65 protein expression. Similar protein expression changes were found in vitro in cortical neurons. In addition, our results provide clear evidence of reduced markers of interneuron population(s), namely SST and NPY, in the PFC, suggesting these cell types may be selectively vulnerable to chronic stress. Together, this work highlights that chronic stress induces regional and cell type-selective effects on GABAergic interneurons in rats. These findings provide additional supporting evidence that stress-induced GABA neuron dysfunction and cell vulnerability play critical roles in the pathophysiology of stress-related illnesses, including major depressive disorder. PMID:28835932

Organotypic cultures as tools for testing neuroactive drugs - link between in-vitro and in-vivo experiments.

PubMed

Drexler, B; Hentschke, H; Antkowiak, B; Grasshoff, C

2010-01-01

The development of neuroactive drugs is a time consuming procedure. Candidate drugs must be run through a battery of tests, including receptor studies and behavioural tests on animals. As a rule, numerous substances with promising properties as assessed in receptor studies must be eliminated from the development pipeline in advanced test phases because of unforeseen problems like intolerable side-effects or unsatisfactory performance in the whole organism. Clearly, test systems of intermediate complexity would alleviate this inefficiency. In this review, we propose cultured organotypic brain slices as model systems that could bridge the 'interpolation gap' between receptors and the brain, with a focus on the development of new general anaesthetics with lesser side effects. General anaesthesia is based on the modulation of neurotransmitter receptors and other conductances located on neurons in diverse brain regions, including cerebral cortex and spinal cord. It is well known that different components of general anaesthesia, e.g. hypnosis and immobility, are produced by the depression of neuronal activity in distinct brain regions. The ventral horn of the spinal cord is an important structure for the induction of immobility. Thus, the potentially immobilizing effects of a newly designed drug can be estimated from its depressant effect on neuronal network activity in cultured spinal slices. A drug's sedative and hypnotic potential can be examined in cortical cultures. Combined with genetically engineered mice, this approach can point to receptor subtypes most relevant to the drug's intended net effect and in return can help in the design of more selective drugs. In conclusion, the use of organotypic cultures permits predictions of neuroactive properties of newly designed drugs on an intermediate level, and should therefore open up avenues for a more creative and economic drug development process.

The Frequency-Dependent Aerobic Exercise Effects of Hypothalamic GABAergic Expression and Cardiovascular Functions in Aged Rats

PubMed Central

Li, Yan; Zhao, Ziqi; Cai, Jiajia; Gu, Boya; Lv, Yuanyuan; Zhao, Li

2017-01-01

A decline in cardiovascular modulation is a feature of the normal aging process and associated with cardiovascular diseases (CVDs) such as hypertension and stroke. Exercise training is known to promote cardiovascular adaptation in young animals and positive effects on motor and cognitive capabilities, as well as on brain plasticity for all ages in mice. Here, we examine the question of whether aerobic exercise interventions may impact the GABAergic neurons of the paraventricular nucleus (PVN) in aged rats which have been observed to have a decline in cardiovascular integration function. In the present study, young (2 months) and old (24 months) male Wistar rats were divided into young control (YC), old sedentary, old low frequency exercise (20 m/min, 60 min/day, 3 days/week, 12 weeks) and old high frequency exercise (20 m/min, 60 min/day, 5 days/week, 12 weeks). Exercise training indexes were obtained, including resting heart rate (HR), blood pressure (BP), plasma norepinephrine (NE), and heart weight (HW)-to-body weight (BW) ratios. The brain was removed and processed according to the immunofluorescence staining and western blot used to analyze the GABAergic terminal density, the proteins of GAD67, GABAA receptor and gephyrin in the PVN. There were significant changes in aged rats compared with those in the YC. Twelve weeks aerobic exercise training has volume-dependent ameliorated effects on cardiovascular parameters, autonomic nervous activities and GABAergic system functions. These data suggest that the density of GABAergic declines in the PVN is associated with imbalance in autonomic nervous activities in normal aging. Additionally, aerobic exercise can rescue aging-related an overactivity of the sympathetic nervous system and induces modifications the resting BP and HR to lower values via improving the GABAergic system in the PVN. PMID:28713263

Treatment of Fragile X Syndrome with a Neuroactive Steroid

DTIC Science & Technology

2015-08-01

in the fragile X mouse model and the Drosophila (fruit fly) models of FXS that the GABAA system, including multiple receptors, is dramatically down... Drosophila (fruit fly) models of FXS that the GABAA system, including multiple receptors, is dramatically down-regulated. Ganaxolone is a drug that

Treatment of Fragile X Syndrome with a Neuroactive Steroid

DTIC Science & Technology

2013-08-01

GABAA activity . We hypothesized that ganaxolone will significantly improve behavioral problems including anxiety, inattention and impulsivity...group I metabotropic glutamate receptors (mGluRs). In the hippocampal field CA1, activation of mGluR5 leads to long-term depression (LTD), which is seen...as a reduction in synaptic responses. Importantly, LTD triggered by mGluR activation (mGluR-LTD) requires the rapid translation of preexisting mRNA in

Treatment of Fragile X Syndrome with a Neuroactive Steroid

DTIC Science & Technology

2014-08-01

Figure 1) and GABA agonists (Figures 2 and 3). Currently, there are animal models of FXS that include the Fmr1-KO mouse and the Drosophila melanogaster ... the Drosophila (fruit fly) model of FXS that the GABAA system including multiple receptors is dramatically down-regulated. Ganaxolone is a drug that...810 males.14 The expansion of the trinucleotide sequence results in lowered FMRP levels. The premutation expansion results in a two- to eightfold

Treatment of Fragile X Syndrome with a Neuroactive Steroid

DTIC Science & Technology

2012-08-01

common form of inherited intellectual disability and autism . The protein (FMRP) encoded by the fragile X mental retardation gene (FMR1), is an RNA...FXS) is the most common inherited cause of mental retardation, and the most common single gene mutation associated with autism (Demark et al. 2003...profile of impairments, with the most interesting being comorbidity with autism . From the most recent studies, the prevalence of autism spectrum

Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: Relationship with spatial impairment

PubMed Central

Bañuelos, C.; LaSarge, C. L.; McQuail, J. A.; Hartman, J. J.; Gilbert, R. J.; Ormerod, B. K.; Bizon, J. L.

2013-01-01

Both cholinergic and GABAergic projections from the rostral basal forebrain have been implicated in hippocampal function and mnemonic abilities. While dysfunction of cholinergic neurons has been heavily implicated in age-related memory decline, significantly less is known regarding how age-related changes in co-distributed GABAergic projection neurons contribute to a decline in hippocampal-dependent spatial learning. In the current study, confocal stereology was used to quantify cholinergic (choline acetyltransferase (ChAT) immunopositive) neurons, GABAergic projection (glutamic decarboxylase 67 (GAD67) immunopositive) neurons, and total (NeuN immunopositive) neurons in the rostral basal forebrain of young and aged rats that were first characterized on a spatial learning task. ChAT immunopositive neurons were significantly but modestly reduced in aged rats. Although ChAT immunopositive neuron number was strongly correlated with spatial learning abilities among young rats, the reduction of ChAT immunopositive neurons was not associated with impaired spatial learning in aged rats. In contrast, the number of GAD67 immunopositive neurons was robustly and selectively elevated in aged rats that exhibited impaired spatial learning. Interestingly, the total number of rostral basal forebrain neurons was comparable in young and aged rats, regardless of their cognitive status. These data demonstrate differential effects of age on phenotypically distinct rostral basal forebrain projection neurons, and implicate dysregulated cholinergic and GABAergic septohippocampal circuitry in age-related mnemonic decline. PMID:22817834

The Effects of GABAergic Polarity Changes on Episodic Neural Network Activity in Developing Neural Systems.

PubMed

Blanco, Wilfredo; Bertram, Richard; Tabak, Joël

2017-01-01

Early in development, neural systems have primarily excitatory coupling, where even GABAergic synapses are excitatory. Many of these systems exhibit spontaneous episodes of activity that have been characterized through both experimental and computational studies. As development progress the neural system goes through many changes, including synaptic remodeling, intrinsic plasticity in the ion channel expression, and a transformation of GABAergic synapses from excitatory to inhibitory. What effect each of these, and other, changes have on the network behavior is hard to know from experimental studies since they all happen in parallel. One advantage of a computational approach is that one has the ability to study developmental changes in isolation. Here, we examine the effects of GABAergic synapse polarity change on the spontaneous activity of both a mean field and a neural network model that has both glutamatergic and GABAergic coupling, representative of a developing neural network. We find some intuitive behavioral changes as the GABAergic neurons go from excitatory to inhibitory, shared by both models, such as a decrease in the duration of episodes. We also find some paradoxical changes in the activity that are only present in the neural network model. In particular, we find that during early development the inter-episode durations become longer on average, while later in development they become shorter. In addressing this unexpected finding, we uncover a priming effect that is particularly important for a small subset of neurons, called the "intermediate neurons." We characterize these neurons and demonstrate why they are crucial to episode initiation, and why the paradoxical behavioral change result from priming of these neurons. The study illustrates how even arguably the simplest of developmental changes that occurs in neural systems can present non-intuitive behaviors. It also makes predictions about neural network behavioral changes that occur during

Acute orexigenic effect of agmatine involves interaction between central α2-adrenergic and GABAergic receptors.

PubMed

Taksande, Brijesh Gulabrao; Sharma, Omi; Aglawe, Manish Manohar; Kale, Mayur Bhimrao; Gawande, Dinesh Yugraj; Umekar, Milind Janraoji; Kotagale, Nandkishor Ramdas

2017-09-01

Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats. Satiated rats fitted with intracerebroventricular (i.c.v.) cannulae and were administered agmatine, alone or jointly with (a) GABA A receptor agonist, muscimol, diazepam or antagonist bicuculline and flumazenil, GABA A positive modulator, allopregnanolone or negative modulator of GABA A receptor, dehydroepiandrosterone (b) In view of the high affinity of agmatine for α 2 -adrenoceptors and the close association between α 2 -adrenoceptors and GABAergic system, the effect of their modulators on feeding elicited by agmatine/GABAergic agonists were also examined. I.c.v. administration of agmatine (40-80μg/rat) induces the significant orexigenic effect in satiated rats. The orexigenic effect of agmatine was potentiated by muscimol (25ng/rat, i.c.v.); diazepam (0.5mg/kg, i.p.); allopregnanolone (0.5mg/kg, s.c.) and blocked by bicuculline (1mg/kg, i.p.) and dehydroepiandrosterone (4mg/kg,s.c.). However, it remained unaffected in presence of flumazenil (25ng/rat, i.c.v.). The orexigenic effect of agmatine and GABAergic agonists was potentiated by a α 2 -adrenoceptors agonist, clonidine (10ng/rat, i.c.v.) and blocked by its antagonist, yohimbine (5μg/rat, i.c.v.). Yohimbine also blocked the hyperphagic effect elicited by ineffective dose combination of agmatine (5μg/rat, i.c.v.) with muscimol (25ng/rat, i.c.v.) or diazepam (0.5mg/kg, i.p.) or allopregnanolone (0.5mg/kg,s.c.). The results of the present study suggest that agmatine induced α 2 -adrenoceptors activation might facilitate GABAergic activity to stimulate food intake in

Septohippocampal GABAergic neurons mediate the altered behaviors induced by n-methyl-D-aspartate receptor antagonists.

PubMed

Ma, Jingyi; Tai, Siew Kian; Leung, L Stan

2012-12-01

We hypothesize that selective lesion of the septohippocampal GABAergic neurons suppresses the altered behaviors induced by an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine or MK-801. In addition, we hypothesize that septohippocampal GABAergic neurons generate an atropine-resistant theta rhythm that coexists with an atropine-sensitive theta rhythm in the hippocampus. Infusion of orexin-saporin (ore-SAP) into the medial septal area decreased parvalbumin-immunoreactive (GABAergic) neurons by ~80%, without significantly affecting choline-acetyltransferase-immunoreactive (cholinergic) neurons. The theta rhythm during walking, or the immobility-associated theta induced by pilocarpine, was not different between ore-SAP and sham-lesion rats. Walking theta was, however, more disrupted by atropine sulfate in ore-SAP than in sham-lesion rats. MK-801 (0.5 mg/kg i.p.) induced hyperlocomotion associated with an increase in frequency, but not power, of the hippocampal theta in both ore-SAP and sham-lesion rats. However, MK-801 induced an increase in 71-100 Hz gamma waves in sham-lesion but not ore-SAP lesion rats. In sham-lesion rats, MK-801 induced an increase in locomotion and an impairment of prepulse inhibition (PPI), and ketamine (3 mg/kg s.c.) induced a loss of gating of hippocampal auditory evoked potentials. MK-801-induced behavioral hyperlocomotion and PPI impairment, and ketamine-induced auditory gating deficit were reduced in ore-SAP rats as compared to sham-lesion rats. During baseline without drugs, locomotion and auditory gating were not different between ore-SAP and sham-lesion rats, and PPI was slightly but significantly increased in ore-SAP as compared with sham lesion rats. It is concluded that septohippocampal GABAergic neurons are important for the expression of hyperactive and psychotic symptoms an enhanced hippocampal gamma activity induced by ketamine and MK-801, and for generating an atropine-resistant theta. Selective suppression of

Causal Evidence for the Role of Specific GABAergic Interneuron Types in Entorhinal Recruitment of Dentate Granule Cells

PubMed Central

Lee, Cheng-Ta; Kao, Min-Hua; Hou, Wen-Hsien; Wei, Yu-Ting; Chen, Chin-Lin; Lien, Cheng-Chang

2016-01-01

The dentate gyrus (DG) is the primary gate of the hippocampus and controls information flow from the cortex to the hippocampus proper. To maintain normal function, granule cells (GCs), the principal neurons in the DG, receive fine-tuned inhibition from local-circuit GABAergic inhibitory interneurons (INs). Abnormalities of GABAergic circuits in the DG are associated with several brain disorders, including epilepsy, autism, schizophrenia, and Alzheimer disease. Therefore, understanding the network mechanisms of inhibitory control of GCs is of functional and pathophysiological importance. GABAergic inhibitory INs are heterogeneous, but it is unclear how individual subtypes contribute to GC activity. Using cell-type-specific optogenetic perturbation, we investigated whether and how two major IN populations defined by parvalbumin (PV) and somatostatin (SST) expression, regulate GC input transformations. We showed that PV-expressing (PV+) INs, and not SST-expressing (SST+) INs, primarily suppress GC responses to single cortical stimulation. In addition, these two IN classes differentially regulate GC responses to θ and γ frequency inputs from the cortex. Notably, PV+ INs specifically control the onset of the spike series, whereas SST+ INs preferentially regulate the later spikes in the series. Together, PV+ and SST+ GABAergic INs engage differentially in GC input-output transformations in response to various activity patterns. PMID:27830729

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice

PubMed Central

Kroeger, Daniel; Ferrari, Loris L.; Mahoney, Carrie E.; Arrigoni, Elda

2017-01-01

The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states. SIGNIFICANCE STATEMENT More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep–wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice.

PubMed

Kroeger, Daniel; Ferrari, Loris L; Petit, Gaetan; Mahoney, Carrie E; Fuller, Patrick M; Arrigoni, Elda; Scammell, Thomas E

2017-02-01

The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states. More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep-wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our

Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

PubMed Central

Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

2012-01-01

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype. PMID:23300939

Interplay between glucose and leptin signaling determines the strength of GABAergic synapses at POMC neurons

PubMed Central

Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun; Chua, Streamson; Jo, Young-Hwan

2015-01-01

Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin’s action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signaling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signaling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons. PMID:25808323

Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

PubMed

Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun; Chua, Streamson; Jo, Young-Hwan

2015-03-26

Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

Association and linkage studies of candidate genes involved in GABAergic neurotransmission in lithium-responsive bipolar disorder.

PubMed Central

Duffy, A; Turecki, G; Grof, P; Cavazzoni, P; Grof, E; Joober, R; Ahrens, B; Berghöfer, A; Müller-Oerlinghausen, B; Dvoráková, M; Libigerová, E; Vojtĕchovský, M; Zvolský, P; Nilsson, A; Licht, R W; Rasmussen, N A; Schou, M; Vestergaard, P; Holzinger, A; Schumann, C; Thau, K; Robertson, C; Rouleau, G A; Alda, M

2000-01-01

OBJECTIVE: To test for genetic linkage and association with GABAergic candidate genes in lithium-responsive bipolar disorder. DESIGN: Polymorphisms located in genes that code for GABRA3, GABRA5 and GABRB3 subunits of the GABAA receptor were investigated using association and linkage strategies. PARTICIPANTS: A total of 138 patients with bipolar 1 disorder with a clear response to lithium prophylaxis, selected from specialized lithium clinics in Canada and Europe that are part of the International Group for the Study of Lithium-Treated Patients, and 108 psychiatrically healthy controls. Families of 24 probands were suitable for linkage analysis. OUTCOME MEASURES: The association between the candidate genes and patients with bipolar disorder versus that of controls and genetic linkage within families. RESULTS: There was no significant association or linkage found between lithium-responsive bipolar disorder and the GABAergic candidate genes investigated. CONCLUSIONS: This study does not support a major role for the GABAergic candidate genes tested in lithium-responsive bipolar disorder. PMID:11022400

Steroid-antivirals treatment versus steroids alone for the treatment of Bell's palsy: a meta-analysis.

PubMed

Dong, Yabing; Zhu, Yong; Ma, Chuan; Zhao, Huaqiang

2015-01-01

To illustrate whether the steroid-antivirals treatment could acquire a better recovery in patients with Bell's palsy than the steroids alone treatment. We conducted an exhaustive search over Pub med/Medline, Ovid, Elsevier search engines and the Cochrane library thereby collecting the randomized controlled trials in the treatment of patients with Bell's palsy with steroid-antivirals and steroids. The qualities of relevant articles were assessed by GRADE, which was used to present the overall quality of evidence as recommended by the Cochrane Handbook for Systematic Reviews of Interventions. Two investigators evaluated these papers independently, and resolved the disagreements by discussion. At last 8 eligible papers (1816 patients included: 896 treated with steroid-antivirals and 920 treated with steroids alone) match the criteria. Owing to the result (chi(2) = 12.57, P = 0.08, I(2) = 44%) presented by the formal test for heterogeneity, the fixed effect meta-analysis model was chosen. The facial muscle recovery between the steroids-antivirals group and the steroids alone group show significant differences (OR = 1.52, 95% CI: 1.20-1.94), while the statistical outcome of adverse effect shows no statistical significance (OR = 1.28, 95% CI: 0.71-2.31). The present meta-analysis indicates that the steroid-antivirals treatment could improve the recovery rate in patients with Bell's palsy when comparing with the steroid alone treatment. This meta-analysis showed that the steroid-antivirals treatment achieved the better outcomes in patients with Bell's palsy. Clinicians should consider that steroid-antivirals therapy is an alternative choice for the patients with Bell's palsy.

Null Mutation of 5α-Reductase Type I Gene Alters Ethanol Consumption Patterns in a Sex-Dependent Manner

PubMed Central

Nickel, Jeffrey D.; Kaufman, Moriah N.; Finn, Deborah A.

2014-01-01

The neuroactive steroid allopregnanolone (ALLO) is a positive modulator of GABAA receptors, and manipulation of neuroactive steroid levels via injection of ALLO or the 5α-reductase inhibitor finasteride alters ethanol self-administration patterns in male, but not female, mice. The Srd5a1 gene encodes the enzyme 5α-reductase-1, which is required for the synthesis of ALLO. The current studies investigated the influence of Srd5a1 deletion on voluntary ethanol consumption in male and female wildtype (WT) and knockout (KO) mice. Under a continuous access condition, 6 and 10 % ethanol intake was significantly greater in KO versus WT females, but significantly lower in KO versus WT males. In 2-h limited access sessions, Srd5a1 deletion retarded acquisition of 10 % ethanol intake in female mice, but facilitated it in males, versus respective WT mice. The present findings demonstrate that the Srd5a1 gene modulates ethanol consumption in a sex-dependent manner that is also contingent upon ethanol access condition and concentration. PMID:25416204

Null mutation of 5α-reductase type I gene alters ethanol consumption patterns in a sex-dependent manner.

PubMed

Ford, Matthew M; Nickel, Jeffrey D; Kaufman, Moriah N; Finn, Deborah A

2015-05-01

The neuroactive steroid allopregnanolone (ALLO) is a positive modulator of GABAA receptors, and manipulation of neuroactive steroid levels via injection of ALLO or the 5α-reductase inhibitor finasteride alters ethanol self-administration patterns in male, but not female, mice. The Srd5a1 gene encodes the enzyme 5α-reductase-1, which is required for the synthesis of ALLO. The current studies investigated the influence of Srd5a1 deletion on voluntary ethanol consumption in male and female wildtype (WT) and knockout (KO) mice. Under a continuous access condition, 6 and 10 % ethanol intake was significantly greater in KO versus WT females, but significantly lower in KO versus WT males. In 2-h limited access sessions, Srd5a1 deletion retarded acquisition of 10 % ethanol intake in female mice, but facilitated it in males, versus respective WT mice. The present findings demonstrate that the Srd5a1 gene modulates ethanol consumption in a sex-dependent manner that is also contingent upon ethanol access condition and concentration.

Neurofeedback Control of the Human GABAergic System Using Non-invasive Brain Stimulation.

PubMed

Koganemaru, Satoko; Mikami, Yusuke; Maezawa, Hitoshi; Ikeda, Satoshi; Ikoma, Katsunori; Mima, Tatsuya

2018-06-01

Neurofeedback has been a powerful method for self-regulating brain activities to elicit potential ability of human mind. GABA is a major inhibitory neurotransmitter in the central nervous system. Transcranial magnetic stimulation (TMS) is a tool that can evaluate the GABAergic system within the primary motor cortex (M1) using paired-pulse stimuli, short intracortical inhibition (SICI). Herein we investigated whether neurofeedback learning using SICI enabled us to control the GABAergic system within the M1 area. Forty-five healthy subjects were randomly divided into two groups: those receiving SICI neurofeedback learning or those receiving no neurofeedback (control) learning. During both learning periods, subjects made attempts to change the size of a circle, which was altered according to the degree of SICI in the SICI neurofeedback learning group, and which was altered independent of the degree of SICI in the control learning group. Results demonstrated that the SICI neurofeedback learning group showed a significant enhancement in SICI. Moreover, this group showed a significant reduction in choice reaction time compared to the control group. Our findings indicate that humans can intrinsically control the intracortical GABAergic system within M1 and can thus improve motor behaviors by SICI neurofeedback learning. SICI neurofeedback learning is a novel and promising approach to control our neural system and potentially represents a new therapy for patients with abnormal motor symptoms caused by CNS disorders. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Genetic Elimination of GABAergic Neurotransmission Reveals Two Distinct Pacemakers for Spontaneous Waves of Activity in the Developing Mouse Cortex

PubMed Central

Easton, Curtis R.; Weir, Keiko; Scott, Adina; Moen, Samantha P.; Barger, Zeke; Folch, Albert; Hevner, Robert F.

2014-01-01

Many structures of the mammalian CNS generate propagating waves of electrical activity early in development. These waves are essential to CNS development, mediating a variety of developmental processes, such as axonal outgrowth and pathfinding, synaptogenesis, and the maturation of ion channel and receptor properties. In the mouse cerebral cortex, waves of activity occur between embryonic day 18 and postnatal day 8 and originate in pacemaker circuits in the septal nucleus and the piriform cortex. Here we show that genetic knock-out of the major synthetic enzyme for GABA, GAD67, selectively eliminates the picrotoxin-sensitive fraction of these waves. The waves that remain in the GAD67 knock-out have a much higher probability of propagating into the dorsal neocortex, as do the picrotoxin-resistant fraction of waves in controls. Field potential recordings at the point of wave initiation reveal different electrical signatures for GABAergic and glutamatergic waves. These data indicate that: (1) there are separate GABAergic and glutamatergic pacemaker circuits within the piriform cortex, each of which can initiate waves of activity; (2) the glutamatergic pacemaker initiates waves that preferentially propagate into the neocortex; and (3) the initial appearance of the glutamatergic pacemaker does not require preceding GABAergic waves. In the absence of GAD67, the electrical activity underlying glutamatergic waves shows greatly increased tendency to burst, indicating that GABAergic inputs inhibit the glutamatergic pacemaker, even at stages when GABAergic pacemaker circuitry can itself initiate waves. PMID:24623764

Desensitization of GABAergic receptors as a mechanism of zolpidem-induced somnambulism.

PubMed

Juszczak, Grzegorz R

2011-08-01

Sleepwalking is a frequently reported side effect of zolpidem which is a short-acting hypnotic drug potentiating activity of GABA(A) receptors. Paradoxically, the most commonly used medications for somnambulism are benzodiazepines, especially clonazepam, which also potentiate activity of GABA(A) receptors. It is proposed that zolpidem-induced sleepwalking can be explained by the desensitization of GABAergic receptors located on serotonergic neurons. According to the proposed model, the delay between desensitization of GABA receptors and a compensatory decrease in serotonin release constitutes the time window for parasomnias. The occurrence of sleepwalking depends on individual differences in receptor desensitization, autoregulation of serotonin release and drug pharmacokinetics. The proposed mechanism of interaction between GABAergic and serotonergic systems can be also relevant for zolpidem abuse and zolpidem-induced hallucinations. It is therefore suggested that special care should be taken when zolpidem is used in patients taking at the same time selective serotonin reuptake inhibitors. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ascl1 as a Novel Player in the Ptf1a Transcriptional Network for GABAergic Cell Specification in the Retina

PubMed Central

Parlier, Damien; Pretto, Silvia; Hamdache, Johanna; Vernier, Philippe; Locker, Morgane; Bellefroid, Eric; Perron, Muriel

2014-01-01

In contrast with the wealth of data involving bHLH and homeodomain transcription factors in retinal cell type determination, the molecular bases underlying neurotransmitter subtype specification is far less understood. Using both gain and loss of function analyses in Xenopus, we investigated the putative implication of the bHLH factor Ascl1 in this process. We found that in addition to its previously characterized proneural function, Ascl1 also contributes to the specification of the GABAergic phenotype. We showed that it is necessary for retinal GABAergic cell genesis and sufficient in overexpression experiments to bias a subset of retinal precursor cells towards a GABAergic fate. We also analysed the relationships between Ascl1 and a set of other bHLH factors using an in vivo ectopic neurogenic assay. We demonstrated that Ascl1 has unique features as a GABAergic inducer and is epistatic over factors endowed with glutamatergic potentialities such as Neurog2, NeuroD1 or Atoh7. This functional specificity is conferred by the basic DNA binding domain of Ascl1 and involves a specific genetic network, distinct from that underlying its previously demonstrated effects on catecholaminergic differentiation. Our data show that GABAergic inducing activity of Ascl1 requires the direct transcriptional regulation of Ptf1a, providing therefore a new piece of the network governing neurotransmitter subtype specification during retinogenesis. PMID:24643195

Initial Steroid Sensitivity in Children with Steroid-Resistant Nephrotic Syndrome Predicts Post-Transplant Recurrence

PubMed Central

Ding, Wen Y.; Koziell, Ania; McCarthy, Hugh J.; Bierzynska, Agnieszka; Bhagavatula, Murali K.; Dudley, Jan A.; Inward, Carol D.; Coward, Richard J.; Tizard, Jane; Reid, Christopher; Antignac, Corinne; Boyer, Olivia

2014-01-01

Of children with idiopathic nephrotic syndrome, 10%–20% fail to respond to steroids or develop secondary steroid resistance (termed initial steroid sensitivity) and the majority progress to transplantation. Although 30%–50% of these patients suffer disease recurrence after transplantation, with poor long-term outcome, no reliable indicator of recurrence has yet been identified. Notably, the incidence of recurrence after transplantation appears reduced in patients with steroid-resistant nephrotic syndrome (SRNS) due to monogenic disorders. We reviewed 150 transplanted patients with SRNS to identify biomarkers that consistently predict outcome of SRNS after transplantation. In all, 25 children had genetic or familial SRNS and did not experience post-transplant recurrence. We reviewed phenotypic factors, including initial steroid sensitivity, donor type, age, ethnicity, time to ESRD, and time on dialysis, in the remaining 125 children. Of these patients, 57 (45.6%) developed post-transplant recurrence; 26 of 28 (92.9%) patients with initial steroid sensitivity recurred after transplantation, whereas only 26 of 86 (30.2%) patients resistant from the outset recurred (odds ratio, 30; 95% confidence interval, 6.62 to 135.86; P<0.001). We were unable to determine recurrence in two patients (one with initial steroid sensitivity), and nine patients did not receive initial steroids. Our data show that initial steroid sensitivity is highly predictive of post-transplant disease recurrence in this pediatric patient population. Because a pathogenic circulating permeability factor in nephrotic syndrome remains to be confirmed, we propose initial steroid sensitivity as a surrogate marker for post-transplant recurrence. PMID:24511128

Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer’s Disease

PubMed Central

Sun, Binggui; Halabisky, Brian; Zhou, Yungui; Palop, Jorge J.; Yu, Guiqiu; Mucke, Lennart; Gan, Li

2009-01-01

SUMMARY Adult neurogenesis regulates plasticity and function in the hippocampus, which is critical for memory and vulnerable to Alzheimer’s disease (AD). Promoting neurogenesis may improve hippocampal function in AD brains. However, how amyloid β (Aβ), the key AD pathogen, affects the development and function of adult-born neurons remains unknown. Adult-born granule cells (GCs) in human amyloid precursor protein (hAPP) transgenic mice, an AD model, showed greater dendritic length, spine density, and functional responses than controls early in development, but were impaired morphologically and functionally during later maturation. Early inhibition of GABAA receptors to suppress GABAergic signaling or late inhibition of calcineurin to enhance glutamatergic signaling normalized the development of adult-born GCs in hAPP mice with high Aβ levels. Aβ-induced increases in GABAergic neurotransmission or an imbalance between GABAergic and glutamatergic neurotransmission may contribute to impaired neurogenesis in AD. PMID:19951690

Unique pH dynamics in GABAergic synaptic vesicles illuminates the mechanism and kinetics of GABA loading.

PubMed

Egashira, Yoshihiro; Takase, Miki; Watanabe, Shoji; Ishida, Junji; Fukamizu, Akiyoshi; Kaneko, Ryosuke; Yanagawa, Yuchio; Takamori, Shigeo

2016-09-20

GABA acts as the major inhibitory neurotransmitter in the mammalian brain, shaping neuronal and circuit activity. For sustained synaptic transmission, synaptic vesicles (SVs) are required to be recycled and refilled with neurotransmitters using an H(+) electrochemical gradient. However, neither the mechanism underlying vesicular GABA uptake nor the kinetics of GABA loading in living neurons have been fully elucidated. To characterize the process of GABA uptake into SVs in functional synapses, we monitored luminal pH of GABAergic SVs separately from that of excitatory glutamatergic SVs in cultured hippocampal neurons. By using a pH sensor optimal for the SV lumen, we found that GABAergic SVs exhibited an unexpectedly higher resting pH (∼6.4) than glutamatergic SVs (pH ∼5.8). Moreover, unlike glutamatergic SVs, GABAergic SVs displayed unique pH dynamics after endocytosis that involved initial overacidification and subsequent alkalization that restored their resting pH. GABAergic SVs that lacked the vesicular GABA transporter (VGAT) did not show the pH overshoot and acidified further to ∼6.0. Comparison of luminal pH dynamics in the presence or absence of VGAT showed that VGAT operates as a GABA/H(+) exchanger, which is continuously required to offset GABA leakage. Furthermore, the kinetics of GABA transport was slower (τ > 20 s at physiological temperature) than that of glutamate uptake and may exceed the time required for reuse of exocytosed SVs, allowing reuse of incompletely filled vesicles in the presence of high demand for inhibitory transmission.

Antipsychotics promote GABAergic interneuron genesis in the adult rat brain: Role of heat-shock protein production.

PubMed

Kaneta, Hiroo; Ukai, Wataru; Tsujino, Hanako; Furuse, Kengo; Kigawa, Yoshiyasu; Tayama, Masaya; Ishii, Takao; Hashimoto, Eri; Kawanishi, Chiaki

2017-09-01

Current antipsychotics reduce positive symptoms and reverse negative symptoms in conjunction with cognitive behavioral issues with the goal of restoring impaired occupational and social functioning. However, limited information is available on their influence on gliogenesis or their neurogenic properties in adult schizophrenia brains, particularly on GABAergic interneuron production. In the present study, we used young adult subventricular zone (SVZ)-derived progenitor cells expressing proteoglycan NG2 cultures to examine the oligodendrocyte and GABAergic interneuron genesis effects of several kinds of antipsychotics on changes in differentiation function induced by exposure to the NMDA receptor antagonist MK-801. We herein demonstrated that antipsychotics promoted or restored changes in the oligodendrocyte/GABAergic interneuron differentiation functions of NG2(+) cells induced by the exposure to MK-801, which was considered to be one of the drug-induced schizophrenia model. We also demonstrated that antipsychotics restored heat-shock protein (HSP) production in NG2(+) cells with differentiation impairment. The antipsychotics olanzapine, aripiprazole, and blonanserin, but not haloperidol increased HSP90 levels, which were reduced by the exposure to MK-801. Our results showed that antipsychotics, particularly those recently synthesized, exerted similar GABAergic interneuron genesis effects on NG2(+) neuronal/glial progenitor cells in the adult rat brain by increasing cellular HSP production, and also suggest that HSP90 may play a crucial role in the pathophysiology of schizophrenia and is a key target for next drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia.

PubMed

Balan, Shabeesh; Yamada, Kazuo; Iwayama, Yoshimi; Hashimoto, Takanori; Toyota, Tomoko; Shimamoto, Chie; Maekawa, Motoko; Takagai, Shu; Wakuda, Tomoyasu; Kameno, Yosuke; Kurita, Daisuke; Yamada, Kohei; Kikuchi, Mitsuru; Hashimoto, Tasuku; Kanahara, Nobuhisa; Yoshikawa, Takeo

2017-07-01

Involvement of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining schizophrenia risk is unknown. We therefore tested the association of 375 tagged SNPs in genes derived from the GABAergic system, such as GABA A receptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese schizophrenia case-control samples (n=2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABA A receptor subunit genes and the GPHN gene with schizophrenia, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (P allele =0.002; uncorrected) and rs1157122 (P allele =0.006; uncorrected) showed top hits, followed by rs723432 (P allele =0.007; uncorrected) in the GPHN gene. All three were significantly associated with schizophrenia and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not GPHN were significantly associated with schizophrenia. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in schizophrenia susceptibility. These results warrant further investigations to replicate the association of GABRA1 and GPHN with schizophrenia and to discern the precise mechanisms of disease pathophysiology. Copyright © 2017 Elsevier B.V. All rights reserved.

GABAergic signaling in the rat pineal gland

PubMed Central

Yu, Haijie; Benitez, Sergio G.; Jung, Seung-Ryoung; Farias Altamirano, Luz E.; Kruse, Martin; Seo, Jong-Bae; Koh, Duk-Su; Muñoz, Estela M.; Hille, Bertil

2017-01-01

Pinealocytes secrete melatonin at night in response to norepinephrine released from sympathetic nerve terminals in the pineal gland. The gland also contains many other neurotransmitters whose cellular disposition, activity, and relevance to pineal function are not understood. Here we clarify sources and demonstrate cellular actions of the neurotransmitter γ-aminobutyric acid (GABA) using Western blotting and immunohistochemistry of the gland and electrical recording from pinealocytes. GABAergic cells and nerve fibers, defined as containing GABA and the synthetic enzyme GAD67, were identified. The cells represent a subset of interstitial cells while the nerve fibers were distinct from the sympathetic innervation. The GABAA receptor subunit α1 was visualized in close proximity of both GABAergic and sympathetic nerve fibers as well as fine extensions among pinealocytes and blood vessels. The GABAB1 receptor subunit was localized in the interstitial compartment but not in pinealocytes. Electrophysiology of isolated pinealocytes revealed that GABA and muscimol elicit strong inward chloride currents sensitive to bicuculline and picrotoxin, clear evidence for functional GABAA receptors on the surface membrane. Applications of elevated potassium solution or the neurotransmitter acetylcholine depolarized the pinealocyte membrane potential enough to open voltage-gated Ca2+ channels leading to intracellular calcium elevations. GABA repolarized the membrane and shut off such calcium rises. In 48–72-h cultured intact glands, GABA application neither triggered melatonin secretion by itself nor affected norepinephrine-induced secretion. Thus strong elements of GABA signaling are present in pineal glands that make large electrical responses in pinealocytes, but physiological roles need to be found. PMID:27019076

Neuroprotection of Sex Steroids

PubMed Central

Liu, Mingyue; Kelley, Melissa H.; Herson, Paco S.; Hurn, Patricia D.

2011-01-01

Sex steroids are essential for reproduction and development in animals and humans, and sex steroids also play an important role in neuroprotection following brain injury. New data indicate that sex-specific responses to brain injury occur at the cellular and molecular levels. This review summarizes the current understanding of neuroprotection by sex steroids, particularly estrogen, androgen, and progesterone, based on both in vitro and in vivo studies. Better understanding of the role of sex steroids under physiological and pathological conditions will help us to develop novel effective therapeutic strategies for brain injury. PMID:20595940

Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii

PubMed Central

Boychuk, Carie R.; Gyarmati, Peter; Xu, Hong

2015-01-01

Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated. PMID:26084907

Low-frequency electrical stimulation enhances the effectiveness of phenobarbital on GABAergic currents in hippocampal slices of kindled rats.

PubMed

Asgari, Azam; Semnanian, Saeed; Atapour, Nafiseh; Shojaei, Amir; Moradi-Chameh, Homeira; Ghafouri, Samireh; Sheibani, Vahid; Mirnajafi-Zadeh, Javad

2016-08-25

Low frequency stimulation (LFS) has been proposed as a new approach in the treatment of epilepsy. The anticonvulsant mechanism of LFS may be through its effect on GABAA receptors, which are the main target of phenobarbital anticonvulsant action. We supposed that co-application of LFS and phenobarbital may increase the efficacy of phenobarbital. Therefore, the interaction of LFS and phenobarbital on GABAergic inhibitory post-synaptic currents (IPSCs) in kindled and control rats was investigated. Animals were kindled by electrical stimulation of basolateral amygdala in a semi rapid manner (12 stimulations/day). The effect of phenobarbital, LFS and phenobarbital+LFS was investigated on GABAA-mediated evoked and miniature IPSCs in the hippocampal brain slices in control and fully kindled animals. Phenobarbital and LFS had positive interaction on GABAergic currents. In vitro co-application of an ineffective pattern of LFS (100 pulses at afterdischarge threshold intensity) and a sub-threshold dose of phenobarbital (100μM) which had no significant effect on GABAergic currents alone, increased the amplitude and area under curve of GABAergic currents in CA1 pyramidal neurons of hippocampal slices significantly. Interestingly, the sub-threshold dose of phenobarbital potentiated the GABAergic currents when applied on the hippocampal slices of kindled animals which received LFS in vivo. Post-synaptic mechanisms may be involved in observed interactions. Obtained results implied a positive interaction between LFS and phenobarbital through GABAA currents. It may be suggested that a combined therapy of phenobarbital and LFS may be a useful manner for reinforcing the anticonvulsant action of phenobarbital. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Glutamatergic and GABAergic neurotransmitter cycling and energy metabolism in rat cerebral cortex during postnatal development.

PubMed

Chowdhury, Golam M I; Patel, Anant B; Mason, Graeme F; Rothman, Douglas L; Behar, Kevin L

2007-12-01

The contribution of glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons to oxidative energy metabolism and neurotransmission in the developing brain is not known. Glutamatergic and GABAergic fluxes were assessed in neocortex of postnatal day 10 (P10) and 30 (P30) urethane-anesthetized rats infused intravenously with [1,6-(13)C(2)]glucose for different time intervals (time course) or with [2-(13)C]acetate for 2 to 3 h (steady state). Amino acid levels and (13)C enrichments were determined in tissue extracts ex vivo using (1)H-[(13)C]-NMR spectroscopy. Metabolic fluxes were estimated from the best fits of a three-compartment metabolic model (glutamatergic neurons, GABAergic neurons, and astroglia) to the (13)C-enrichment time courses of amino acids from [1,6-(13)C(2)]glucose, constrained by the ratios of neurotransmitter cycling (V(cyc))-to-tricarboxylic acid (TCA) cycle flux (V(TCAn)) calculated from the steady-state [2-(13)C]acetate enrichment data. From P10 to P30 increases in total neuronal (glutamate plus GABA) TCA cycle flux (3 x ; 0.24+/-0.05 versus 0.71+/-0.07 micromol per g per min, P<0.0001) and total neurotransmitter cycling flux (3.1 to 5 x ; 0.07 to 0.11 (+/-0.03) versus 0.34+/-0.03 micromol per g per min, P<0.0001) were approximately proportional. Incremental changes in total cycling (DeltaV(cyc(tot))) and neuronal TCA cycle flux (DeltaV(TCAn(tot))) between P10 and P30 were 0.23 to 0.27 and 0.47 micromol per g per min, respectively, similar to the approximately 1:2 relationship previously reported for adult cortex. For the individual neurons, increases in V(TCAn) and V(cyc) were similar in magnitude (glutamatergic neurons, 2.7 x versus 2.8 to 4.6 x ; GABAergic neurons, approximately 5 x versus approximately 7 x), although GABAergic flux changes were larger. The findings show that glutamate and GABA neurons undergo large and approximately proportional increases in neurotransmitter cycling and oxidative energy metabolism during this major

Distribution and Intrinsic Membrane Properties of Basal Forebrain GABAergic and Parvalbumin Neurons in the Mouse

PubMed Central

McKenna, James T.; Yang, Chun; Franciosi, Serena; Winston, Stuart; Abarr, Kathleen K.; Rigby, Matthew S.; Yanagawa, Yuchio; McCarley, Robert W.; Brown, Ritchie E.

2013-01-01

The basal forebrain (BF) strongly regulates cortical activation, sleep homeostasis, and attention. Many BF neurons involved in these processes are GABAergic, including a subpopulation of projection neurons containing the calcium-binding protein, parvalbumin (PV). However, technical difficulties in identification have prevented a precise mapping of the distribution of GABAergic and GABA/PV+ neurons in the mouse or a determination of their intrinsic membrane properties. Here we used mice expressing fluorescent proteins in GABAergic (GAD67-GFP knock-in mice) or PV+ neurons (PV-Tomato mice) to study these neurons. Immunohistochemical staining for GABA in GAD67-GFP mice confirmed that GFP selectively labeled BF GABAergic neurons. GFP+ neurons and fibers were distributed throughout the BF, with the highest density in the magnocellular preoptic area (MCPO). Immunohistochemistry for PV indicated that the majority of PV+ neurons in the BF were large (>20 μm) or medium-sized (15–20 μm) GFP+ neurons. Most medium and large-sized BF GFP+ neurons, including those retrogradely labeled from the neocortex, were fast-firing and spontaneously active in vitro. They exhibited prominent hyperpolarization-activated inward currents and subthreshold “spikelets,” suggestive of electrical coupling. PV+ neurons recorded in PV-Tomato mice had similar properties but had significantly narrower action potentials and a higher maximal firing frequency. Another population of smaller GFP+ neurons had properties similar to striatal projection neurons. The fast firing and electrical coupling of BF GABA/PV+ neurons, together with their projections to cortical interneurons and the thalamic reticular nucleus, suggest a strong and synchronous control of the neocortical fast rhythms typical of wakefulness and REM sleep. PMID:23254904

Dopamine modulation of GABAergic function enables network stability and input selectivity for sustaining working memory in a computational model of the prefrontal cortex.

PubMed

Lew, Sergio E; Tseng, Kuei Y

2014-12-01

Dopamine modulation of GABAergic transmission in the prefrontal cortex (PFC) is thought to be critical for sustaining cognitive processes such as working memory and decision-making. Here, we developed a neurocomputational model of the PFC that includes physiological features of the facilitatory action of dopamine on fast-spiking interneurons to assess how a GABAergic dysregulation impacts on the prefrontal network stability and working memory. We found that a particular non-linear relationship between dopamine transmission and GABA function is required to enable input selectivity in the PFC for the formation and retention of working memory. Either degradation of the dopamine signal or the GABAergic function is sufficient to elicit hyperexcitability in pyramidal neurons and working memory impairments. The simulations also revealed an inverted U-shape relationship between working memory and dopamine, a function that is maintained even at high levels of GABA degradation. In fact, the working memory deficits resulting from reduced GABAergic transmission can be rescued by increasing dopamine tone and vice versa. We also examined the role of this dopamine-GABA interaction for the termination of working memory and found that the extent of GABAergic excitation needed to reset the PFC network begins to occur when the activity of fast-spiking interneurons surpasses 40 Hz. Together, these results indicate that the capability of the PFC to sustain working memory and network stability depends on a robust interplay of compensatory mechanisms between dopamine tone and the activity of local GABAergic interneurons.

Steroid-antivirals treatment versus steroids alone for the treatment of Bell’s palsy: a meta-analysis

PubMed Central

Dong, Yabing; Zhu, Yong; Ma, Chuan; Zhao, Huaqiang

2015-01-01

Background: To illustrate whether the steroid-antivirals treatment could acquire a better recovery in patients with Bell’s palsy than the steroids alone treatment. Materials and methods: We conducted an exhaustive search over Pub med/Medline, Ovid, Elsevier search engines and the Cochrane library thereby collecting the randomized controlled trials in the treatment of patients with Bell’s palsy with steroid-antivirals and steroids. The qualities of relevant articles were assessed by GRADE, which was used to present the overall quality of evidence as recommended by the Cochrane Handbook for Systematic Reviews of Interventions. Results: Two investigators evaluated these papers independently, and resolved the disagreements by discussion. At last 8 eligible papers (1816 patients included: 896 treated with steroid-antivirals and 920 treated with steroids alone) match the criteria. Owing to the result (chi2 = 12.57, P = 0.08, I2 = 44%) presented by the formal test for heterogeneity, the fixed effect meta-analysis model was chosen. The facial muscle recovery between the steroids-antivirals group and the steroids alone group show significant differences (OR = 1.52, 95% CI: 1.20-1.94), while the statistical outcome of adverse effect shows no statistical significance (OR = 1.28, 95% CI: 0.71-2.31). Conclusions: The present meta-analysis indicates that the steroid-antivirals treatment could improve the recovery rate in patients with Bell’s palsy when comparing with the steroid alone treatment. Clinical significance: This meta-analysis showed that the steroid-antivirals treatment achieved the better outcomes in patients with Bell’s palsy. Clinicians should consider that steroid-antivirals therapy is an alternative choice for the patients with Bell’s palsy. PMID:25785012

Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission

PubMed Central

Du, Xiaona; Hao, Han; Yang, Yuehui; Huang, Sha; Wang, Caixue; Gigout, Sylvain; Ramli, Rosmaliza; Li, Xinmeng; Jaworska, Ewa; Edwards, Ian; Yanagawa, Yuchio; Qi, Jinlong; Guan, Bingcai; Jaffe, David B.; Zhang, Hailin

2017-01-01

The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention. PMID:28375159

Sex steroids and neurogenesis.

PubMed

Heberden, Christine

2017-10-01

The brain has long been known as a dimorphic organ and as a target of sex steroids. It is also a site for their synthesis. Sex steroids in numerous ways can modify cerebral physiology, and along with many processes adult neurogenesis is also modulated by sex steroids. This review will focus on the effects of the main steroids, estrogens, androgens and progestogens, and unveil some aspects of their partly disclosed mechanisms of actions. Gonadal steroids act on different steps of neurogenesis: cell proliferation seems to be increased by estrogens only, while androgens and progestogens favor neuronal renewal by increasing cell survival; differentiation is a common target. Aging is characterized by a cognitive deficiency, paralleled by a decrease in the rate of neuronal renewal and in the levels of circulating gonadal hormones. Therefore, the effects of gonadal hormones on the aging brain are important to consider. The review will also be expanded to related molecules which are agonists to the nuclear receptors. Sex steroids can modify adult neuronal renewal and the extensive knowledge of their actions on neurogenesis is essential, as it can be a leading pathway to therapeutic perspectives. Copyright © 2017 Elsevier Inc. All rights reserved.

GABAergic signaling in the rat pineal gland.

PubMed

Yu, Haijie; Benitez, Sergio G; Jung, Seung-Ryoung; Farias Altamirano, Luz E; Kruse, Martin; Seo, Jong Bae; Koh, Duk-Su; Muñoz, Estela M; Hille, Bertil

2016-08-01

Pinealocytes secrete melatonin at night in response to norepinephrine released from sympathetic nerve terminals in the pineal gland. The gland also contains many other neurotransmitters whose cellular disposition, activity, and relevance to pineal function are not understood. Here, we clarify sources and demonstrate cellular actions of the neurotransmitter γ-aminobutyric acid (GABA) using Western blotting and immunohistochemistry of the gland and electrical recording from pinealocytes. GABAergic cells and nerve fibers, defined as containing GABA and the synthetic GAD67, were identified. The cells represent a subset of interstitial cells while the nerve fibers were distinct from the sympathetic innervation. The GABAA receptor subunit α1 was visualized in close proximity of both GABAergic and sympathetic nerve fibers as well as fine extensions among pinealocytes and blood vessels. The GABAB 1 receptor subunit was localized in the interstitial compartment but not in pinealocytes. Electrophysiology of isolated pinealocytes revealed that GABA and muscimol elicit strong inward chloride currents sensitive to bicuculline and picrotoxin, clear evidence for functional GABAA receptors on the surface membrane. Applications of elevated potassium solution or the neurotransmitter acetylcholine depolarized the pinealocyte membrane potential enough to open voltage-gated Ca(2+) channels leading to intracellular calcium elevations. GABA repolarized the membrane and shut off such calcium rises. In 48-72-h cultured intact glands, GABA application neither triggered melatonin secretion by itself nor affected norepinephrine-induced secretion. Thus, strong elements of GABA signaling are present in pineal glands that make large electrical responses in pinealocytes, but physiological roles need to be found. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Nonprescription steroids on the Internet.

PubMed

Clement, Christen L; Marlowe, Douglas B; Patapis, Nicholas S; Festinger, David S; Forman, Robert F

2012-02-01

This study evaluated the degree to which anabolic-androgenic steroids are proffered for sale over the Internet and how they are characterized on popular Web sites. Searches for specific steroid product labels (e.g., Dianabol) between March 2006 and June 2006 revealed that approximately half of the Web sites advocated their "safe" use, and roughly one third offered to sell them without prescriptions. The Web sites frequently presented misinformation about steroids and minimized their dangers. Less than 5% of the Web sites presented accurate health risk information about steroids or provided information to abusers seeking to discontinue their steroid use. Implications for education, prevention, treatment, and policy are discussed.

Nonprescription Steroids on the Internet

PubMed Central

McDonald, Christen L.; Marlowe, Douglas B.; Patapis, Nicholas S.; Festinger, David S.; Forman, Robert F.

2008-01-01

This study evaluated the degree to which anabolic-androgenic steroids are proffered for sale over the Internet and how they are characterized on popular websites. Searches for specific steroid product labels (e.g., Dianabol) between March and June, 2006 revealed that approximately half of the websites advocated their “safe” use, and roughly one-third offered to sell them without prescriptions. The websites frequently presented misinformation about steroids and minimized their dangers. Less than 5% of the websites presented accurate health risk information about steroids or provided information to abusers seeking to discontinue their steroid use. Implications for education, prevention, treatment and policy are discussed. PMID:22080724

Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques.

PubMed

Garcia-Marin, Virginia; Blazquez-Llorca, Lidia; Rodriguez, José-Rodrigo; Boluda, Susana; Muntane, Gerard; Ferrer, Isidro; Defelipe, Javier

2009-01-01

One of the main pathological hallmarks of Alzheimer's disease (AD) is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic) and perisomatic (mostly GABAergic) regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought.

Successful treatment of dwarfism secondary to long-term steroid therapy in steroid-dependent nephrotic syndrome.

PubMed

Sun, Linlin; Chen, Dongping; Zhao, Xuezhi; Xu, Chenggang; Mei, Changlin

2010-01-01

Prolonged steroid therapy is generally used for steroid-dependent nephrotic syndrome in pediatric patients. However, dwarfism secondary to a long-term regimen and its successful reverse is rarely reported. The underlying mechanism of dwarfism is still poorly understood, as both long-term steroid use and nephrotic syndrome may interact or independently interfere with the process of growth. Here, we present a 17-year-old patient with dwarfism and steroid-dependent nephrotic syndrome and the successful treatment by recombinant human growth factor and cyclosporine A with withdrawal of steroid. We also briefly review the current understanding and the management of dwarfism in pediatric patients with nephrotic syndrome.

Discreet charm of the GABAergic bourgeoisie: superconnected cells conduct developmental symphonies.

PubMed

Case, Marianne; Soltesz, Ivan

2009-12-24

In an exciting study in the December 4(th) issue of Science, Bonifazi and colleagues demonstrated the existence and importance of exceedingly rare but unusually richly connected cells in the developing hippocampus. Manipulating the activity of single GABAergic hub cells modulated network activity patterns, demonstrating their importance for coordinating synchronous activity. 2009 Elsevier Inc. All rights reserved.

[Steroid hormones and pancreas: a new paradigm].

PubMed

Morales-Miranda, Angélica; Robles-Díaz, Guillermo; Díaz-Sánchez, Vicente

2007-01-01

The relation between steroid hormones and pancreatic function has been poorly discussed and not very well understood. In general, there is a lack of recognition among the scientific community about the importance of steroids in pancreatic function (current paradigm). In the present article we present basic, as well as clinic and epidemiologic data that demonstrate steroid synthesis and steroid biotransformation by pancreatic tissue, how exocrine and endocrine functions are modulated by steroids, the gender specific frequency and behavior of some tumors and the use of synthetic steroids and steroid action antagonists as therapeutic agents. With the available information it is possible to establish that: 1. Pancreatic tissue synthesize and transform steroid hormones. 2. Pancreatic tissue respond to steroid hormones and express steroid specific receptor molecules. 3. Some endocrine functions such as insulin synthesis and release are modulated by steroids. 4. Tumor growth is modulated by steroids and anti-steroid drugs. This set of data creates a new paradigm for the holistic study of pancreas and opens new research fields. The application of this new paradigm might result in an increase in the knowledge of pancreatic physiology, in the design of new and better diagnostic methods and eventually in the design of more effective medical treatments for the pancreatic cancers.

Medial septal GABAergic projection neurons promote object exploration behavior and type 2 theta rhythm

PubMed Central

Gangadharan, Gireesh; Shin, Jonghan; Kim, Seong-Wook; Kim, Angela; Paydar, Afshin; Kim, Duk-Soo; Miyazaki, Taisuke; Watanabe, Masahiko; Yanagawa, Yuchio; Kim, Jinhyun; Kim, Yeon-Soo; Kim, Daesoo; Shin, Hee-Sup

2016-01-01

Exploratory drive is one of the most fundamental emotions, of all organisms, that are evoked by novelty stimulation. Exploratory behavior plays a fundamental role in motivation, learning, and well-being of organisms. Diverse exploratory behaviors have been described, although their heterogeneity is not certain because of the lack of solid experimental evidence for their distinction. Here we present results demonstrating that different neural mechanisms underlie different exploratory behaviors. Localized Cav3.1 knockdown in the medial septum (MS) selectively enhanced object exploration, whereas the null mutant (KO) mice showed enhanced-object exploration as well as open-field exploration. In MS knockdown mice, only type 2 hippocampal theta rhythm was enhanced, whereas both type 1 and type 2 theta rhythm were enhanced in KO mice. This selective effect was accompanied by markedly increased excitability of septo-hippocampal GABAergic projection neurons in the MS lacking T-type Ca2+ channels. Furthermore, optogenetic activation of the septo-hippocampal GABAergic pathway in WT mice also selectively enhanced object exploration behavior and type 2 theta rhythm, whereas inhibition of the same pathway decreased the behavior and the rhythm. These findings define object exploration distinguished from open-field exploration and reveal a critical role of T-type Ca2+ channels in the medial septal GABAergic projection neurons in this behavior. PMID:27208094

[Intramuscular depot steroids : Possible treatment of postsurgical cystoid macula edema with steroid response?

PubMed

Seuthe, A-M; Szurman, P; Boden, K T

2017-11-01

We report on a patient with postsurgical cystoid macular edema (CME) after phacoemulsification and multifocal intraocular lens (MIOL) implantation. At first, there was a very good reaction to intravitreal triamcinolone, inducing complete regression of the edema without increasing intraocular pressure (IOP). One year later the patient suffered from retinal detachment and was treated with vitrectomy, laser, and gas tamponade. Afterward, he developed macular pucker with edema. After surgical treatment with pucker peeling and intravitreal triamcinolone, the patient showed a steroid response and an increase IOP. Postoperatively, there was a recurrence of CME. A coincidental administration of a steroid injection intramuscularly by the general practitioner achieved a prompt reduction of the CME without increasing IOP. This case shows that an initially good reaction to triamcinolone without increasing IOP does not rule out a future steroid response, and that a potential treatment option for CME in patients with a known steroid response could consist of intramuscularly injected steroids.

Pharmacology of anabolic steroids.

PubMed

Kicman, A T

2008-06-01

Athletes and bodybuilders have recognized for several decades that the use of anabolic steroids can promote muscle growth and strength but it is only relatively recently that these agents are being revisited for clinical purposes. Anabolic steroids are being considered for the treatment of cachexia associated with chronic disease states, and to address loss of muscle mass in the elderly, but nevertheless their efficacy still needs to be demonstrated in terms of improved physical function and quality of life. In sport, these agents are performance enhancers, this being particularly apparent in women, although there is a high risk of virilization despite the favourable myotrophic-androgenic dissociation that many xenobiotic steroids confer. Modulation of androgen receptor expression appears to be key to partial dissociation, with consideration of both intracellular steroid metabolism and the topology of the bound androgen receptor interacting with co-activators. An anticatabolic effect, by interfering with glucocorticoid receptor expression, remains an attractive hypothesis. Behavioural changes by non-genomic and genomic pathways probably help motivate training. Anabolic steroids continue to be the most common adverse finding in sport and, although apparently rare, designer steroids have been synthesized in an attempt to circumvent the dope test. Doping with anabolic steroids can result in damage to health, as recorded meticulously in the former German Democratic Republic. Even so, it is important not to exaggerate the medical risks associated with their administration for sporting or bodybuilding purposes but to emphasize to users that an attitude of personal invulnerability to their adverse effects is certainly misguided.

Pharmacology of anabolic steroids

PubMed Central

Kicman, A T

2008-01-01

Athletes and bodybuilders have recognized for several decades that the use of anabolic steroids can promote muscle growth and strength but it is only relatively recently that these agents are being revisited for clinical purposes. Anabolic steroids are being considered for the treatment of cachexia associated with chronic disease states, and to address loss of muscle mass in the elderly, but nevertheless their efficacy still needs to be demonstrated in terms of improved physical function and quality of life. In sport, these agents are performance enhancers, this being particularly apparent in women, although there is a high risk of virilization despite the favourable myotrophic–androgenic dissociation that many xenobiotic steroids confer. Modulation of androgen receptor expression appears to be key to partial dissociation, with consideration of both intracellular steroid metabolism and the topology of the bound androgen receptor interacting with co-activators. An anticatabolic effect, by interfering with glucocorticoid receptor expression, remains an attractive hypothesis. Behavioural changes by non-genomic and genomic pathways probably help motivate training. Anabolic steroids continue to be the most common adverse finding in sport and, although apparently rare, designer steroids have been synthesized in an attempt to circumvent the dope test. Doping with anabolic steroids can result in damage to health, as recorded meticulously in the former German Democratic Republic. Even so, it is important not to exaggerate the medical risks associated with their administration for sporting or bodybuilding purposes but to emphasize to users that an attitude of personal invulnerability to their adverse effects is certainly misguided. PMID:18500378

Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking

PubMed Central

Van den Oever, Michel C; Lubbers, Bart R; Goriounova, Natalia A; Li, Ka W; Van der Schors, Roel C; Loos, Maarten; Riga, Danai; Wiskerke, Joost; Binnekade, Rob; Stegeman, M; Schoffelmeer, Anton N M; Mansvelder, Huibert D; Smit, August B; De Vries, Taco J; Spijker, Sabine

2010-01-01

Successful treatment of drug addiction is hampered by high relapse rates during periods of abstinence. Neuroadaptation in the medial prefrontal cortex (mPFC) is thought to have a crucial role in vulnerability to relapse to drug seeking, but the molecular and cellular mechanisms remain largely unknown. To identify protein changes that contribute to relapse susceptibility, we investigated synaptic membrane fractions from the mPFC of rats that underwent 21 days of forced abstinence following heroin self-administration. Quantitative proteomics revealed that long-term abstinence from heroin self-administration was associated with reduced levels of extracellular matrix (ECM) proteins. After extinction of heroin self-administration, downregulation of ECM proteins was also present in the mPFC, as well as nucleus accumbens (NAc), and these adaptations were partially restored following cue-induced reinstatement of heroin seeking. In the mPFC, these ECM proteins are condensed in the perineuronal nets that exclusively surround GABAergic interneurons, indicating that ECM adaptation might alter the activity of GABAergic interneurons. In support of this, we observed an increase in the inhibitory GABAergic synaptic inputs received by the mPFC pyramidal cells after the re-exposure to heroin-conditioned cues. Recovering levels of ECM constituents by metalloproteinase inhibitor treatment (FN-439; i.c.v.) prior to a reinstatement test attenuated subsequent heroin seeking, suggesting that the reduced synaptic ECM levels during heroin abstinence enhanced sensitivity to respond to heroin-conditioned cues. We provide evidence for a novel neuroadaptive mechanism, in which heroin self-administration-induced adaptation of the ECM increased relapse vulnerability, potentially by augmenting the responsivity of mPFC GABAergic interneurons to heroin-associated stimuli. PMID:20592718

Preprodynorphin-expressing neurons constitute a large subgroup of somatostatin-expressing GABAergic interneurons in the mouse neocortex.

PubMed

Sohn, Jaerin; Hioki, Hiroyuki; Okamoto, Shinichiro; Kaneko, Takeshi

2014-05-01

Dynorphins, leumorphin, and neoendorphins are preprodynorphin (PPD)-derived peptides and ligands for κ-opioid receptors. Using an antibody to PPD C-terminal, we investigated the chemical and molecular characteristics of PPD-expressing neurons in mouse neocortex. PPD-immunopositive neuronal somata were distributed most frequently in layer 5 and less frequently in layers 2-4 and 6 throughout neocortical regions. Combined labeling of immunofluorescence and fluorescent mRNA signals revealed that almost all PPD-immunopositive neurons expressed glutamic acid decarboxylase but not vesicular glutamate transporter, indicating their γ-aminobutyric acid (GABA)ergic characteristics, and that PPD-immunopositive neurons accounted for 15% of GABAergic interneurons in the primary somatosensory area. As GABAergic interneurons were divided into several groups by specific markers, we further examined the chemical characteristics of PPD-expressing neurons by the double immunofluorescence labeling method. More than 95% of PPD-immunopositive neurons were also somatostatin (SOM)-immunopositive in the primary somatosensory, primary motor, orbitofrontal, and primary visual areas, but only 24% were SOM-immunopositive in the medial prefrontal cortex. In the primary somatosensory area, PPD-immunopositive neurons constituted 50%, 79%, 55%, and 17% of SOM-immunopositive neurons in layers 2-3, 4, 5, and 6, respectively. Although SOM-expressing neurons contained calretinin-, neuropeptide Y-, nitric oxide synthase-, and reelin-expressing neurons as subgroups, only reelin immunoreactivity was detected in many PPD-immunopositive neurons. These results indicate that PPD-expressing neurons constitute a large subgroup of SOM-expressing cortical interneurons, and the PPD/SOM-expressing GABAergic neurons might serve not only as inhibitory elements in the local cortical circuit, but also as modulators for cortical neurons expressing κ-opioid and/or SOM receptors. Copyright © 2013 Wiley Periodicals

Steroids in Athletics: One University's Experience.

ERIC Educational Resources Information Center

Lopez, Mike

1990-01-01

Presents an account of one university's experience in conducting an investigation into possible steroid use by student athletes and the development of a program to deal with the problem. Discusses why athletes use steroids and how steroids are taken. Concludes it is likely many steroid-related deaths of athletes go undetected. (Author/ABL)

Update on Postnatal Steroids.

PubMed

Halliday, Henry L

2017-01-01

Antenatal steroid treatment to enhance fetal lung maturity and surfactant treatment to prevent or treat respiratory distress syndrome have been major advances in perinatal medicine in the past 40 years contributing to improved outcomes for preterm infants. Use of postnatal steroids to prevent or treat chronic lung disease in preterm infants has been less successful and associated with adverse neurodevelopmental outcomes. Although early (in the first week of life) postnatal steroid treatment facilitates earlier extubation and reduces the risk of chronic lung disease, it is associated with adverse effects, such as hyperglycemia, hypertension, gastrointestinal bleeding and perforation, hypertrophic cardiomyopathy, growth failure, and cerebral palsy, and cannot be recommended. Early treatment with hydrocortisone may also improve survival without chronic lung disease, but concerns remain about possible adverse effects such as gastrointestinal perforation and sepsis, particularly in very preterm infants. Early inhaled budesonide also reduces the incidence of chronic lung disease but there are concerns that this may occur at the expense of increased risk of death. More studies of early low-dose steroids with adequate long-term follow-up are needed before they can be recommended for the prevention of chronic lung disease. Late (after the first week of life) postnatal steroids may have a better benefit-to-harm ratio than early steroids. A Cochrane Review shows that late steroid treatment reduces chronic lung disease, the combination of death and chronic lung disease at both 28 days and 36 weeks' corrected age, and the need for later rescue dexamethasone. Adverse effects include hyperglycemia, hypertension, hypertrophic cardiomyopathy, and severe retinopathy of prematurity but without an increase in blindness. Long-term neurodevelopmental effects are not significantly increased by late postnatal steroid treatment. Current recommendations are that postnatal steroid treatment

Extracellular Signal-regulated Kinase and Glycogen Synthase Kinase 3β Regulate Gephyrin Postsynaptic Aggregation and GABAergic Synaptic Function in a Calpain-dependent Mechanism*

PubMed Central

Tyagarajan, Shiva K.; Ghosh, Himanish; Yévenes, Gonzalo E.; Imanishi, Susumu Y.; Zeilhofer, Hanns Ulrich; Gerrits, Bertran; Fritschy, Jean-Marc

2013-01-01

Molecular mechanisms of plasticity at GABAergic synapses are currently poorly understood. To identify signaling cascades that converge onto GABAergic postsynaptic density proteins, we performed MS analysis using gephyrin isolated from rat brain and identified multiple novel phosphorylation and acetylation residues on gephyrin. Here, we report the characterization of one of these phosphoresidues, Ser-268, which when dephosphorylated leads to the formation of larger postsynaptic scaffolds. Using a combination of mutagenesis, pharmacological treatment, and biochemical assays, we identify ERK as the kinase phosphorylating Ser-268 and describe a functional interaction between residues Ser-268 and Ser-270. We further demonstrate that alterations in gephyrin clustering via ERK modulation are reflected by amplitude and frequency changes in miniature GABAergic postsynaptic currents. We unravel novel mechanisms for activity- and ERK-dependent calpain action on gephyrin, which are likely relevant in the context of cellular signaling affecting GABAergic transmission and homeostatic synaptic plasticity in pathology. PMID:23408424

Abnormal GABAergic function and negative affect in schizophrenia.

PubMed

Taylor, Stephan F; Demeter, Elise; Phan, K Luan; Tso, Ivy F; Welsh, Robert C

2014-03-01

Deficits in the γ-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1-3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated-directly or indirectly-with GABAergic function on a continuum with normal behavior.

The development of benzo- and naphtho-fused quinoline-2,4-dicarboxylic acids as vesicular glutamate transporter (VGLUT) inhibitors reveals a possible role for neuroactive steroids

PubMed Central

Carrigan, Christina N.; Patel, Sarjubhai A.; Cox, Holly D.; Bolstad, Erin S.; Gerdes, John M.; Smith, Wesley E.; Bridges, Richard J.

2014-01-01

Substituted quinoline-2,4-dicarboxylates (QDCs) are conformationally-restricted mimics of glutamate that were previously reported to selectively block the glutamate vesicular transporters (VGLUTs). We find that expanding the QDC scaffold to benzoquinoline dicarboxylic acids (BQDC) and naphthoquinoline dicarboxylic acids (NQDCs) improves inhibitory activity with the NQDCs showing IC50 ~ 70 µM. Modeling overlay studies showed that the polycyclic QDCs resembled steroid structures and led to the identification and testing of estrone sulfate, pregnenolone sulfate and pregnanolone sulfate that blocked the uptake of l-Glu by 50%, 70% and 85% of control, respectively. Pregnanolone sulfate was further characterized by kinetic pharmacological determinations that demonstrated competitive inhibition and a Ki of ≈ 20 µM. PMID:24424130

Narcissism and empathy in steroid users.

PubMed

Porcerelli, J H; Sandler, B A

1995-11-01

In an effort to begin to construct a psychological profile of anabolic steroid users, the authors compared weight lifters and bodybuilders who did or did not use anabolic steroids on an objective measure of narcissism and on clinical ratings of empathy. The subjects were 16 weight lifters and bodybuilders who reported that they had used anabolic steroids within the past year and a comparison group of 20 weight lifters who had not used steroids. The Narcissistic Personality Inventory and clinical ratings of empathy were used to assess narcissism. Steroid users had significantly higher scores on dimensions of pathological narcissism and significantly lower scores on clinical ratings of empathy. These preliminary results document a relationship between anabolic steroid use and narcissistic personality traits. They also indicate the need for further research to determine whether narcissistic personality traits contribute to the initiation of anabolic steroid use or result from their use.

Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study.

PubMed

Tso, Ivy F; Fang, Yu; Phan, K Luan; Welsh, Robert C; Taylor, Stephan F

2015-10-01

The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli ("Do you like this face?"). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.

Body fluid levels of neuroactive amino acids in autism spectrum disorders: a review of the literature.

PubMed

Zheng, Hui-Fei; Wang, Wen-Qiang; Li, Xin-Min; Rauw, Gail; Baker, Glen B

2017-01-01

A review of studies on the body fluid levels of neuroactive amino acids, including glutamate, glutamine, taurine, gamma-aminobutyric acid (GABA), glycine, tryptophan, D-serine, and others, in autism spectrum disorders (ASD) is given. The results reported in the literature are generally inconclusive and contradictory, but there has been considerable variation among the previous studies in terms of factors such as age, gender, number of subjects, intelligence quotient, and psychoactive medication being taken. Future studies should include simultaneous analyses of a large number of amino acids [including D-serine and branched-chain amino acids (BCAAs)] and standardization of the factors mentioned above. It may also be appropriate to use saliva sampling to detect amino acids in ASD patients in the future-this is noninvasive testing that can be done easily more frequently than other sampling, thus providing more dynamic monitoring.

Startling Differences: Using the Acoustic Startle Response to Study Sex Differences and Neurosteroids in Affective Disorders.

PubMed

Hantsoo, Liisa; Golden, Carla E M; Kornfield, Sara; Grillon, Christian; Epperson, C Neill

2018-05-18

Neuroactive steroid hormones, such as estradiol and progesterone, likely play a role in the pathophysiology of female-specific psychiatric disorders such as premenstrual dysphoric disorder (PMDD) and postpartum depression and may contribute to the marked sex differences observed in the incidence and presentation of affective disorders. However, few tools are available to study the precise contributions of these neuroactive steroids (NSs). In this review, we propose that the acoustic startle response (ASR), an objective measure of an organism's response to an emotional context or stressor, is sensitive to NSs. As such, the ASR represents a unique translational tool that may help to elucidate the contribution of NSs to sex differences in psychiatric disorders. Findings suggest that anxiety-potentiated startle (APS) and prepulse inhibition of startle (PPI) are the most robust ASR paradigms for assessing contribution of NSs to affective disorders, while affective startle response modulation (ASRM) appears less diagnostic of sex or menstrual cycle (MC) effects. However, few studies have appropriately used ASR to test a priori hypotheses about sex or MC differences. We recommend that ASR studies account for sex as a biological variable (SABV) and hormonal status to further knowledge of NS contribution to affective disorders.

Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice.

PubMed

Andrews-Zwilling, Yaisa; Bien-Ly, Nga; Xu, Qin; Li, Gang; Bernardo, Aubrey; Yoon, Seo Yeon; Zwilling, Daniel; Yan, Tonya Xue; Chen, Ligong; Huang, Yadong

2010-10-13

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease. However, the underlying mechanisms are unclear. We found that female apoE4 knock-in (KI) mice had an age-dependent decrease in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined in the Morris water maze, in aged mice. Treating apoE4-KI mice with daily peritoneal injections of the GABA(A) receptor potentiator pentobarbital at 20 mg/kg for 4 weeks rescued the learning and memory deficits. In neurotoxic apoE4 fragment transgenic mice, hilar GABAergic interneuron loss was even more pronounced and also correlated with the extent of learning and memory deficits. Neurodegeneration and tauopathy occurred earliest in hilar interneurons in apoE4 fragment transgenic mice; eliminating endogenous Tau prevented hilar GABAergic interneuron loss and the learning and memory deficits. The GABA(A) receptor antagonist picrotoxin abolished this rescue, while pentobarbital rescued learning deficits in the presence of endogenous Tau. Thus, apoE4 causes age- and Tau-dependent impairment of hilar GABAergic interneurons, leading to learning and memory deficits in mice. Consequently, reducing Tau and enhancing GABA signaling are potential strategies to treat or prevent apoE4-related Alzheimer's disease.

Repeated Binge-Like Ethanol Drinking Alters Ethanol Drinking Patterns and Depresses Striatal GABAergic Transmission

PubMed Central

Wilcox, Mark V; Carlson, Verginia C Cuzon; Sherazee, Nyssa; Sprow, Gretchen M; Bock, Roland; Thiele, Todd E; Lovinger, David M; Alvarez, Veronica A

2014-01-01

Repeated cycles of binge alcohol drinking and abstinence are key components in the development of dependence. However, the precise behavioral mechanisms underlying binge-like drinking and its consequences on striatal synaptic physiology remain unclear. In the present study, ethanol and water drinking patterns were recorded with high temporal resolution over 6 weeks of binge-like ethanol drinking using the ‘drinking in the dark' (DID) protocol. The bottle exchange occurring at the beginning of each session prompted a transient increase in the drinking rate that might facilitate the acquisition of ethanol binge-like drinking. Ethanol drinking mice also displayed a ‘front-loading' behavior, in which the highest rate of drinking was recorded during the first 15 min. This rate increased over weeks and paralleled the mild escalation of blood ethanol concentrations. GABAergic and glutamatergic transmission in the dorsal striatum were examined following DID. Spontaneous glutamatergic transmission and the density of dendritic spines were unchanged after ethanol drinking. However, the frequency of GABAA receptor-mediated inhibitory postsynaptic currents was depressed in medium spiny neurons of ethanol drinking mice. A history of ethanol drinking also increased ethanol preference and altered the acute ethanol effects on GABAergic transmission differentially in dorsolateral and dorsomedial striatum. Together, the study shows that the bottle exchange during DID promotes fast, voluntary ethanol drinking and that this intermittent pattern of ethanol drinking causes a depression of GABAergic transmission in the dorsal striatum. PMID:23995582

Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala

PubMed Central

Varodayan, Florence P.; Soni, Neeraj; Bajo, Michal; Luu, George; Madamba, Samuel G.; Schweitzer, Paul; Parsons, Loren H.; Roberto, Marisa

2015-01-01

The endogenous cannabinoids (eCBs) influence the acute response to ethanol and the development of tolerance, dependence and relapse. Chronic alcohol exposure alters eCB levels and type 1 cannabinoid receptor (CB1) expression and function in brain regions associated with addiction. CB1 inhibits GABA release, and GABAergic dysregulation in the central nucleus of the amygdala (CeA) is critical in the transition to alcohol dependence. We investigated possible disruptions in CB1 signaling of rat CeA GABAergic transmission following intermittent ethanol exposure. In the CeA of alcohol-naïve rats, CB1 agonist WIN 55,212-2 (WIN) decreased the frequency of spontaneous and miniature GABAA receptor-mediated inhibitory postsynaptic currents (s/mIPSCs). This effect was prevented by CB1 antagonism, but not type 2 cannabinoid receptor (CB2) antagonism. After 2–3 weeks of intermittent ethanol exposure, these WIN inhibitory effects were attenuated, suggesting ethanol-induced impairments in CB1 function. The CB1 antagonist AM251 revealed a tonic eCB/CB1 control of GABAergic transmission in the alcohol-naïve CeA that was occluded by calcium chelation in the postsynaptic cell. Chronic ethanol exposure abolished this tonic CB1 influence on mIPSC, but not sIPSC, frequency. Finally, acute ethanol increased CeA GABA release in both naïve and ethanol exposed rats. Although CB1 activation prevented this effect, the AM251- and ethanol-induced GABA release were additive, ruling out a direct participation of CB1 signaling in the ethanol effect. Collectively, these observations demonstrate an important CB1 influence on CeA GABAergic transmission and indicate that the CeA is particularly sensitive to alcohol-induced disruptions of CB1 signaling. PMID:25940135

Efficacy of steroidal vs non-steroidal agents in oral lichen planus: a randomised, open-label study.

PubMed

Singh, A R; Rai, A; Aftab, M; Jain, S; Singh, M

2017-01-01

This study compared the therapeutic efficacy of steroidal and non-steroidal agents for treating oral lichen planus. Forty patients with clinical and/or histologically proven oral lichen planus were randomly placed into four groups and treated with topical triamcinolone, oral dapsone, topical tacrolimus or topical retinoid for three months. Pre- and post-treatment symptoms and signs were scored for each patient. Patients in all treatment groups showed significant clinical improvement after three months (p 0.05) and for topical retinoid vs topical tacrolimus (p > 0.05). Non-steroidal drugs such as dapsone, tacrolimus and retinoid are as efficacious as steroidal drugs for treating oral lichen planus, and avoid the side effects associated with steroids.

Female contact modulates male aggression via a sexually dimorphic GABAergic circuit in Drosophila

PubMed Central

Yuan, Quan; Song, Yuanquan; Yang, Chung-Hui; Jan, Lily Yeh; Jan, Yuh Nung

2014-01-01

Intraspecific male-male aggression, important for sexual selection, is regulated by environment, experience and internal states through largely undefined molecular and cellular mechanisms. To understand the basic neural pathway underlying the modulation of this innate behavior, we established a behavioral paradigm in Drosophila melanogaster and investigated the relationship between sexual experience and aggression. In the presence of mating partners, adult male flies exhibited elevated levels of aggression, which was largely suppressed by prior exposure to females via a sexually dimorphic neural mechanism. The suppression involved the ability of male flies to detect females by contact chemosensation through the pheromone-sensing ion channel, ppk29, and was mediated by male specific GABAergic neurons acting upon GABA-a receptor RDL in target cells. Silencing or activation of this circuit led to dis-inhibition or elimination of sex-related aggression, respectively. We propose that the GABAergic inhibition represents a critical cellular mechanism that enables prior experience to modulate aggression. PMID:24241395

A new role for GABAergic transmission in the control of male rat sexual behavior expression.

PubMed

Rodríguez-Manzo, Gabriela; Canseco-Alba, Ana

2017-03-01

GABAergic transmission in the ventral tegmental area (VTA) exerts a tonic inhibitory influence on mesolimbic dopaminergic neurons' activity. Blockade of VTA GABA A receptors increases dopamine release in the nucleus accumbens (NAcc). Increases in NAcc dopamine levels typically accompany sexual behavior display. Copulation to satiety is characterized by the instatement of a long lasting (72h) sexual behavior inhibition and the mesolimbic system appears to be involved in this phenomenon. GABAergic transmission in the VTA might play a role in the maintenance of this long lasting sexual inhibitory state. To test this hypothesis, in the present work we investigated the effect of GABA A receptor blockade in sexually exhausted males 24h after copulation to satiety, once the sexual inhibitory state is established, and compared it with its effect in sexually experienced rats. Results showed that low doses of systemically administered bicuculline induced sexual behavior expression in sexually exhausted rats, but lacked an effect on copulation of sexually experienced animals. Intra-VTA bilateral infusion of bicuculline did not modify sexual behavior of sexually experienced rats, but induced sexual behavior expression in all the sexually exhausted males. Hence, GABA plays a role in the control of sexual behavior expression at the VTA. The role played by GABAergic transmission in male sexual behavior expression of animals with distinct sexual behavior conditions is discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Profiling intact steroid sulfates and unconjugated steroids in biological fluids by liquid chromatography-tandem mass spectrometry (LC-MS-MS).

PubMed

Galuska, Christina E; Hartmann, Michaela F; Sánchez-Guijo, Alberto; Bakhaus, Katharina; Geyer, Joachim; Schuler, Gerhard; Zimmer, Klaus-Peter; Wudy, Stefan A

2013-07-07

Within the combined DFG research project "Sulfated Steroids in Reproduction" an analytical method was needed for determining sulfated and unconjugated steroids with highest specificity out of different biological matrices such as aqueous solution, cell lysate and serum. With regard to this analytical challenge, LC-MS-MS presents the technique of choice because it permits (1) analysis of the intact steroid conjugate, (2) allows for simultaneous determination of multiple analytes (profiling, targeted metabolomics approach) and (3) is independent of phenomena such as cross-reactivity. Sample work up consisted of incubation of sample with internal standards (deuterium labeled steroids) followed by solid phase extraction. Only serum samples required a protein precipitation step prior to solid phase extraction. The extract was divided in two parts: six steroid sulfates (E1S, E2S, AS, 16-OH-DHEAS, PREGS, DHEAS) were analyzed by C18aQ-ESI-MS-MS in negative ion mode and eleven unconjugated steroids (E3, 16-OH-DHEA, E1, E2, (4)A, DHEA, T, 17-OH-PREG, Prog, An, PREG) were analyzed by C18-APCI-MS-MS in positive ion mode. For steroid sulfates, we found high sensitivities with LoQ values ranging from 0.08 to 1 ng mL(-1). Unconjugated steroids showed LoQ values between 0.5 and 10 ng mL(-1). Calibration plots showed excellent linearity. Mean intra- and inter-assay CVs were 2.4% for steroid sulfates and 6.4% for unconjugated steroids. Accuracy - determined in a two-level spike experiment - showed mean relative errors of 5.9% for steroid sulfates and 6.1% for unconjugated steroids. In summary, we describe a novel LC-MS-MS procedure capable of profiling six steroid sulfates and eleven unconjugated steroids from various biological matrices.

Anabolic Steroids (For Teens)

MedlinePlus

... left or right to scroll. Monitoring the Future Study: Trends in Prevalence of Steroids for 8th Graders, 10th Graders, and 12th Graders; 2017 (in percent)* Drug Time Period 8th Graders 10th Graders 12th Graders Steroids ...

Behavior-Dependent Activity and Synaptic Organization of Septo-hippocampal GABAergic Neurons Selectively Targeting the Hippocampal CA3 Area.

PubMed

Joshi, Abhilasha; Salib, Minas; Viney, Tim James; Dupret, David; Somogyi, Peter

2017-12-20

Rhythmic medial septal (MS) GABAergic input coordinates cortical theta oscillations. However, the rules of innervation of cortical cells and regions by diverse septal neurons are unknown. We report a specialized population of septal GABAergic neurons, the Teevra cells, selectively innervating the hippocampal CA3 area bypassing CA1, CA2, and the dentate gyrus. Parvalbumin-immunopositive Teevra cells show the highest rhythmicity among MS neurons and fire with short burst duration (median, 38 ms) preferentially at the trough of both CA1 theta and slow irregular oscillations, coincident with highest hippocampal excitability. Teevra cells synaptically target GABAergic axo-axonic and some CCK interneurons in restricted septo-temporal CA3 segments. The rhythmicity of their firing decreases from septal to temporal termination of individual axons. We hypothesize that Teevra neurons coordinate oscillatory activity across the septo-temporal axis, phasing the firing of specific CA3 interneurons, thereby contributing to the selection of pyramidal cell assemblies at the theta trough via disinhibition. VIDEO ABSTRACT. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons.

PubMed

Yamada, Mayumi; Seto, Yusuke; Taya, Shinichiro; Owa, Tomoo; Inoue, Yukiko U; Inoue, Takayoshi; Kawaguchi, Yoshiya; Nabeshima, Yo-Ichi; Hoshino, Mikio

2014-04-02

In the cerebellum, the bHLH transcription factors Ptf1a and Atoh1 are expressed in distinct neuroepithelial regions, the ventricular zone (VZ) and the rhombic lip (RL), and are required for producing GABAergic and glutamatergic neurons, respectively. However, it is unclear whether Ptf1a or Atoh1 is sufficient for specifying GABAergic or glutamatergic neuronal fates. To test this, we generated two novel knock-in mouse lines, Ptf1a(Atoh1) and Atoh1(Ptf1a), that are designed to express Atoh1 and Ptf1a ectopically in the VZ and RL, respectively. In Ptf1a(Atoh1) embryos, ectopically Atoh1-expressing VZ cells produced glutamatergic neurons, including granule cells and deep cerebellar nuclei neurons. Correspondingly, in Atoh1(Ptf1a) animals, ectopically Ptf1a-expressing RL cells produced GABAergic populations, such as Purkinje cells and GABAergic interneurons. Consistent results were also obtained from in utero electroporation of Ptf1a or Atoh1 into embryonic cerebella, suggesting that Ptf1a and Atoh1 are essential and sufficient for GABAergic versus glutamatergic specification in the neuroepithelium. Furthermore, birthdating analyses with BrdU in the knock-in mice or with electroporation studies showed that ectopically produced fate-changed neuronal types were generated at temporal schedules closely simulating those of the wild-type RL and VZ, suggesting that the VZ and RL share common temporal information. Observations of knock-in brains as well as electroporated brains revealed that Ptf1a and Atoh1 mutually negatively regulate their expression, probably contributing to formation of non-overlapping neuroepithelial domains. These findings suggest that Ptf1a and Atoh1 specify spatial identities of cerebellar neuron progenitors in the neuroepithelium, leading to appropriate production of GABAergic and glutamatergic neurons, respectively.

Screening hybridomas for anabolic androgenic steroids by steroid analog antigen microarray.

PubMed

Du, Hongwu; Chen, Guangyu; Bian, Yongzhong; Xing, Cenzan; Ding, Xue; Zhu, Mengliang; Xun, Yiping; Chen, Peng; Zhou, Yabin; Li, Shaoxu

2015-01-01

Currently, dozens of anabolic androgenic steroids (AAS) are forbidden in the World Anti-Doping Agency Prohibited List, however, despite extensive investigation, there are still lots of AAS without corresponding monoclonal antibodies. A steroid analog antigen microarray made up of ten AAS was fabricated to screen the hybridoma and it was found an original unsuccessful clone turned out to be a candidate anti-boldenone antibody, without any cross-reactions with endogenous AAS or 44 different AAS standard reference materials tested. Our findings suggested that steroid analog antigen microarray could be a promising tool to screen and characterize new applications of antibodies for structure analogs, and this also exhibits the potential to fast identify effective epitopes of hybridomas in a single assay.

Role of GABAergic neurones in the nucleus tractus solitarii in modulation of cardiovascular activity.

PubMed

Zubcevic, Jasenka; Potts, Jeffrey T

2010-09-01

GABAergic neurones are interspersed throughout the nucleus tractus solitarii (NTS), and their tonic activity is crucial to the maintenance of cardiorespiratory homeostasis. However, the mechanisms that regulate the magnitude of GABAergic inhibition in the NTS remain unknown. We hypothesized that the level of GABAergic inhibition is proportionally regulated by the level of excitatory synaptic input to the NTS from baroreceptors. Using the in situ working heart-brainstem preparation in normotensive and spontaneously hypertensive rats, we blocked GABA(A) receptor-mediated neurotransmission in the NTS with gabazine (a specific GABA(A) receptor antagonist) at two levels of perfusion pressure (low PP, 60-70 mmHg; and high PP, 105-125 mmHg) while monitoring the immediate changes in cardiorespiratory variables. In normotensive rats, gabazine produced an immediate bradycardia consistent with disinhibition of NTS circuit neurones that regulate heart rate (HR) which was proportional to the level of arterial pressure (HR at low PP, 57 +/- 9 beats min(1); at high PP, 177 +/- 9 beats min(1); P < 0.001), suggesting that GABAergic circuitry in the NTS modulating heart rate was arterial pressure dependent. In contrast, there was no significant difference in the magnitude of gabazine-induced bradycardia in spontaneously hypertensive rats at low or high PP (HR at low PP, 45 +/- 10 beats min(1); at high PP, 58 +/- 7 beats min(1)). With regard to thoracic sympathetic nerve activity (tSNA), at high PP there was a significant reduction in tSNA during the inspiratory (I) phase of the respiratory cycle, but only in the normotensive rat (tSNA = 18.7 +/- 10%). At low PP, gabazine caused an elevation of the postinspiration phase of tSNA in both normotensive (tSNA = 23.7 +/- 2.9%) and hypertensive rats (tSNA = 44.2 +/- 14%). At low PP, gabazine produced no change in tSNA during the mid-expiration phase in either rat strain, but at high PP we observed a significant reduction in the mid

Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: alcohol and CRF effects

PubMed Central

Herman, Melissa; Kallupi, Marsida; Luu, George; Oleata, Christopher; Heilig, Markus; Koob, George F.; Ciccocioppo, Roberto; Roberto, Marisa

2012-01-01

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. Alcohol dependence is associated with increased corticotropin releasing factor (CRF) influence on CeA GABA release and CRF type 1 receptor (CRF1) antagonists prevent the excessive alcohol consumption associated with dependence. Genetically-selected Marchigian Sardinian (msP) rats have an overactive extrahypothalamic CRF1 system, are highly sensitive to stress, and display an innate preference for alcohol. The present study examined differences in CeA GABAergic transmission and the effects of ethanol, CRF and a CRF1 antagonist in msP, Sprague-Dawley, and Wistar rats using an electrophysiological approach. We found no significant differences in membrane properties or mean amplitude of evoked GABAA-inhibitory postsynaptic potentials (IPSPs). However, paired-pulse facilitation (PPF) ratios of evoked IPSPs were significantly lower and spontaneous miniature inhibitory postsynaptic current (mIPSC) frequencies were higher in msP rats, suggesting increased CeA GABA release in msP as compared to Sprague-Dawley and Wistar rats. The sensitivity of spontaneous GABAergic transmission to ethanol (44 mM), CRF (200 nM) and CRF1 antagonist (R121919, 1 μM) was comparable in msP, Sprague Dawley, and Wistar rats. However, a history of ethanol drinking significantly increased the baseline mIPSC frequency and decreased the effects of a CRF1 antagonist in msP rats, suggesting increased GABA release and decreased CRF1 sensitivity. These results provide electrophysiological evidence that msP rats display distinct CeA GABAergic activity as compared to Sprague Dawley and Wistar rats. The elevated GABAergic transmission observed in naïve mSP rats is consistent with the neuroadaptations reported in Sprague Dawley rats after the development of ethanol dependence. PMID:23220399

Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria.

PubMed

Wang, Tianying; Kumada, Tatsuro; Morishima, Toshitaka; Iwata, Satomi; Kaneko, Takeshi; Yanagawa, Yuchio; Yoshida, Sachiko; Fukuda, Atsuo

2014-04-01

Although focal cortical malformations are considered neuronal migration disorders, their formation mechanisms remain unknown. We addressed how the γ-aminobutyric acid (GABA)ergic system affects the GABAergic and glutamatergic neuronal migration underlying such malformations. A focal freeze-lesion (FFL) of the postnatal day zero (P0) glutamic acid decarboxylase-green fluorescent protein knock-in mouse neocortex produced a 3- or 4-layered microgyrus at P7. GABAergic interneurons accumulated around the necrosis including the superficial region during microgyrus formation at P4, whereas E17.5-born, Cux1-positive pyramidal neurons outlined the GABAergic neurons and were absent from the superficial layer, forming cell-dense areas in layer 2 of the P7 microgyrus. GABA imaging showed that an extracellular GABA level temporally increased in the GABAergic neuron-positive area, including the necrotic center, at P4. The expression of the Cl(-) transporter KCC2 was downregulated in the microgyrus-forming GABAergic and E17.5-born glutamatergic neurons at P4; these cells may need a high intracellular Cl(-) concentration to induce depolarizing GABA effects. Bicuculline decreased the frequency of spontaneous Ca(2+) oscillations in these microgyrus-forming cells. Thus, neonatal FFL causes specific neuronal accumulation, preceded by an increase in ambient GABA during microgyrus formation. This GABA increase induces GABAA receptor-mediated Ca(2+) oscillation in KCC2-downregulated microgyrus-forming cells, as seen in migrating cells during early neocortical development.

Birdsong and the neural production of steroids

PubMed Central

Remage-Healey, Luke; London, Sarah E.; Schinger, Barney A.

2009-01-01

The forebrain circuits involved in singing and audition (the ‘song system’) in songbirds exhibit a remarkable capacity to synthesize and respond to steroid hormones. This review considers how local brain steroid production impacts the development, sexual differentiation, and activity of song system circuitry. The songbird forebrain contains all of the enzymes necessary for the de novo synthesis of steroids - including neuroestrogens - from cholesterol. Steroid production enzymes are found in neuronal cell bodies, but they are also expressed in pre-synaptic terminals in the song system, indicating a novel mode of brain steroid delivery to local circuits. The song system expresses nuclear hormone receptors, consistent with local action of brain-derived steroids. Local steroid production also occurs in brain regions that do not express nuclear hormone receptors, suggesting a non-classical mode-of-action. Recent evidence indicates that local steroid levels can change rapidly within the forebrain, in a manner similar to traditional neuromodulators. Lastly, we consider growing evidence for modulatory interactions between brain-derived steroids and neurotransmitter/neuropeptide networks within the song system. Songbirds have therefore emerged as a rich and powerful model system to explore the neural and neurochemical regulation of social behavior. PMID:19589382

Steroids versus No Steroids in Nonarteritic Anterior Ischemic Optic Neuropathy: A Randomized Controlled Trial.

PubMed

Saxena, Rohit; Singh, Digvijay; Sharma, Medha; James, Mathew; Sharma, Pradeep; Menon, Vimla

2018-04-25

To examine the role of oral steroid therapy in the treatment of nondiabetic cases of acute nonarteritic anterior ischemic optic neuropathy (NAAION). Randomized double-blind clinical trial. Thirty-eight patients with acute nondiabetic NAAION divided into 2 arms of 19 patients each. One arm constituted the cases and the other constituted the controls. Cases received oral steroid therapy and were designated the steroid group, whereas controls received placebo and were designated the nonsteroid group. Best-corrected visual acuity (BCVA), visual evoked response (VER), and OCT were performed at baseline, 1 month, 3 months, and 6 months after recruitment into the trial. Best-corrected visual acuity, VER, and retinal nerve fiber layer changes on OCT. Both groups showed significant improvement in BCVA, VER latency, and resolution of disc edema on OCT parameters over 6 months. Final outcome showed no statistically significant difference with regard to visual acuity, although VER was better in the steroid group (P = 0.011). Best-corrected visual acuity, VER amplitude, and VER latency (P = 0.02, P = 0.02, and P = 0.04, respectively) showed a greater percentage improvement in the steroid group, which also saw a faster resolution of disc edema on OCT (1-month follow-up). Oral steroids in acute NAAION did not improve the visual acuity significantly at 6 months. However, they improved resolution of disc edema significantly and enabled a greater improvement in VER parameters. This subtle benefit of oral steroids in NAAION is clinically unimportant and does not provide support for its use. Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Steroid toxicity and detoxification in ascomycetous fungi.

PubMed

Cvelbar, Damjana; Zist, Vanja; Kobal, Katja; Zigon, Dušan; Zakelj-Mavrič, Marija

2013-02-25

In the last couple of decades fungal infections have become a significant clinical problem. A major interest into fungal steroid action has been provoked since research has proven that steroid hormones are toxic to fungi and affect the host/fungus relationship. Steroid hormones were found to differ in their antifungal activity in ascomycetous fungi Hortaea werneckii, Saccharomyces cerevisiae and Aspergillus oryzae. Dehydroepiandrosterone was shown to be the strongest inhibitor of growth in all three varieties of fungi followed by androstenedione and testosterone. For their protection, fungi use several mechanisms to lower the toxic effects of steroids. The efficiency of biotransformation in detoxification depended on the microorganism and steroid substrate used. Biotransformation was a relatively slow process as it also depended on the growth phase of the fungus. In addition to biotransformation, steroid extrusion out of the cells contributed to the lowering of the active intracellular steroid concentration. Plasma membrane Pdr5 transporter was found to be the most effective, followed by Snq2 transporter and vacuolar transporters Ybt1 and Ycf1. Proteins Aus1 and Dan1 were not found to be involved in steroid import. The research of possible targets of steroid hormone action in fungi suggests that steroid hormones inhibit ergosterol biosynthesis in S. cerevisiae and H. werneckii. Results of this inhibition caused changes in the sterol content of the cellular membrane. The presence of steroid hormones most probably causes the degradation of the Tat2 permease and impairment of tryptophan import. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Interactions between hypocretinergic and GABAergic systems in the control of activity of neurons in the cat pontine reticular formation.

PubMed

Xi, M; Fung, S J; Yamuy, J; Chase, M H

2015-07-09

Anatomical studies have demonstrated that hypocretinergic and GABAergic neurons innervate cells in the nucleus pontis oralis (NPO), a nucleus responsible for the generation of active (rapid eye movement (REM)) sleep (AS) and wakefulness (W). Behavioral and electrophysiological studies have shown that hypocretinergic and GABAergic processes in the NPO are involved in the generation of AS as well as W. An increase in hypocretin in the NPO is associated with both AS and W, whereas GABA levels in the NPO are elevated during W. We therefore examined the manner in which GABA modulates NPO neuronal responses to hypocretin. We hypothesized that interactions between the hypocretinergic and GABAergic systems in the NPO play an important role in determining the occurrence of AS or W. To determine the veracity of this hypothesis, we examined the effects of the juxtacellular application of hypocretin-1 and GABA on the activity of NPO neurons, which were recorded intracellularly, in chloralose-anesthetized cats. The juxtacellular application of hypocretin-1 significantly increased the mean amplitude of spontaneous EPSPs and the frequency of discharge of NPO neurons; in contrast, the juxtacellular microinjection of GABA produced the opposite effects, i.e., there was a significant reduction in the mean amplitude of spontaneous EPSPs and a decrease in the discharge of these cells. When hypocretin-1 and GABA were applied simultaneously, the inhibitory effect of GABA on the activity of NPO neurons was reduced or completely blocked. In addition, hypocretin-1 also blocked GABAergic inhibition of EPSPs evoked by stimulation of the laterodorsal tegmental nucleus. These data indicate that hypocretin and GABA function within the context of a neuronal gate that controls the activity of AS-on neurons. Therefore, we suggest that the occurrence of either AS or W depends upon interactions between hypocretinergic and GABAergic processes as well as inputs from other sites that project to AS

Canadian boreal pulp and paper feedstocks contain neuroactive substances that interact in vitro with GABA and dopaminergic systems in the brain.

PubMed

Waye, Andrew; Annal, Malar; Tang, Andrew; Picard, Gabriel; Harnois, Frédéric; Guerrero-Analco, José A; Saleem, Ammar; Hewitt, L Mark; Milestone, Craig B; MacLatchy, Deborah L; Trudeau, Vance L; Arnason, John T

2014-01-15

Pulp and paper wood feedstocks have been previously implicated as a source of chemicals with the ability to interact with or disrupt key neuroendocrine endpoints important in the control of reproduction. We tested nine Canadian conifers commonly used in pulp and paper production as well as 16 phytochemicals that have been observed in various pulp and paper mill effluent streams for their ability to interact in vitro with the enzymes monoamine oxidase (MAO), glutamic acid decarboxylase (GAD), and GABA-transaminase (GABA-T), and bind to the benzodiazepine-binding site of the GABA(A) receptor (GABA(A)-BZD). These neuroendocrine endpoints are also important targets for treatment of neurological disorders such as anxiety, epilepsy, or depression. MAO and GAD were inhibited by various conifer extracts of different polarities, including major feedstocks such as balsam fir, black spruce, and white spruce. MAO was selectively stimulated or inhibited by many of the tested phytochemicals, with inhibition observed by a group of phenylpropenes (e.g. isoeugenol and vanillin). Selective GAD inhibition was also observed, with all of the resin acids tested being inhibitory. GABA(A)-BZD ligand displacement was also observed. We compiled a table identifying which of these phytochemicals have been described in each of the species tested here. Given the diversity of conifer species and plant chemicals with these specific neuroactivities, it is reasonable to propose that MAO and GAD inhibition reported in effluents is phytochemical in origin. We propose disruption of these neuroendocrine endpoints as a possible mechanism of reproductive inhibition, and also identify an avenue for potential research and sourcing of conifer-derived neuroactive natural products. © 2013.

Characterizing the distribution of steroid sulfatase during embryonic development: when and where might metabolites of maternal steroids be reactivated?

PubMed

Paitz, Ryan T; Duffield, Kristin R; Bowden, Rachel M

2017-12-15

All vertebrate embryos are exposed to maternally derived steroids during development. In placental vertebrates, metabolism of maternal steroids by the placenta modulates embryonic exposure, but how exposure is regulated in oviparous vertebrates is less clear. Recent work in oviparous vertebrates has demonstrated that steroids are not static molecules, as they can be converted to more polar steroid sulfates by sulfotransferase enzymes. Importantly, these steroid sulfates can be converted back to the parent compound by the enzyme steroid sulfatase (STS). We investigated when and where STS was present during embryonic development in the red-eared slider turtle, Trachemys scripta We report that STS is present during all stages of development and in all tissues we examined. We conclude that STS activity may be particularly important for regulating maternal steroid exposure in oviparous vertebrates. © 2017. Published by The Company of Biologists Ltd.

Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures.

PubMed

Castillo, Claudia G; Mendoza-Trejo, Soledad; Aguilar, Manuel B; Freed, William J; Giordano, Magda

2008-11-03

We have previously shown that intranigral transplants of immortalized GABAergic cells decrease the number of kainic acid-induced seizures [Castillo CG, Mendoza S, Freed WJ, Giordano M. Intranigral transplants of immortalized GABAergic cells decrease the expression of kainic acid-induced seizures in the rat. Behav Brain Res 2006;171:109-15] in an animal model. In the present study, recurrent spontaneous behavioral seizures were established by repeated systemic injections of this excitotoxin into male Sprague-Dawley rats. After the seizures had been established, cells were transplanted into the substantia nigra. Animals with transplants of control cells (without hGAD67 expression) or with sham transplants showed a death rate of more than 40% over the 12 weeks of observation, whereas in animals with M213-2O CL-4 transplants, the death rate was reduced to less than 20%. The M213-2O CL-4 transplants significantly reduced the percentage of animals showing behavioral seizures; animals with these transplants also showed a lower occurrence of stage V seizures than animals in the other groups. In vivo and in vitro analyses provided evidence that the GABAergic cells show sustained expression of both GAD67 and hGAD67 cDNA, as well as increased gamma-aminobutyric acid (GABA) levels in the ventral mesencephalon of transplanted animals. Therefore, transplantation of GABA-producing cells can produce long-term alleviation of behavioral seizures in an animal model.

Adolescents and Steroids: A User Perspective.

ERIC Educational Resources Information Center

Office of Inspector General (DHHS), Washington, DC.

Anabolic-androgenic steroids ("steroids") are synthetic derivatives of the natural male hormone testosterone. They were first used non-medically by elite athletes seeking to improve performance. More recently, however, steroid use has filtered down to high school and junior high school levels. The purpose of this study was to describe…

Steroid use in acute liver failure.

PubMed

Karkhanis, Jamuna; Verna, Elizabeth C; Chang, Matthew S; Stravitz, R Todd; Schilsky, Michael; Lee, William M; Brown, Robert S

2014-02-01

Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (>40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH < 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores. © 2013 by the American Association for the Study of Liver Diseases.

The benefits of steroids versus steroids plus antivirals for treatment of Bell's palsy: a meta-analysis.

PubMed

Quant, Eudocia C; Jeste, Shafali S; Muni, Rajeev H; Cape, Alison V; Bhussar, Manveen K; Peleg, Anton Y

2009-09-07

To determine whether steroids plus antivirals provide a better degree of facial muscle recovery in patients with Bell's palsy than steroids alone. Meta-analysis. PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies published in all languages from 1984 to January 2009. Additional studies were identified from cited references. Selection criteria Randomised controlled trials that compared steroids with the combination of steroids and antivirals for the treatment of Bell's palsy were included in this study. At least one month of follow-up and a primary end point of at least partial facial muscle recovery, as defined by a House-Brackmann grade of at least 2 (complete palsy is designated a grade of 6) or an equivalent score on an alternative recognised scoring system, were required. Review methods Two authors independently reviewed studies for methodological quality, treatment regimens, duration of symptoms before treatment, length of follow-up, and outcomes. Odds ratios with 95% confidence intervals were calculated and pooled using a random effects model. Six trials were included, a total of 1145 patients; 574 patients received steroids alone and 571 patients received steroids and antivirals. The pooled odds ratio for facial muscle recovery showed no benefit of steroids plus antivirals compared with steroids alone (odds ratio 1.50, 95% confidence interval 0.83 to 2.69; P=0.18). A one study removed analysis showed that the highest quality studies had the greatest effect on the lack of difference between study arms shown by the odds ratio. Subgroup analyses assessing causes of heterogeneity defined a priori (time from symptom onset to treatment, length of follow-up, and type of antiviral studied) showed no benefit of antivirals in addition to that provided by steroids. Antivirals did not provide an added benefit in achieving at least partial facial muscle recovery compared with steroids alone in patients with

Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures

PubMed Central

Ruusuvuori, Eva; Huebner, Antje K; Kirilkin, Ilya; Yukin, Alexey Y; Blaesse, Peter; Helmy, Mohamed; Jung Kang, Hyo; El Muayed, Malek; Christopher Hennings, J; Voipio, Juha; Šestan, Nenad; Hübner, Christian A; Kaila, Kai

2013-01-01

Brain carbonic anhydrases (CAs) are known to modulate neuronal signalling. Using a novel CA VII (Car7) knockout (KO) mouse as well as a CA II (Car2) KO and a CA II/VII double KO, we show that mature hippocampal pyramidal neurons are endowed with two cytosolic isoforms. CA VII is predominantly expressed by neurons starting around postnatal day 10 (P10). The ubiquitous isoform II is expressed in neurons at P20. Both isoforms enhance bicarbonate-driven GABAergic excitation during intense GABAA-receptor activation. P13–14 CA VII KO mice show behavioural manifestations atypical of experimental febrile seizures (eFS) and a complete absence of electrographic seizures. A low dose of diazepam promotes eFS in P13–P14 rat pups, whereas seizures are blocked at higher concentrations that suppress breathing. Thus, the respiratory alkalosis-dependent eFS are exacerbated by GABAergic excitation. We found that CA VII mRNA is expressed in the human cerebral cortex before the age when febrile seizures (FS) occur in children. Our data indicate that CA VII is a key molecule in age-dependent neuronal pH regulation with consequent effects on generation of FS. PMID:23881097

Kavalactones and dihydrokavain modulate GABAergic activity in a rat gastric-brainstem preparation.

PubMed

Yuan, Chun-Su; Dey, Lucy; Wang, Anbao; Mehendale, Sangeeta; Xie, Jing-Tian; Aung, Han H; Ang-Lee, Michael K

2002-12-01

Using an in vitro neonatal rat gastric-brainstem preparation, the activity of majority neurons recorded in the nucleus tractus solitarius (NTS) of the brainstem were significantly inhibited by GABA A receptor agonist, muscimol (30 microM), and this inhibition was reversed by selective GABA A receptor antagonist, bicuculline (10 microM). Application of kavalactones (300 microg/ml) and dihydrokavain (300 microM) into the brainstem compartment of the preparation also significantly reduced the discharge rate of these NTS neurons (39 % and 32 %, respectively, compared to the control level), and this reduction was partially reversed by bicuculline (10 microM). Kavalactones or dihydrokavain induced inhibitory effects were not reduced after co-application of saclofen (10 microM; a selective GABA B receptor antagonist) or naloxone (100 nM; an opioid receptor antagonist). Pretreatment with kavalactones (300 microg/ml) or dihydrokavain (300 microM) significantly decreased the NTS inhibitory effects induced by muscimol (30 microM), approximately from 51 % to 36 %. Our results demonstrated modulation of brainstem GABAergic mechanism by kavalactones and dihydrokavain, and suggested that these compounds may play an important role in regulation of GABAergic neurotransmission.

Steroid withdrawal in lung transplant recipients.

PubMed

Borro, J M; Solé, A; De la Torre, M; Pastor, A; Tarazona, V

2005-11-01

Many of the long-term complications in lung transplantations are secondary effects of immunosuppression. Corticosteroids are partially responsible for the development of osteoporosis, raised blood pressure, diabetes, muscular disorders, gastric ulcers, and other conditions. We analyzed the long-term result of steroid withdrawal in our lung transplant recipients. When respiratory function stabilized, to avoid secondary effects, steroid treatment was withdrawn in 34 of the 375 lung transplant patients in our centers We evaluated the characteristics of the donors and recipients, their compatibility, the pre, and post-steroid withdrawal complications, and type of immunosuppressant. The mean age of patients was 42 +/- 7 years and of donors, 25 +/- 9 years. The primary diseases were: 15 emphysema, six pulmonary fibrosis, 10 cystic fibrosis, and three primary pulmonary hypertension. Twenty seven patients had double lung transplants and seven single lung. The mean steroid withdrawal period was 881 +/- 237 days posttransplantation. The most frequent treatment regimen at the time of steroid withdrawal was cyclosporine, azathioprine, and minimal steroid doses. Six recipients had to be restarted on steroids one patient who required a kidney transplant, three cases due to an infectious process with a differential diagnosis of rejection, and two cases due to loss of FEV1 (forced expiratory volume in 1 s), suggestive of chronic rejection. There was an improvement in blood pressure in five patients, in plasma cholesterol and triglyceride levels in eight patients, and insulin withdrawal in two diabetic patients. Steroid treatment may be suspended 2 to 3 years, posttransplant in selected lung transplant recipients. The usual patient profile shows few rejection episodes with cyclosporine and azathioprine immunosuppression. What is notable is the low mean age of donors. Close clinical monitoring and lung function testing are of major importance in the weeks following steroid

Presynaptic miniature GABAergic currents in developing interneurons.

PubMed

Trigo, Federico F; Bouhours, Brice; Rostaing, Philippe; Papageorgiou, George; Corrie, John E T; Triller, Antoine; Ogden, David; Marty, Alain

2010-04-29

Miniature synaptic currents have long been known to represent random transmitter release under resting conditions, but much remains to be learned about their nature and function in central synapses. In this work, we describe a new class of miniature currents ("preminis") that arise by the autocrine activation of axonal receptors following random vesicular release. Preminis are prominent in gabaergic synapses made by cerebellar interneurons during the development of the molecular layer. Unlike ordinary miniature postsynaptic currents in the same cells, premini frequencies are strongly enhanced by subthreshold depolarization, suggesting that the membrane depolarization they produce belongs to a feedback loop regulating neurotransmitter release. Thus, preminis could guide the formation of the interneuron network by enhancing neurotransmitter release at recently formed synaptic contacts. Copyright 2010 Elsevier Inc. All rights reserved.

New steroid derivative with hypoglycemic activity

PubMed Central

Lauro, Figueroa-Valverde; Francisco, Díaz-Cedillo; Lenin, Hau-Heredia; Elodia, García-Cervera; Eduardo, Pool-Gómez; Marcela, Rosas-Nexticapa; Bety, Sarabia-Alcocer

2014-01-01

Data indicates that some steroid derivatives may induce changes on glucose levels; nevertheless, data are very confusing. Therefore, more pharmacological data are needed to characterize the activity induced by the steroid derivatives on glucose levels. The aim of this study was to synthesize a new steroid derivative for evaluate its hypoglycemic activity. The effects of steroid derivative on glucose concentration were evaluated in a diabetic animal model using glibenclamide and metformin as controls. In addition, the pregnenolone-dihydrotestosterone conjugate was bound to Tc-99m using radioimmunoassay methods, to evaluate the pharmacokinetics of the steroid derivative over time. The results showed that the pregnenolone-dihydrotestosterone conjugate induces changes on the glucose levels in similar form than glibenclamide. Other data showed that the biodistribution of Tc-99m-steroid derivativein brain was higher in comparison with spleen, stomach, intestine liver and kidney. In conclusion, the pregnenolone-dihydrotestosterone conjugate exerts hypoglycemic activity and this phenomenon could depend of its physicochemical properties which could be related to the degree of lipophilicity of the steroidderivative. PMID:25550906

Are Steroids Worth the Risk?

MedlinePlus

... balding or hair loss weight gain mood swings aggression problems sleeping high blood pressure greater chance of ... only use steroids for a season or a school year. Unfortunately, steroids can be addictive, making it ...

ent-Steroids: novel tools for studies of signaling pathways.

PubMed

Covey, Douglas F

2009-07-01

Membrane receptors are often modulated by steroids and it is necessary to distinguish the effects of steroids at these receptors from effects occurring at nuclear receptors. Additionally, it may also be mechanistically important to distinguish between direct effects caused by binding of steroids to membrane receptors and indirect effects on membrane receptor function caused by steroid perturbation of the membrane containing the receptor. In this regard, ent-steroids, the mirror images of naturally occurring steroids, are novel tools for distinguishing between these various actions of steroids. The review provides a background for understanding the different actions that can be expected of steroids and ent-steroids in biological systems, references for the preparation of ent-steroids, a short discussion about relevant forms of stereoisomerism and the requirements that need to be fulfilled for the interaction between two molecules to be enantioselective. The review then summarizes results of biophysical, biochemical and pharmacological studies published since 1992 in which ent-steroids have been used to investigate the actions of steroids in membranes and/or receptor-mediated signaling pathways.

ent-Steroids: Novel Tools for Studies of Signaling Pathways

PubMed Central

Covey, Douglas F.

2008-01-01

Membrane receptors are often modulated by steroids and it is necessary to distinguish the effects of steroids at these receptors from effects occurring at nuclear receptors. Additionally, it may also be mechanistically important to distinguish between direct effects caused by binding of steroids to membrane receptors and indirect effects on membrane receptor function caused by steroid perturbation of the membrane containing the receptor. In this regard, ent-steroids, the mirror images of naturally occurring steroids, are novel tools for distinguishing between these various actions of steroids. The review provides a background for understanding the different actions that can be expected of steroids and ent-steroids in biological systems, references for the preparation of ent-steroids, a short discussion about relevant forms of stereoisomerism and the requirements that need to be fulfilled for the interaction between two molecules to be enantioselective. The review then summarizes results of biophysical, biochemical and pharmacological studies published since 1992 in which ent-steroids have been used to investigate the actions of steroids in membranes and/or receptor-mediated signaling pathways. PMID:19103212

Oral steroids alone or followed by intranasal steroids versus watchful waiting in the management of otitis media with effusion.

PubMed

Hussein, A; Fathy, H; Amin, S M; Elsisy, N

2017-10-01

To evaluate the effects of oral steroids alone or followed by intranasal steroids versus watchful waiting on the resolution of otitis media with effusion in children aged 2-11 years. A total of 290 children with bilateral otitis media with effusion were assigned to 3 groups: group A was treated with oral steroids followed by intranasal steroids, group B was treated with oral steroids alone and group C was managed with watchful waiting. Patients were evaluated with audiometry and tympanometry. The complete resolution rates of otitis media with effusion were higher in groups A and B than in group C at six weeks. There were no significant differences in otitis media with effusion resolution rates between the groups at three, six and nine months. Oral steroids lead only to a quick resolution of otitis media with effusion, with no long-term benefits. There was no benefit of using intranasal steroids in the management of otitis media with effusion.

Cortical GABAergic excitation contributes to epileptic activities around human glioma

PubMed Central

Pallud, Johan; Varlet, Pascale; Cresto, Noemie; Baulac, Michel; Duyckaerts, Charles; Kourdougli, Nazim; Chazal, Geneviève; Devaux, Bertrand; Rivera, Claudio; Miles, Richard; Capelle, Laurent; Huberfeld, Gilles

2015-01-01

Rationale Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study. Objective We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities. Results Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride co-transporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. Conclusions Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients. PMID:25009229

Steroid avoidance or withdrawal for kidney transplant recipients.

PubMed

Haller, Maria C; Royuela, Ana; Nagler, Evi V; Pascual, Julio; Webster, Angela C

2016-08-22

Steroid-sparing strategies have been attempted in recent decades to avoid morbidity from long-term steroid intake among kidney transplant recipients. Previous systematic reviews of steroid withdrawal after kidney transplantation have shown a significant increase in acute rejection. There are various protocols to withdraw steroids after kidney transplantation and their possible benefits or harms are subject to systematic review. This is an update of a review first published in 2009. To evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. We searched the Cochrane Kidney and Transplant Specialised Register to 15 February 2016 through contact with the Information Specialist using search terms relevant to this review. All randomised and quasi-randomised controlled trials (RCTs) in which steroids were avoided or withdrawn at any time point after kidney transplantation were included. Assessment of risk of bias and data extraction was performed by two authors independently and disagreement resolved by discussion. Statistical analyses were performed using the random-effects model and dichotomous outcomes were reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals. We included 48 studies (224 reports) that involved 7803 randomised participants. Of these, three studies were conducted in children (346 participants). The 2009 review included 30 studies (94 reports, 5949 participants). Risk of bias was assessed as low for sequence generation in 19 studies and allocation concealment in 14 studies. Incomplete outcome data were adequately addressed in 22 studies and 37 were free of selective reporting.The 48 included studies evaluated three different comparisons: steroid avoidance or withdrawal compared with steroid maintenance, and steroid avoidance compared with steroid withdrawal. For the adult studies there was no significant difference in patient mortality either in studies

Steroid treatment of posttraumatic anosmia.

PubMed

Jiang, Rong-San; Wu, Shang-Heng; Liang, Kai-Li; Shiao, Jiun-Yih; Hsin, Chung-Han; Su, Mao-Chang

2010-10-01

The objective of this study was to treat posttraumatic anosmia with oral steroid and evaluate its effect. One-hundred sixteen posttraumatic patients whose olfactory thresholds were -1.0 by the phenyl ethyl alcohol threshold test assembled in our department. They were treated with a course of high-dose steroid, and followed up for at least 3 months. During the latter period of this study, magnetic resonance imaging was performed to measure the volumes of olfactory bulbs and to detect subfrontal lobe damage. Among them, 19 (16.4%) patients' olfactory thresholds improved after steroid treatment, but the other 97 patients' thresholds did not change. The incidences of loss of consciousness and intracranial hemorrhage after head injury, the ratios of admission and craniotomy, the intervals between head injury and steroid treatment, the volumes of olfactory bulbs, and the incidences of subfrontal lobe damage were not significantly different between patients whose thresholds improved and those whose thresholds did not improve. However, patients with olfactory improvement were significantly younger than those who remained unchanged. Our study showed that oral steroid treatment might improve olfactory acuity in some patients with posttraumatic anosmia, but the possibility of spontaneous recovery cannot be ruled out.

Effects of Sex Steroids in the Human Brain.

PubMed

Nguyen, Tuong-Vi; Ducharme, Simon; Karama, Sherif

2017-11-01

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.

Hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility

PubMed Central

Bae, Mihyun H.; Bissonette, Gregory B.; Mars, Wendy M.; Michalopoulos, George K.; Achim, Cristian L.; Depireux, Didier A.; Powell, Elizabeth M.

2009-01-01

Disrupted ontogeny of forebrain inhibitory interneurons leads to neurological disorders, including epilepsy. Adult mice lacking the urokinase plasminogen activator receptor (Plaur) have decreased numbers of neocortical GABAergic interneurons and spontaneous seizures, attributed to a reduction of hepatocyte growth factor/scatter factor (HGF/SF). We report that by increasing endogenous HGF/SF concentration in the postnatal Plaur null mouse brain maintains the interneuron populations in the adult, reverses the seizure behavior and stabilizes the spontaneous electroencephalogram activity. The perinatal intervention provides a pathway to reverse potential birth defects and ameliorate seizures in the adult. PMID:19853606

GABAergic modulation of visual gamma and alpha oscillations and its consequences for working memory performance.

PubMed

Lozano-Soldevilla, Diego; ter Huurne, Niels; Cools, Roshan; Jensen, Ole

2014-12-15

Impressive in vitro research in rodents and computational modeling has uncovered the core mechanisms responsible for generating neuronal oscillations. In particular, GABAergic interneurons play a crucial role for synchronizing neural populations. Do these mechanistic principles apply to human oscillations associated with function? To address this, we recorded ongoing brain activity using magnetoencephalography (MEG) in healthy human subjects participating in a double-blind pharmacological study receiving placebo, 0.5 mg and 1.5 mg of lorazepam (LZP; a benzodiazepine upregulating GABAergic conductance). Participants performed a demanding visuospatial working memory (WM) task. We found that occipital gamma power associated with WM recognition increased with LZP dosage. Importantly, the frequency of the gamma activity decreased with dosage, as predicted by models derived from the rat hippocampus. A regionally specific gamma increase correlated with the drug-related performance decrease. Despite the system-wide pharmacological intervention, gamma power drug modulations were specific to visual cortex: sensorimotor gamma power and frequency during button presses remained unaffected. In contrast, occipital alpha power modulations during the delay interval decreased parametrically with drug dosage, predicting performance impairment. Consistent with alpha oscillations reflecting functional inhibition, LZP affected alpha power strongly in early visual regions not required for the task demonstrating a regional specific occipital impairment. GABAergic interneurons are strongly implicated in the generation of gamma and alpha oscillations in human occipital cortex where drug-induced power modulations predicted WM performance. Our findings bring us an important step closer to linking neuronal dynamics to behavior by embracing established animal models. Copyright © 2014 Elsevier Ltd. All rights reserved.

Long-interval Cytapheresis as a Novel Therapeutic Strategy Leading to Dosage Reduction and Discontinuation of Steroids in Steroid-dependent Ulcerative Colitis

PubMed Central

Iizuka, Masahiro; Etou, Takeshi; Kumagai, Makoto; Matsuoka, Atsushi; Numata, Yuka; Sagara, Shiho

2017-01-01

Objective This study was performed to confirm the efficacy of long-interval cytapheresis on steroid-dependent ulcerative colitis (UC). Methods To discontinue steroids in patients with steroid-dependent UC, we previously designed a novel regimen of cytapheresis (CAP), which we termed “long-interval cytapheresis (LI-CAP)”, in which CAP was performed as one session every two or three weeks and continued during the whole period of tapering steroid dosage. In this study, we performed LI-CAP therapy 20 times (11 male and 9 female; mean age 41.8 years) between April 2010 and April 2015 for 14 patients with steroid-dependent UC. We evaluated the effectiveness of LI-CAP by examining the improvement in Lichtiger's clinical activity index (CAI), the rate of clinical remission, and the rate of steroid discontinuation. We further examined the rate of sustained steroid-free clinical remission at 6 and 12 months after LI-CAP in patients who successfully discontinued steroid-use after LI-CAP. The primary endpoint was the rate of discontinuation of steroids after LI-CAP. Results The mean CAI score before LI-CAP (7.550) significantly decreased to 1.65 after LI-CAP (p<0.0001). The rate of clinical remission after LI-CAP was 80%. The rate of steroid discontinuation after LI-CAP was 60.0%. The mean dose of daily prednisolone was significantly decreased after LI-CAP (2.30 mg) compared with that before therapy (17.30 mg) (p=0.0003). The rate of sustained steroid-free clinical remission after LI-CAP was 66.7% at 6 months and 66.7% at 12 months. Conclusion We confirmed that LI-CAP has therapeutic effects on reducing the dosage and discontinuing steroids in patients with steroid-dependent UC. PMID:28924114

Long-interval Cytapheresis as a Novel Therapeutic Strategy Leading to Dosage Reduction and Discontinuation of Steroids in Steroid-dependent Ulcerative Colitis.

PubMed

Iizuka, Masahiro; Etou, Takeshi; Kumagai, Makoto; Matsuoka, Atsushi; Numata, Yuka; Sagara, Shiho

2017-10-15

Objective This study was performed to confirm the efficacy of long-interval cytapheresis on steroid-dependent ulcerative colitis (UC). Methods To discontinue steroids in patients with steroid-dependent UC, we previously designed a novel regimen of cytapheresis (CAP), which we termed "long-interval cytapheresis (LI-CAP)", in which CAP was performed as one session every two or three weeks and continued during the whole period of tapering steroid dosage. In this study, we performed LI-CAP therapy 20 times (11 male and 9 female; mean age 41.8 years) between April 2010 and April 2015 for 14 patients with steroid-dependent UC. We evaluated the effectiveness of LI-CAP by examining the improvement in Lichtiger's clinical activity index (CAI), the rate of clinical remission, and the rate of steroid discontinuation. We further examined the rate of sustained steroid-free clinical remission at 6 and 12 months after LI-CAP in patients who successfully discontinued steroid-use after LI-CAP. The primary endpoint was the rate of discontinuation of steroids after LI-CAP. Results The mean CAI score before LI-CAP (7.550) significantly decreased to 1.65 after LI-CAP (p<0.0001). The rate of clinical remission after LI-CAP was 80%. The rate of steroid discontinuation after LI-CAP was 60.0%. The mean dose of daily prednisolone was significantly decreased after LI-CAP (2.30 mg) compared with that before therapy (17.30 mg) (p=0.0003). The rate of sustained steroid-free clinical remission after LI-CAP was 66.7% at 6 months and 66.7% at 12 months. Conclusion We confirmed that LI-CAP has therapeutic effects on reducing the dosage and discontinuing steroids in patients with steroid-dependent UC.

The benefits of steroids versus steroids plus antivirals for treatment of Bell’s palsy: a meta-analysis

PubMed Central

Quant, Eudocia C; Jeste, Shafali S; Muni, Rajeev H; Cape, Alison V; Bhussar, Manveen K

2009-01-01

Objective To determine whether steroids plus antivirals provide a better degree of facial muscle recovery in patients with Bell’s palsy than steroids alone. Design Meta-analysis. Data sources PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies published in all languages from 1984 to January 2009. Additional studies were identified from cited references. Selection criteria Randomised controlled trials that compared steroids with the combination of steroids and antivirals for the treatment of Bell’s palsy were included in this study. At least one month of follow-up and a primary end point of at least partial facial muscle recovery, as defined by a House-Brackmann grade of at least 2 (complete palsy is designated a grade of 6) or an equivalent score on an alternative recognised scoring system, were required. Review methods Two authors independently reviewed studies for methodological quality, treatment regimens, duration of symptoms before treatment, length of follow-up, and outcomes. Odds ratios with 95% confidence intervals were calculated and pooled using a random effects model. Results Six trials were included, a total of 1145 patients; 574 patients received steroids alone and 571 patients received steroids and antivirals. The pooled odds ratio for facial muscle recovery showed no benefit of steroids plus antivirals compared with steroids alone (odds ratio 1.50, 95% confidence interval 0.83 to 2.69; P=0.18). A one study removed analysis showed that the highest quality studies had the greatest effect on the lack of difference between study arms shown by the odds ratio. Subgroup analyses assessing causes of heterogeneity defined a priori (time from symptom onset to treatment, length of follow-up, and type of antiviral studied) showed no benefit of antivirals in addition to that provided by steroids. Conclusions Antivirals did not provide an added benefit in achieving at least partial facial muscle

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

21 CFR 1308.34 - Exempt anabolic steroid products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Exempt anabolic steroid products. 1308.34 Section... SUBSTANCES Exempt Anabolic Steroid Products § 1308.34 Exempt anabolic steroid products. The list of compounds, mixtures, or preparations that contain an anabolic steroid that have been exempted by the Administrator...

Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness.

PubMed

Megahed, Tarick; Hattiangady, Bharathi; Shuai, Bing; Shetty, Ashok K

2014-01-01

Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI.

Role of opioidergic and GABAergic neurotransmission of the nucleus raphe magnus in the modulation of tonic immobility in guinea pigs.

PubMed

da Silva, Luis Felipe Souza; Menescal-de-Oliveira, Leda

2007-04-02

Tonic immobility (TI) is an inborn defensive behavior characterized by a temporary state of profound and reversible motor inhibition elicited by some forms of physical restraint. Previous results from our laboratory have demonstrated that nucleus raphe magnus (NRM) is also a structure involved in the modulation of TI behavior, as chemical stimulation through carbachol decreases the duration of TI in guinea pigs. In view of the fact that GABAergic and opioidergic circuits participate in the regulation of neuronal activity in the NRM and since these neurotransmitters are also involved in the modulation of TI, the objective of the present study was to evaluate the role of these circuits of the NRM in the modulation of the behavioral TI response. Microinjection of morphine (4.4 nmol/0.2 microl) or bicuculline (0.4 nmol/0.2 microl) into the NRM increased the duration of TI episodes while muscimol (0.5 nmol/0.2 microl) decreased it. The effect of morphine injection into the NRM was blocked by previous microinjection of naloxone (2.7 nmol/0.2 microl). Muscimol at 0.25 nmol did not produce any change in TI duration; however, it blocked the increased response induced by morphine. Our results indicate a facilitatory role of opioidergic neurotransmission in the modulation of the TI response within the NRM, whereas GABAergic activity plays an inhibitory role. In addition, in the present study the modulation of TI in the NRM possibly occurred via an interaction between opioidergic and GABAergic systems, where the opioidergic effect might be due to inhibition of tonically active GABAergic interneurons.

Steroid acne vs. Pityrosporum folliculitis: the incidence of Pityrosporum ovale and the effect of antifungal drugs in steroid acne.

PubMed

Yu, H J; Lee, S K; Son, S J; Kim, Y S; Yang, H Y; Kim, J H

1998-10-01

Steroid acne is a folliculitis that can result from systemic or topical administration of steroid, and has been described as showing a similar clinical picture to Pityrosporum folliculitis, but there have been few reports about the incidence of Pityrosporum ovale and the effect of antimycotic drugs in steroid acne and other acneiform eruptions. Our purpose was to describe the association between steroid acne and P. ovale, and to confirm the superior efficacy of oral antifungal drugs over anti-acne drugs in the treatment of steroid acne. The history, clinical features direct microscopy, histopathologic analysis, and therapeutic results of 125 cases with steroid acne or other acneiform eruptions were described and compared. Over 80% of patients with acneiform eruption receiving systemic steroid revealed significant numbers of P. ovale in the lesional follicle. Furthermore, oral antifungal drug (itraconazole) showed significantly better clinical and mycologic effects than any other group of medications used in this study. Steroid acne and other acneiform eruptions showing discrete follicular papules and/or pustules localized to the upper trunk and acneiform facial skin lesions associated with multiple acneiform lesions on the body in the summer period should be suspected as Pityrosporum folliculitis. In addition, oral antifungal drugs recommended for Pityrosporum folliculitis; however, it will require a larger case-control study to confirm the superiority of antifungal therapy over anti-acne treatment.

MACF1 Controls Migration and Positioning of Cortical GABAergic Interneurons in Mice.

PubMed

Ka, Minhan; Moffat, Jeffrey J; Kim, Woo-Yang

2017-12-01

GABAergic interneurons develop in the ganglionic eminence in the ventral telencephalon and tangentially migrate into the cortical plate during development. However, key molecules controlling interneuron migration remain poorly identified. Here, we show that microtubule-actin cross-linking factor 1 (MACF1) regulates GABAergic interneuron migration and positioning in the developing mouse brain. To investigate the role of MACF1 in developing interneurons, we conditionally deleted the MACF1 gene in mouse interneuron progenitors and their progeny using Dlx5/6-Cre-IRES-EGFP and Nkx2.1-Cre drivers. We found that MACF1 deletion results in a marked reduction and defective positioning of interneurons in the mouse cerebral cortex and hippocampus, suggesting abnormal interneuron migration. Indeed, the speed and mode of interneuron migration were abnormal in the MACF1-mutant brain, compared with controls. Additionally, MACF1-deleted interneurons showed a significant reduction in the length of their leading processes and dendrites in the mouse brain. Finally, loss of MACF1 decreased microtubule stability in cortical interneurons. Our findings suggest that MACF1 plays a critical role in cortical interneuron migration and positioning in the developing mouse brain. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging.

PubMed

Albayram, Onder; Alferink, Judith; Pitsch, Julika; Piyanova, Anastasia; Neitzert, Kim; Poppensieker, Karola; Mauer, Daniela; Michel, Kerstin; Legler, Anne; Becker, Albert; Monory, Krisztina; Lutz, Beat; Zimmer, Andreas; Bilkei-Gorzo, Andras

2011-07-05

Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.

Optimised deconjugation of androgenic steroid conjugates in bovine urine.

PubMed

Pedersen, Mikael; Frandsen, Henrik L; Andersen, Jens H

2017-04-01

After administration of steroids to animals the steroids are partially metabolised in the liver and kidney to phase 2 metabolites, i.e., glucuronic acid or sulphate conjugates. During analysis these conjugated metabolites are normally deconjugated enzymatically with aryl sulphatase and glucuronidase resulting in free steroids in the extract. It is well known that some sulphates are not deconjugated using aryl sulphatase; instead, for example, solvolysis can be used for deconjugation of these aliphatic sulphates. The effectiveness of solvolysis on androgenic steroid sulphates was tested with selected aliphatic steroid sulphates (boldenone sulphate, nortestosteron sulphate and testosterone sulphate), and the method was validated for analysis of androgenic steroids in bovine urine using free steroids, steroid sulphates and steroid glucuronides as standards. Glucuronidase and sulphuric acid in ethyl acetate were used for deconjugation and the extract was purified by solid-phase extraction. The final extract was evaporated to dryness, re-dissolved and analysed by LC-MS/MS.

Steroid Assays in Paediatric Endocrinology

PubMed Central

2010-01-01

Most steroid disorders of the adrenal cortex come to clinical attention in childhood and in order to investigate these problems, there are many challenges to the laboratory which need to be appreciated to a certain extent by clinicians. The analysis of sex steroids in biological fluids from neonates, over adrenarche and puberty present challenges of specificities and concentrations often in small sample sizes. Different reference ranges are also needed for interpretations. For around 40 years, quantitative assays for the steroids and their regulatory peptide hormones have been possible using immunoassay techniques. Problems are recognised and this review aims to summarise the benefits and failings of immunoassays and introduce where tandem mass spectrometry is anticipated to meet the clinical needs for steroid analysis in paediatric endocrine investigations. It is important to keep a dialogue between clinicians and the laboratory, especially when any laboratory result does not make sense in the clinical investigation. Conflict of interest:None declared. PMID:21274330

Non-avoidance behaviour in enchytraeids to boric acid is related to the GABAergic mechanism.

PubMed

Bicho, Rita C; Gomes, Susana I L; Soares, Amadeu M V M; Amorim, Mónica J B

2015-05-01

Soil invertebrates, e.g. enchytraeids, are known to be able to avoid unfavourable conditions, which gives them an important ecological advantage. These organisms possess chemoreceptors that can detect stressors, which in turn activate responses such as avoidance behaviour. We studied the avoidance behaviour in response to boric acid (BA) using enchytraeids. Results showed not only no avoidance, but that increasing concentrations seemed to have an "attraction" effect. To study the underlying mechanism, a selection of genes targeting for neurotransmission pathways (acetylcholinesterase (AChE) and gamma-aminobutyric acid receptor (GABAr)) were quantified via quantitative real-time polymerase chain reaction (qPCR). Evidences were that BA is neurotoxic via the GABAergic system mechanism where it acts as a GABA-associated protein receptor (GABAAR) antagonist possibly causing anaesthetic effects. This is the first time that (non)avoidance behaviour in invertebrates was studied in relation with the GABAergic system. We strongly recommend the combination of such gene and/or functional assay studies with the avoidance behaviour test as it can bring many advantages and important interpretation lines for ecotoxicity with minor effort.

Medicare Part D Payments for Topical Steroids

PubMed Central

Song, Hannah; Adamson, Adewole

2017-01-01

Importance Rising pharmaceutical costs in the United States are an increasing source of financial burden for payers and patients. Although topical steroids are among the most commonly prescribed medications in dermatology, there are limited data on steroid-related spending and utilization. Objective To characterize Medicare and patient out-of-pocket costs for topical steroids, and to model potential savings that could result from substitution of the cheapest topical steroid from the corresponding potency class. Design, Setting, and Participants This study was a retrospective cost analysis of the Medicare Part D Prescriber Public Use File, which details annual drug utilization and spending on both generic and branded drugs from 2011 to 2015 by Medicare Part D participants who filled prescriptions for topical steroids. Main Outcomes and Measures Total and potential Medicare and out-of-pocket patient spending. Costs were adjusted for inflation and reported in 2015 dollars. Results Medicare Part D expenditures on topical steroids between 2011 and 2015 were $2.3 billion. Patients’ out-of-pocket spending for topical steroids over the same period was $333.7 million. The total annual spending increased from $237.6 million to $775.9 million, an increase of 226.5%. Patients’ annual out-of-pocket spending increased from $41.4 million to $101.8 million, an increase of 145.9%. The total number of prescriptions were 7.7 million in 2011 and 10.6 million in 2015, an increase of 37.0%. Generic medication costs accounted for 97.8% of the total spending during this time period. The potential health care savings and out-of-pocket patient savings from substitution of the cheapest topical steroid within the corresponding potency class were $944.8 million and $66.6 million, respectively. Conclusions and Relevance Most topical steroids prescribed were generic drugs. There has been a sharp increase in Medicare and out-of-pocket spending on topical steroids that is driven by higher

A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs steroid alone in low-risk cataract surgery patients.

PubMed

Wittpenn, John R; Silverstein, Steven; Heier, Jeffrey; Kenyon, Kenneth R; Hunkeler, John D; Earl, Melissa

2008-10-01

To evaluate whether adding perioperative topical ketorolac tromethamine 0.4% improves cataract surgery outcomes relative to topical steroids alone in patients without known risk factors for cystoid macular edema (CME). Prospective, randomized, investigator-masked, multicenter clinical trial. Patients scheduled to undergo phacoemulsification and with no recognized CME risks (diabetic retinopathy, retinal vascular disease, or macular abnormality) were randomized to receive either prednisolone acetate 1% 4 times daily (QID) alone (steroid group; n = 278) or prednisolone 1% QID plus ketorolac 0.4% QID (ketorolac/steroid group; n = 268) for approximately four weeks postoperatively. In the ketorolac/steroid group, patients also received topical ketorolac 0.4% QID for three days preoperatively. In both groups, patients received four doses of ketorolac 0.4% one hour before surgery. Patients with capsular disruption or vitreous loss intraoperatively were exited from the study. Outcome measures included CME incidence, retinal thickness as measured by optical coherence tomography (OCT), best-corrected visual acuity, and contrast sensitivity. No patients in the ketorolac/steroid group and five patients in the steroid group had clinically apparent CME (P = .032). Based on OCT, no ketorolac/steroid patient had definite or probable CME, compared with six steroid patients (2.4%; P = .018). In the ketorolac/steroid group, mean retinal thickening was less (3.9 microm vs 9.6 microm; P = .003), and fewer patients had retinal thickening of more than 10 microm as compared with the steroid group (26% vs 51%; P < .001). This study suggests that adding perioperative ketorolac to postoperative prednisolone significantly reduces the incidences of CME and macular thickening in cataract surgery patients already at low risk for this condition.

Effect of oxidizing adulterants on human urinary steroid profiles.

PubMed

Kuzhiumparambil, Unnikrishnan; Fu, Shanlin

2013-02-01

Steroid profiling is the most versatile and informative technique adapted by doping control laboratories for detection of steroid abuse. The absolute concentrations and ratios of endogenous steroids including testosterone, epitestosterone, androsterone, etiocholanolone, 5α-androstane-3α,17β-diol and 5β-androstane-3α,17β-diol constitute the significant characteristics of a steroid profile. In the present study we report the influence of various oxidizing adulterants on the steroid profile of human urine. Gas chromatography-mass spectrometry analysis was carried out to develop the steroid profile of human male and female urine. Oxidants potassium nitrite, sodium hypochlorite, potassium permanganate, cerium ammonium nitrate, sodium metaperiodate, pyridinium chlorochromate, potassium dichromate and potassium perchlorate were reacted with urine at various concentrations and conditions and the effect of these oxidants on the steroid profile were analyzed. Most of the oxidizing chemicals led to significant changes in endogenous steroid profile parameters which were considered stable under normal conditions. These oxidizing chemicals can cause serious problems regarding the interpretation of steroid profiles and have the potential to act as masking agents that can complicate or prevent the detection of the steroid abuse. Copyright © 2012 Elsevier Inc. All rights reserved.

Dysfunctional stress responses in chronic pain.

PubMed

Woda, Alain; Picard, Pascale; Dutheil, Frédéric

2016-09-01

Many dysfunctional and chronic pain conditions overlap. This review describes the different modes of chronic deregulation of the adaptive response to stress which may be a common factor for these conditions. Several types of dysfunction can be identified within the hypothalamo-pituitary-adrenal axis: basal hypercortisolism, hyper-reactivity, basal hypocortisolism and hypo-reactivity. Neuroactive steroid synthesis is another component of the adaptive response to stress. Dehydroepiandrosterone (DHEA) and its sulfated form DHEA-S, and progesterone and its derivatives are synthetized in cutaneous, nervous, and adipose cells. They are neuroactive factors that act locally. They may have a role in the localization of the symptoms and their levels can vary both in the central nervous system and in the periphery. Persistent changes in neuroactive steroid levels or precursors can induce localized neurodegeneration. The autonomic nervous system is another component of the stress response. Its dysfunction in chronic stress responses can be expressed by decreased basal parasympathethic activity, increased basal sympathetic activity or sympathetic hyporeactivity to a stressful stimulus. The immune and genetic systems also participate. The helper-T cells Th1 secrete pro-inflammatory cytokines such as IL-1-β, IL-2, IL-6, IL-8, IL-12, IFN-γ, and TNF-α, whereas Th2 secrete anti-inflammatory cytokines: IL-4, IL-10, IGF-10, IL-13. Chronic deregulation of the Th1/Th2 balance can occur in favor of anti- or pro-inflammatory direction, locally or systemically. Individual vulnerability to stress can be due to environmental factors but can also be genetically influenced. Genetic polymorphisms and epigenetics are the main keys to understanding the influence of genetics on the response of individuals to constraints. Copyright © 2016 Elsevier Ltd. All rights reserved.

Microbial biotransformation of bioactive and clinically useful steroids and some salient features of steroids and biotransformation.

PubMed

Sultana, Nighat

2018-01-31

Steroids are perhaps one of the most widely used group of drugs in present day. Beside the established utilization as immunosuppressive, anti-inflammatory, anti-rheumatic, progestational, diuretic, sedative, anabolic and contraceptive agents, recent applications of steroid compounds include the treatment of some forms of cancer, osteoporosis, HIV infections and treatment of declared AIDS. Steroids isolated are often available in minute amounts. So biotransformation of natural products provides a powerful means in solving supply problems in clinical trials and marketing of the drug for obtaining natural products in bulk amounts. If the structure is complex, it is often an impossible task to isolate enough of the natural products for clinical trials. The microbial biotransformation of steroids yielded several novel metabolites, exhibiting different activities. The metabolites produced from pregnenolone acetate by Cunning hamella elegans and Rhizopus stolonifer were screened against tyrosinase and cholinesterase showed significant inhibitory activities than the parent compound. Diosgenin and its transformed sarsasapogenin were screened for their acetyl cholinesterase and butyryl cholinesterase inhibitory activities. Sarsasapogenin was screened for phytotoxicity, and was found to be more active than the parent compound. Diosgenin, prednisone and their derivatives were screened for their anti-leishmanial activity. All derivatives were found to be more active than the parent compound. The biotransformation of steroids have been reviewed to a little extent. This review focuses on the biotransformation and functions of selected steroids, the classification, advantages and agents of enzymatic biotransformation and examines the potential role of new enzymatically transformed steroids and their derivatives in the chemoprevention and treatment of other diseases. tyrosinase and cholinesterase inhibitory activities, severe asthma, rheumatic disorders, renal disorders and

In vivo clonal overexpression of neuroligin 3 and neuroligin 2 in neurons of the rat cerebral cortex. Differential effects on GABAergic synapses and neuronal migration

PubMed Central

Fekete, Christopher D.; Chiou, Tzu-Ting; Miralles, Celia P.; Harris, Rachel S.; Fiondella, Christopher G.; LoTurco, Joseph J.; De Blas, Angel L.

2015-01-01

We have studied the effect of clonal overexpression of neuroligin 3 (NL3) or neuroligin 2 (NL2) in the adult rat cerebral cortex following in utero electroporation (IUEP) at embryonic stage E14. Overexpression of NL3 leads to a large increase in vGAT and GAD65 in the GABAergic contacts that the overexpressing neurons receive. Overexpression of NL2 produced a similar effect but to a lesser extent. In contrast, overexpression of NL3 or NL2 after IUEP, does not affect vGlut1 in the glutamatergic contacts that the NL3 or NL2 overexpressing neurons receive. The NL3 or NL2 overexpressing neurons do not show increased innervation by parvalbumin-containing GABAergic terminals or increased parvalbumin in the same terminals that show increased vGAT. These results indicate that the observed increase in vGAT and GAD65 is not due to increased GABAergic innervation but to increased expression of vGAT and GAD65 in the GABAergic contacts that NL3 or NL2 overexpressing neurons receive. The majority of bright vGAT puncta contacting the NL3 overexpressing neurons have no gephyrin juxtaposed to them indicating that many of these contacts are non-synaptic. This contrasts with the majority of the NL2 overexpressing neurons, which show plenty of synaptic gephyrin clusters juxtaposed to vGAT. Besides having an effect on GABAergic contacts, overexpression of NL3 interferes with the neuronal radial migration, in the cerebral cortex, of the neurons overexpressing NL3. PMID:25565602

Are steroids useful to treat cerebral venous thrombosis?

PubMed

Canhão, Patrícia; Cortesão, Ana; Cabral, Marta; Ferro, José M; Stam, Jan; Bousser, Marie-Germaine; Barinagarrementeria, Fernando

2008-01-01

No randomized controlled trial has evaluated the efficacy of steroids in acute cerebral venous thrombosis (CVT). We aimed to analyze the effect of steroids on the outcome of patients in the International Study on Cerebral Veins and Dural Sinus Thrombosis (ISCVT). ISCVT is a prospective observational study that included 624 CVT patients. Death or dependence at 6 months was compared between cases (patients treated with steroids) and controls (patients not treated with steroids), using 3 designs: (1) Matched case-control study (each case matched with a control for prognostic factors); (2) Nonmatched case-control study of the ISCVT cohort; (3) Case-control study in different strata according to the number of poor prognostic variables in each patient. One hundred and fifty (24%) patients were treated with steroids. (1) In the matched case-control study, poor outcome was similar in the two groups of patients (26/146 versus 17/149, OR=1.7; 95% CI 0.9 to 3.3, P=0.119). (2) In the ISCVT cohort, no significant difference in poor outcomes was found whether patients were treated with steroids or not (26/146 versus 60/469, OR=1.5; 95% CI 0.9 to 2.4). Patients without parenchymal lesions treated with steroids had worse prognosis than those treated without steroids (8/45 versus 9/184, OR=4.2, 95% CI 1.6 to 11.6, P=0.008). (3) Treatment with steroids was not associated with a better outcome in any strata of patients according to the number of poor prognostic factors. Steroids in the acute phase of CVT were not useful and were detrimental in patients without parenchymal cerebral lesions. These results do not support the use of steroids in CVT (evidence level III).

GABAergic neurons in cerebellar interposed nucleus modulate cellular and humoral immunity via hypothalamic and sympathetic pathways.

PubMed

Lu, Jian-Hua; Wang, Xiao-Qin; Huang, Yan; Qiu, Yi-Hua; Peng, Yu-Ping

2015-06-15

Our previous work has shown that cerebellar interposed nucleus (IN) modulates immune function. Herein, we reveal mechanism underlying the immunomodulation. Treatment of bilateral cerebellar IN of rats with 3-mercaptopropionic acid (3-MP), a glutamic acid decarboxylase antagonist that reduces γ-aminobutyric acid (GABA) synthesis, enhanced cellular and humoral immune responses to bovine serum albumin, whereas injection of vigabatrin, a GABA-transaminase inhibitor that inhibits GABA degradation, in bilateral cerebellar IN attenuated the immune responses. The 3-MP or vigabatrin administrations in the cerebellar IN decreased or increased hypothalamic GABA content and lymphoid tissues' norepinephrine content, respectively, but did not alter adrenocortical or thyroid hormone levels in serum. In addition, a direct GABAergic projection from cerebellar IN to hypothalamus was found. These findings suggest that GABAergic neurons in cerebellar IN regulate immune system via hypothalamic and sympathetic pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

Reference ranges for urinary concentrations and ratios of endogenous steroids, which can be used as markers for steroid misuse, in a Caucasian population of athletes.

PubMed

Van Renterghem, Pieter; Van Eenoo, Peter; Geyer, Hans; Schänzer, Wilhelm; Delbeke, Frans T

2010-02-01

The detection of misuse with naturally occurring steroids is a great challenge for doping control laboratories. Intake of natural anabolic steroids alters the steroid profile. Thus, screening for exogenous use of these steroids can be established by monitoring a range of endogenous steroids, which constitute the steroid profile, and evaluate their concentrations and ratios against reference ranges. Elevated values of the steroid profile constitute an atypical finding after which a confirmatory IRMS procedure is needed to unequivocally establish the exogenous origin of a natural steroid. However, the large inter-individual differences in urinary steroid concentrations and the recent availability of a whole range of natural steroids (e.g. dehydroepiandrosterone and androstenedione) which each exert a different effect on the monitored parameters in doping control complicate the interpretation of the current steroid profile. The screening of an extended steroid profile can provide additional parameters to support the atypical findings and can give specific information upon the steroids which have been administered. The natural concentrations of 29 endogenous steroids and 11 ratios in a predominantly Caucasian population of athletes were determined. The upper reference values at 97.5%, 99% and 99.9% levels were assessed for male (n=2027) and female (n=1004) populations. Monitoring minor metabolites and evaluation of concentration ratios with respect to their natural abundances could improve the interpretation of the steroid profile in doping analysis. Copyright 2009 Elsevier Inc. All rights reserved.

DEVELOPMENTAL HYPOTHYROIDISM REDUCES PARVALBUMIN EXPRESSION IN GABAERGIC NEURONS OF CORTEX AND HIPPOCAMPUS: IMMUNOHISTOCHEMICAL FINDINGS AND FUNCTIONAL CORRELATES.

EPA Science Inventory

GABAergic interneurons comprise the bulk of local inhibitory neuronal circuitry in cortex and hippocampus and a subpopulation of these interneurons contain the calcium binding protein, parvalbumin (PV). A previous report indicated that severe hypothyroidism reduced PV immunoreact...

Comparative Effectiveness of Tacrolimus-Based Steroid Sparing versus Steroid Maintenance Regimens in Kidney Transplantation: Results from Discrete Event Simulation.

PubMed

Desai, Vibha C A; Ferrand, Yann; Cavanaugh, Teresa M; Kelton, Christina M L; Caro, J Jaime; Goebel, Jens; Heaton, Pamela C

2017-10-01

Corticosteroids used as immunosuppressants to prevent acute rejection (AR) and graft loss (GL) following kidney transplantation are associated with serious cardiovascular and other adverse events. Evidence from short-term randomized controlled trials suggests that many patients on a tacrolimus-based immunosuppressant regimen can withdraw from steroids without increased AR or GL risk. To measure the long-term tradeoff between GL and adverse events for a heterogeneous-risk population and determine the optimal timing of steroid withdrawal. A discrete event simulation was developed including, as events, AR, GL, myocardial infarction (MI), stroke, cytomegalovirus, and new onset diabetes mellitus (NODM), among others. Data from the United States Renal Data System were used to estimate event-specific parametric regressions, which accounted for steroid-sparing regimen (avoidance, early 7-d withdrawal, 6-mo withdrawal, 12-mo withdrawal, and maintenance) as well as patients' demographics, immunologic risks, and comorbidities. Regression-equation results were used to derive individual time-to-event Weibull distributions, used, in turn, to simulate the course of patients over 20 y. Patients on steroid avoidance or an early-withdrawal regimen were more likely to experience AR (45.9% to 55.0% v. 33.6%, P < 0.05) and GL (51.5% to 68.8% v. 37.8%, P < 0.05) compared to patients on steroid maintenance. Patients in 6-mo and 12-mo steroid withdrawal groups were less likely to experience MI (11.1% v. 13.3%, P < 0.05), NODM (30.7% to 34.4% v. 37.7%, P < 0.05), and cardiac death (29.9% to 30.5% v. 32.4%, P < 0.05), compared to steroid maintenance. Strategies of 6- and 12-mo steroid withdrawal post-kidney transplantation are expected to reduce the rates of adverse cardiovascular events and other outcomes with no worsening of AR or GL rates compared with steroid maintenance.

Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: effects on proactive interference.

PubMed

Pang, Kevin C H; Jiao, Xilu; Sinha, Swamini; Beck, Kevin D; Servatius, Richard J

2011-08-01

The medial septum and diagonal band (MSDB) are important in spatial learning and memory. On the basis of the excitotoxic damage of GABAergic MSDB neurons, we have recently suggested a role for these neurons in controlling proactive interference. Our study sought to test this hypothesis in different behavioral procedures using a new GABAergic immunotoxin. GABA-transporter-saporin (GAT1-SAP) was administered into the MSDB of male Sprague-Dawley rats. Following surgery, rats were trained in a reference memory water maze procedure for 5 days, followed by a working memory (delayed match to position) water maze procedure. Other rats were trained in a lever-press avoidance procedure after intraseptal GAT1-SAP or sham surgery. Intraseptal GAT1-SAP extensively damaged GABAergic neurons while sparing most cholinergic MSDB neurons. Rats treated with GAT1-SAP were not impaired in acquiring a spatial reference memory, learning the location of the escape platform as rapidly as sham rats. In contrast, GAT1-SAP rats were slower than sham rats to learn the platform location in a delayed match to position procedure, in which the platform location was changed every day. Moreover, GAT1-SAP rats returned to previous platform locations more often than sham rats. In the active avoidance procedure, intraseptal GAT1-SAP impaired extinction but not acquisition of the avoidance response. Using a different neurotoxin and behavioral procedures than previous studies, the results of this study paint a similar picture that GABAergic MSDB neurons are important for controlling proactive interference. Copyright © 2010 Wiley-Liss, Inc.

Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats.

PubMed

Hu, Wen; Zhang, Mingyue; Czéh, Boldizsár; Zhang, Weiqi; Flügge, Gabriele

2011-07-15

Chronic stress, a risk factor for the development of psychiatric disorders, is known to induce alterations in neuronal networks in many brain areas. Previous studies have shown that chronic stress changes the expression of the cannabinoid receptor 1 (CB1) in the brains of adult rats, but neurophysiological consequences of these changes remained unclear. Here we demonstrate that chronic restraint stress causes a dysfunction in CB1 mediated modulation of GABAergic transmission in the hippocampus. Using an established protocol, adult male Sprague Dawley rats were daily restrained for 21 days and whole-cell voltage clamp was performed at CA1 pyramidal neurons. When recording carbachol-evoked inhibitory postsynaptic currents (IPSCs) which presumably originate from CB1 expressing cholecystokinin (CCK) interneurons, we found that depolarization-induced suppression of inhibition (DSI) was impaired by the stress. DSI is a form of short-term plasticity at GABAergic synapses that is known to be CB1 mediated and has been suggested to be involved in hippocampal information encoding. Chronic stress attenuated the depolarization-induced suppression of the frequency of carbachol-evoked IPSCs. Incubation with a CB1 receptor antagonist prevented this DSI effect in control but not in chronically stressed animals. The stress-induced impairment of CB1-mediated short-term plasticity at GABAergic synapses may underlie cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

Steroidal saponins from Sansevieria trifasciata.

PubMed

Mimaki, Y; Inoue, T; Kuroda, M; Sashida, Y

1996-12-01

The methanol extract of the whole plant of Sansevieria trifasciata has yielded 12 steroidal saponins, 10 of which are new constituents. The respective structures of the new compounds have been shown by the spectroscopic evidence, and alkaline- and acid-catalysed degradation. This is the first report of the isolation of steroidal saponins from S. trifasciata.

Crystallization of steroids in gels

NASA Astrophysics Data System (ADS)

Kalkura, S. Narayana; Devanarayanan, S.

1991-03-01

The crystal growth and characterization of certain steriods, viz., cholesterol, cholesteryl acetate, β-sitosterol, progesterone and testosterone, in a silica gel medium is discussed. The present study shows that the single test tube diffusion method can be used to grow crystals of steroids in a silica gel medium by the reduction of steroid solubility.

Trichoscopy of Steroid-Induced Atrophy.

PubMed

Pirmez, Rodrigo; Abraham, Leonardo S; Duque-Estrada, Bruna; Damasco, Patrícia; Farias, Débora Cadore; Kelly, Yanna; Doche, Isabella

2017-10-01

Intralesional corticosteroid (IL-CS) injections have been used to treat a variety of dermatological and nondermatological diseases. Although an important therapeutic tool in dermatology, a number of local side effects, including skin atrophy, have been reported following IL-CS injections. We recently noticed that a subset of patients with steroid-induced atrophy presented with ivory-colored areas under trichoscopy. We performed a retrospective analysis of trichoscopic images and medical records from patients presenting ivory-colored areas associated with atrophic scalp lesions. In this paper, we associate this feature with the presence of steroid deposits in the dermis and report additional trichoscopic features of steroid-induced atrophy on the scalp, such as prominent blood vessels and visualization of hair bulbs.

Hypochlorite Oxidation of Select Androgenic Steroids

EPA Science Inventory

Steroid hormones are vital for regulation of various biological functions including sexual development. Elevated concentrations of natural and synthetic androgenic steroids have been shown to adversely affect normal development in indigenous aqueous species. Androgens and their s...

Characteristics of Steroid Users in an Adolescent School Population.

ERIC Educational Resources Information Center

Adlaf, Edward M.; Smart, Reginald G.

1992-01-01

Examined rates of steroid use among Ontario adolescent students. Findings from 3,892 students revealed that 1.1 percent reported using steroids over past year. Steroid users were significantly more likely to use stimulants, caffeine, and relaxants than were nonsteroid users. Demographically, steroid users were significantly more likely to be male…

Variant BDNF-Val66Met Polymorphism is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia.

PubMed

Chen, Yi-Wen; Surgent, Olivia; Rana, Barkha S; Lee, Francis; Aoki, Chiye

2017-08-01

Previously, we determined that rodents' vulnerability to food restriction (FR)-evoked wheel running during adolescence (activity-based anorexia, ABA) is associated with failures to increase GABAergic innervation of hippocampal and medial prefrontal pyramidal neurons. Since brain-derived neurotrophic factor (BDNF) promotes GABAergic synaptogenesis, we hypothesized that individual differences in this vulnerability may arise from differences in the link between BDNF bioavailability and FR-evoked wheel running. We tested this hypothesis in male BDNF-Val66Met knock-in mice (BDNFMet/Met), known for reduction in the activity-dependent BDNF secretion and elevated anxiety-like behaviors. We found that 1) in the absence of FR or a wheel (i.e., control), BDNFMet/Met mice are more anxious than wild-type (WT) littermates, 2) electron microscopically verified GABAergic innervations of pyramidal neurons of BDNFMet/Met mice are reduced at distal dendrites in hippocampal CA1 and medial prefrontal cortex, 3) following ABA, WT mice exhibit anxiety equal to those of the BDNFMet/Met mice and have lost GABAergic innervation along distal dendrites, 4) BDNFMet/Met mice show blunted ABA vulnerability, and 5) unexpectedly, GABAergic innervation is higher at somata of BDNFMet/Met mice than of WT. We conclude that lamina-specific GABAergic inhibition is important for regulating anxiety, whether arising from environmental stress, such as food deprivation, or genetically, such as BDNFMet/Met single nucleotide polymorphism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development.

PubMed

Li, Jun; Han, Wenyan; Pelkey, Kenneth A; Duan, Jingjing; Mao, Xia; Wang, Ya-Xian; Craig, Michael T; Dong, Lijin; Petralia, Ronald S; McBain, Chris J; Lu, Wei

2017-11-15

In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development. Published by Elsevier Inc.

Steroid therapy in children with fulminant hepatitis A.

PubMed

Zakaria, H M; Salem, T A; El-Araby, H A; Salama, R M; Elbadry, D Y; Sira, A M; Ali, M A; Salem, M E; Abd-Alaaty, B M; Goda, S S; Eltaras, S M; Khalil, F O; Abou-Zeinah, S S; Sira, M M

2018-02-03

Fulminant hepatic failure is a life-threatening disease. Hepatitis A virus (HAV) can cause fulminant hepatic failure and death in about 0.2% of cases. Extensive destruction of infected hepatocytes by immune-mediated lysis is thought to be the cause. We aimed to evaluate the use of steroid therapy in children with fulminant HAV. This study included 33 children with fulminant HAV in two groups. Steroid group: comprised of 18 children who received prednisolone (1 mg/kg/d) or its equivalent dose of methylprednisolone, and the nonsteroid group: comprised another 15 children who did not receive steroid therapy. Age and sex were matched for both groups (P > .05), and they were comparable regarding baseline clinical and laboratory characteristics. Of the steroid group, 15 patients survived and 3 died, while in the nonsteroid group, 4 patients survived and 11 died (P = .001). Of the living patients, 15 of 19 (78.9%) received steroids while only 3 of 14 (21.4%) of the dead patients received steroids (P = .001). Stepwise regression analysis showed that steroid therapy was the only independent variable associated with recovery (P = .001). Steroid therapy in children with fulminant HAV associated significantly with improved outcome and survival. Future studies on a larger population size are strongly recommended. © 2018 John Wiley & Sons Ltd.

Pre-differentiation of human neural stem cells into GABAergic neurons prior to transplant results in greater repopulation of the damaged brain and accelerates functional recovery after transient ischemic stroke.

PubMed

Abeysinghe, Hima C S; Bokhari, Laita; Quigley, Anita; Choolani, Mahesh; Chan, Jerry; Dusting, Gregory J; Crook, Jeremy M; Kobayashi, Nao R; Roulston, Carli L

2015-09-29

Despite attempts to prevent brain injury during the hyperacute phase of stroke, most sufferers end up with significant neuronal loss and functional deficits. The use of cell-based therapies to recover the injured brain offers new hope. In the current study, we employed human neural stem cells (hNSCs) isolated from subventricular zone (SVZ), and directed their differentiation into GABAergic neurons followed by transplantation to ischemic brain. Pre-differentiated GABAergic neurons, undifferentiated SVZ-hNSCs or media alone were stereotaxically transplanted into the rat brain (n=7/group) 7 days after endothelin-1 induced stroke. Neurological outcome was assessed by neurological deficit scores and the cylinder test. Transplanted cell survival, cellular phenotype and maturation were assessed using immunohistochemistry and confocal microscopy. Behavioral assessments revealed accelerated improvements in motor function 7 days post-transplant in rats treated with pre-differentiated GABAergic cells in comparison to media alone and undifferentiated hNSC treated groups. Histopathology 28 days-post transplant indicated that pre-differentiated cells maintained their GABAergic neuronal phenotype, showed evidence of synaptogenesis and up-regulated expression of both GABA and calcium signaling proteins associated with neurotransmission. Rats treated with pre-differentiated cells also showed increased neurogenic activity within the SVZ at 28 days, suggesting an additional trophic role of these GABAergic cells. In contrast, undifferentiated SVZ-hNSCs predominantly differentiated into GFAP-positive astrocytes and appeared to be incorporated into the glial scar. Our study is the first to show enhanced exogenous repopulation of a neuronal phenotype after stroke using techniques aimed at GABAergic cell induction prior to delivery that resulted in accelerated and improved functional recovery.

Sex steroid signaling: implications for lung diseases.

PubMed

Sathish, Venkatachalem; Martin, Yvette N; Prakash, Y S

2015-06-01

There is increasing recognition that sex hormones (estrogen, progesterone, and testosterone) have biological and pathophysiological actions in peripheral, non-reproductive organs, including the lung. Clinically, sex differences in the incidence, morbidity and mortality of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, lung cancer and pulmonary hypertension have been noted, although intrinsic sex differences vs. the roles of sex steroids are still not well-understood. Accordingly, it becomes important to ask the following questions: 1) Which sex steroids are involved? 2) How do they affect different components of the lung under normal circumstances? 3) How does sex steroid signaling change in or contribute to lung disease, and in this regard, are sex steroids detrimental or beneficial? As our understanding of sex steroid signaling in the lung improves, it is important to consider whether such information can be used to develop new therapeutic strategies to target lung diseases, perhaps in both sexes or in a sex-specific manner. In this review, we focus on the basics of sex steroid signaling, and the current state of knowledge regarding how they influence structure and function of specific lung components across the life span and in the context of some important lung diseases. We then summarize the potential for sex steroids as useful biomarkers and therapeutic targets in these lung diseases as a basis for future translational research in the area of gender and individualized medicine. Copyright © 2015 Elsevier Inc. All rights reserved.

Sex Steroid Signaling: Implications for Lung Diseases

PubMed Central

Sathish, Venkatachalem; Martin, Yvette N.; Prakash, Y.S.

2015-01-01

There is increasing recognition that the sex hormones (estrogen, progesterone, and testosterone) have biological and pathophysiological actions in peripheral, non-reproductive organs, including the lung. Clinically, sex differences in the incidence, morbidity and mortality of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, lung cancer and pulmonary hypertension have been noted, although intrinsic sex differences vs. the roles of sex steroids are still not well-understood. Accordingly, it becomes important to ask the following questions: 1) Which sex steroids are involved? 2) How do they affect different components of the lung under normal circumstances? 3) How does sex steroid signaling change in or contribute to lung disease, and in this regard, are sex steroids detrimental or beneficial? As our understanding of sex steroid signaling in the lung improves, it is important to consider whether such information can be used to develop new therapeutic strategies to target lung diseases, perhaps in both sexes or in a sex-specific manner. In this review, we focus on the basics of sex steroid signaling, and the current state of knowledge regarding how they influence structure and function of specific lung components across the life span and in the context of some important lung diseases. We then summarize the potential for sex steroids as useful biomarkers and therapeutic targets in these lung diseases as a basis for future translational research in the area of gender and individualized medicine. PMID:25595323

The Regulation of Steroid Action by Sulfation and Desulfation

PubMed Central

Mueller, Jonathan W.; Gilligan, Lorna C.; Idkowiak, Jan; Arlt, Wiebke

2015-01-01

Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined. PMID:26213785

Glutamatergic and GABAergic TCA cycle and neurotransmitter cycling fluxes in different regions of mouse brain.

PubMed

Tiwari, Vivek; Ambadipudi, Susmitha; Patel, Anant B

2013-10-01

The (13)C nuclear magnetic resonance (NMR) studies together with the infusion of (13)C-labeled substrates in rats and humans have provided important insight into brain energy metabolism. In the present study, we have extended a three-compartment metabolic model in mouse to investigate glutamatergic and GABAergic tricarboxylic acid (TCA) cycle and neurotransmitter cycle fluxes across different regions of the brain. The (13)C turnover of amino acids from [1,6-(13)C2]glucose was monitored ex vivo using (1)H-[(13)C]-NMR spectroscopy. The astroglial glutamate pool size, one of the important parameters of the model, was estimated by a short infusion of [2-(13)C]acetate. The ratio Vcyc/VTCA was calculated from the steady-state acetate experiment. The (13)C turnover curves of [4-(13)C]/[3-(13)C]glutamate, [4-(13)C]glutamine, [2-(13)C]/[3-(13)C]GABA, and [3-(13)C]aspartate from [1,6-(13)C2]glucose were analyzed using a three-compartment metabolic model to estimate the rates of the TCA cycle and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The glutamatergic TCA cycle rate was found to be highest in the cerebral cortex (0.91 ± 0.05 μmol/g per minute) and least in the hippocampal region (0.64 ± 0.07 μmol/g per minute) of the mouse brain. In contrast, the GABAergic TCA cycle flux was found to be highest in the thalamus-hypothalamus (0.28 ± 0.01 μmol/g per minute) and least in the cerebral cortex (0.24 ± 0.02 μmol/g per minute). These findings indicate that the energetics of excitatory and inhibitory function is distinct across the mouse brain.

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

PubMed Central

Sosulina, L.; Strippel, C.; Romo-Parra, H.; Walter, A. L.; Kanyshkova, T.; Sartori, S. B.; Lange, M. D.; Singewald, N.

2015-01-01

Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at −101.5 ± 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K+ conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar9,Met(O2)11]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKCδ-negative neurons (80%) and in few PKCδ-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKCδ-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala. PMID:26334021

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation.

PubMed

Sosulina, L; Strippel, C; Romo-Parra, H; Walter, A L; Kanyshkova, T; Sartori, S B; Lange, M D; Singewald, N; Pape, H-C

2015-10-01

Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at -101.5 ± 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K(+) conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar(9),Met(O2)(11)]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKCδ-negative neurons (80%) and in few PKCδ-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKCδ-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala. Copyright © 2015 the American Physiological Society.

Critical Roles of the Direct GABAergic Pallido-cortical Pathway in Controlling Absence Seizures

PubMed Central

Li, Min; Ma, Tao; Wu, Shengdun; Ma, Jingling; Cui, Yan; Xia, Yang; Xu, Peng; Yao, Dezhong

2015-01-01

The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies. PMID:26496656

A high-throughput UPC2-MS/MS method for the separation and quantification of C19 and C21 steroids and their C11-oxy steroid metabolites in the classical, alternative, backdoor and 11OHA4 steroid pathways.

PubMed

du Toit, Therina; Stander, Maria A; Swart, Amanda C

2018-03-30

In the present study an ultra-performance convergence chromatography tandem mass spectrometry (UPC 2 -MS/MS) analytical method was developed and validated for the determination of 17 C 19 and 14 C 21 steroids, including C11-oxy C 19 and C11-oxy C 21 steroids. The limit of detection and limit of quantification ranged from 0.01 to 10 ng/mL and from 0.01 to 20 ng/mL, respectively, and the method shows the recovery, matrix effect and process efficiency of steroids isolated from a serum matrix to be within acceptable limits. Good accuracy, repeatability and reproducibility were also shown and the method provided excellent sensitivity and selectivity as stereoisomers and regioisomers were also resolved and quantified accurately. Clinical conditions such as congenital adrenal hyperplasia, polycystic ovary syndrome in females and disorders of sex development in neonates and in children, amongst others, are characterized by abnormal steroid levels. Steroid profiling is essential to accurately diagnose steroid levels in the above settings as well as in androgen excess or deficiency in adrenal-linked endocrine diseases. Our method, separating C 19 and C 21 steroids in a single chromatographic step, offers a reduced sample turnover rate in the clinical setting, while providing comprehensive steroid profiles of in vivo steroids in the nmol/L range. This is, to our knowledge, the first method reported to simultaneously separate C 19 and C 21 steroids, together with their C11-hydroxy and C11-keto metabolites -one which may hold promise in the identification of new steroid markers in steroid-linked endocrine diseases, in addition to profiling steroid metabolism and abnormal enzyme activity in patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Autistic behavior in Scn1a+/− mice and rescue by enhanced GABAergic transmission

PubMed Central

Han, Sung; Tai, Chao; Westenbroek, Ruth E.; Yu, Frank H.; Cheah, Christine S.; Potter, Gregory B.; Rubenstein, John L.; Scheuer, Todd; de la Iglesia, Horacio O; Catterall, William A

2012-01-01

Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel NaV1.1 causes Dravet Syndrome (DS), a childhood neuropsychiatric disorder including recurrent intractable seizures, cognitive deficit, and autism-spectrum behaviors. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviors in DS are poorly understood. Here we show that mice with Scn1a haploinsufficiency display hyperactivity, stereotyped behaviors, social interaction deficits, and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odors and social odors are aversive to Scn1a+/− mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of NaV1.1 channels in forebrain interneurons is sufficient to cause these behavioral and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABAA receptors, completely rescued the abnormal social behaviors and deficits in fear memory in DS mice, demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. These results demonstrate a critical role for NaV1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviors in DS. PMID:22914087

Anabolic steroid induced hypogonadism in young men.

PubMed

Coward, Robert M; Rajanahally, Saneal; Kovac, Jason R; Smith, Ryan P; Pastuszak, Alexander W; Lipshultz, Larry I

2013-12-01

The use of anabolic androgenic steroids has not been traditionally discussed in mainstream medicine. With the increased diagnosis of hypogonadism a heterogeneous population of men is now being evaluated. In this larger patient population the existence of anabolic steroid induced hypogonadism, whether transient or permanent, should now be considered. We performed an initial retrospective database analysis of all 6,033 patients who sought treatment for hypogonadism from 2005 to 2010. An anonymous survey was subsequently distributed in 2012 to established patients undergoing testosterone replacement therapy. Profound hypogonadism, defined as testosterone 50 ng/dl or less, was identified in 97 men (1.6%) in the large retrospective cohort initially reviewed. The most common etiology was prior anabolic androgenic steroid exposure, which was identified in 42 men (43%). Because of this surprising data, we performed an anonymous followup survey of our current hypogonadal population of 382 men with a mean±SD age of 49.2±13.0 years. This identified 80 patients (20.9%) with a mean age of 40.4±8.4 years who had prior anabolic androgenic steroid exposure. Hypogonadal men younger than 50 years were greater than 10 times more likely to have prior anabolic androgenic steroid exposure than men older than 50 years (OR 10.16, 95% CI 4.90-21.08). Prior anabolic androgenic steroid use significantly correlated negatively with education level (ρ=-0.160, p=0.002) and number of children (ρ=-0.281, p<0.0001). Prior anabolic androgenic steroid use is common in young men who seek treatment for symptomatic hypogonadism and anabolic steroid induced hypogonadism is the most common etiology of profound hypogonadism. These findings suggest that it is necessary to refocus the approach to evaluation and treatment paradigms in young hypogonadal men. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Passiflora incarnata attenuation of neuropathic allodynia and vulvodynia apropos GABA-ergic and opioidergic antinociceptive and behavioural mechanisms.

PubMed

Aman, Urooj; Subhan, Fazal; Shahid, Muhammad; Akbar, Shehla; Ahmad, Nisar; Ali, Gowhar; Fawad, Khwaja; Sewell, Robert D E

2016-02-24

Passiflora incarnata is widely used as an anxiolytic and sedative due to its putative GABAergic properties. Passiflora incarnata L. methanolic extract (PI-ME) was evaluated in an animal model of streptozotocin-induced diabetic neuropathic allodynia and vulvodynia in rats along with antinociceptive, anxiolytic and sedative activities in mice in order to examine possible underlying mechanisms. PI-ME was tested preliminary for qualitative phytochemical analysis and then quantitatively by proximate and GC-MS analysis. The antinociceptive property was evaluated using the abdominal constriction assay and hot plate test. The anxiolytic activity was performed in a stair case model and sedative activity in an open field test. The antagonistic activities were evaluated using naloxone and/or pentylenetetrazole (PTZ). PI-ME was evaluated for prospective anti-allodynic and anti-vulvodynic properties in a rat model of streptozotocin induced neuropathic pain using the static and dynamic testing paradigms of mechanical allodynia and vulvodynia. GC-MS analysis revealed that PI-ME contained predominant quantities of oleamide (9-octadecenamide), palmitic acid (hexadecanoic acid) and 3-hydroxy-dodecanoic acid, among other active constituents. In the abdominal constriction assay and hot plate test, PI-ME produced dose dependant, naloxone and pentylenetetrazole reversible antinociception suggesting an involvement of opioidergic and GABAergic mechanisms. In the stair case test, PI-ME at 200 mg/kg increased the number of steps climbed while at 600 mg/kg a significant decrease was observed. The rearing incidence was diminished by PI-ME at all tested doses and in the open field test, PI-ME decreased locomotor activity to an extent that was analagous to diazepam. The effects of PI-ME were antagonized by PTZ in both the staircase and open field tests implicating GABAergic mechanisms in its anxiolytic and sedative activities. In the streptozotocin-induced neuropathic nociceptive model, PI

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

PubMed Central

Cruz, Maureen T; Herman, Melissa A; Cote, Dawn M; Ryabinin, Andrey E; Roberto, Marisa

2013-01-01

The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists 𝒟-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. 𝒟-Lys3-GHRP-6 and JMV 3002

Kv2.2: A Novel Molecular Target to Study the Role of Basal Forebrain GABAergic Neurons in the Sleep-Wake Cycle

PubMed Central

Hermanstyne, Tracey O.; Subedi, Kalpana; Le, Wei Wei; Hoffman, Gloria E.; Meredith, Andrea L.; Mong, Jessica A.; Misonou, Hiroaki

2013-01-01

Study Objectives: The basal forebrain (BF) has been implicated as an important brain region that regulates the sleep-wake cycle of animals. Gamma-aminobutyric acidergic (GABAergic) neurons are the most predominant neuronal population within this region. However, due to the lack of specific molecular tools, the roles of the BF GABAergic neurons have not been fully elucidated. Previously, we have found high expression levels of the Kv2.2 voltage-gated potassium channel on approximately 60% of GABAergic neurons in the magnocellular preoptic area and horizontal limb of the diagonal band of Broca of the BF and therefore proposed it as a potential molecular target to study this neuronal population. In this study, we sought to determine the functional roles of the Kv2.2-expressing neurons in the regulation of the sleep-wake cycle. Design: Sleep analysis between two genotypes and within each genotype before and after sleep deprivation. Setting: Animal sleep research laboratory. Participants: Adult mice. Wild-type and Kv2.2 knockout mice with C57/BL6 background. Interventions: EEG/EMG recordings from the basal state and after sleep-deprivation which was induced by mild aggitation for 6 h. Results: Immunostaining of a marker of neuronal activity indicates that these Kv2.2-expressing neurons appear to be preferentially active during the wake state. Therefore, we tested whether Kv2.2-expressing neurons in the BF are involved in arousal using Kv2.2-deficient mice. BF GABAergic neurons exhibited augmented expression of c-Fos. These knockout mice exhibited longer consolidated wake bouts than wild-type littermates, and that phenotype was further exacerbated by sleep deprivation. Moreover, in-depth analyses of their cortical electroencephalogram revealed a significant decrease in the delta-frequency activity during the nonrapid eye movement sleep state. Conclusions: These results revealed the significance of Kv2.2-expressing neurons in the regulation of the sleep-wake cycle

Developmental disruption of medial prefrontal cortical GABAergic function by non-contingent cocaine exposure during early adolescence

PubMed Central

Cass, Daryn K.; Thomases, Daniel R.; Caballero, Adriana; Tseng, Kuei Y.

2013-01-01

Background Drug experimentation during adolescence is associated with increased risk of drug addiction relative to any other age group. To further our understanding on the neurobiology underlying such liability, we investigate how early adolescent cocaine experience impacts the overall medial prefrontal cortex (mPFC) network function in adulthood. Methods A non-contingent administration paradigm was used to assess the impact of early adolescent cocaine treatment (rats; postnatal days -PD- 35-40) on the overall inhibitory regulation of mPFC activity in adulthood (PD65-75) by means of histochemical and in vivo electrophysiological measures combined with pharmacological manipulations. Results Cocaine exposure during early adolescence yields a distinctive hyper-metabolic PFC state that was not observed in adult (PD75-80)-treated rats. Local field potential recordings expand upon these findings by showing that early adolescent cocaine exposure is associated with an attenuation of mPFC GABAergic inhibition evoked by ventral hippocampal stimulation at beta and gamma frequencies that endures throughout adulthood. Such cocaine-induced mPFC disinhibition was not observed in adult-exposed animals. Furthermore, the normal developmental upregulation of parvalbumin immunoreactivity observed in the mPFC from PD35 to PD65 is lacking following early adolescent cocaine treatment. Conclusion Our data indicate that repeated cocaine exposure during early adolescence can elicit a state of mPFC disinhibition resulting from a functional impairment of the local prefrontal GABAergic network that endures through adulthood. A lack of acquisition of prefrontal GABAergic function during adolescence could trigger long-term deficits in the mPFC that may increase the susceptibility for the onset of substance abuse and related psychiatric disorders. PMID:23558299

Four GABAergic interneurons impose feeding restraint in Drosophila

PubMed Central

Pool, Allan-Hermann; Kvello, Pal; Mann, Kevin; Cheung, Samantha K.; Gordon, Michael D.; Wang, Liming; Scott, Kristin

2014-01-01

Summary Feeding is dynamically regulated by the palatability of the food source and the physiological needs of the animal. How consumption is controlled by external sensory cues and internal metabolic state remains under intense investigation. Here, we identify four GABAergic interneurons in the Drosophila brain that establish a central feeding threshold which is required to inhibit consumption. Inactivation of these cells results in indiscriminate and excessive intake of all compounds, independent of taste quality or nutritional state. Conversely, acute activation of these neurons suppresses consumption of water and nutrients. The output from these neurons is required to gate activity in motor neurons that control meal initiation and consumption. Thus, our study reveals a new layer of inhibitory control in feeding circuits that is required to suppress a latent state of unrestricted and non-selective consumption. PMID:24991960

[Comparative study of the conventional scheme and prolonged treatment with steroids on primary steroid-sensitive nephrotic syndrome in children].

PubMed

Liern, Miguel; Codianni, Paola; Vallejo, Graciela

In the steroid-sensitive nephrotic syndrome (SSNS) the prolonged treatment with steroids could decrease the frequency of relapses. We conducted a comparative study of prolonged steroid scheme and the usual treatment of primary SSNS to assess: the number of patients with relapses, mean time to treatment initiation, to remission and to first relapse, total number of relapses, total cumulative dose of steroids, and the steroid toxicity. Patients were divided into two groups: group A (27 patients) received 16-β-methylprednisolone for 12 weeks, reducing the steroid until week 24. Group B (29 patients) received 16-β-methylprednisolone for 12 weeks and placebo until week 24. Cumulative incidence rate of relapse (person/years) for group A was of 36/100 and 66/100 for group B (p=0.04). Average elapsed time to first relapse was of 114 days for group A and of 75 days to for group B (p=0.01). The difference in time for initial response to treatment and up to achieve remission between both groups was not significant. Total cumulative relapses were 9 for group A and 17 for group B (p=0.04). Total patients with relapses were 3 for group A and 7 for group B (p=0.17). Cumulative average dose per patient was 5,243mg/m 2 for group A and 4,306mg/m 2 for group B (p=0.3), and serum cortisol was 14μg/dl for group A and 16μg/dl for group B (p=0.4). There were no steroid toxicity differences between groups. The duration of the treatment had an impact on the number of relapses without increasing steroid toxicity. Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Cell type specificity of GABA(A) receptor mediated signaling in the hippocampus.

PubMed

Semyanov, A

2003-08-01

Inhibitory signaling mediated by ionotropic GABA(1) receptors generally acts as a major brake against excessive excitability in the brain. This is especially relevant in epilepsy-prone structures such as the hippocampus, in which GABA(A) receptor mediated inhibition is critical in suppressing epileptiform activity. Indeed, potentiating GABA(A) receptor mediated signaling is an important target for antiepileptic drug therapy. GABA(A) receptor mediated inhibition has different roles in the network dependent on the target neuron. Inhibiting principal cells will thus reduce network excitability, whilst inhibiting interneurons will increase network excitability; GABAergic therapeutic agents do not distinguish between these two alternatives, which may explain why, on occasion, GABAergic antiepileptic drugs can be proconvulsant. The importance of the target-cell for the effect of neuroactive drugs has emerged from a number of recent studies. Immunocytochemical data have suggested non-uniform distribution of GABA(A) receptor subunits among hippocampal interneurons and pyramidal cells. This has been confirmed by subsequent electropharmacological data. These have demonstrated that compounds which act on GABA(A) receptors or the extracellular GABA concentration can have distinct effects in different neuronal populations. Recently, it has also been discovered that presynaptic glutamate heteroreceptors can modulate GABA release in the hippocampus in a postsynaptic cell-specific manner. Since systemically administrated drugs may act on different neuronal subtypes, they can exhibit paradoxical effects. Distinguishing compounds that have target specific effects on GABAergic signaling may lead to novel and more effective treatments against epilepsy.

Distinct GABAergic targets of feedforward and feedback connections between lower and higher areas of rat visual cortex.

PubMed

Gonchar, Yuri; Burkhalter, Andreas

2003-11-26

Processing of visual information is performed in different cortical areas that are interconnected by feedforward (FF) and feedback (FB) pathways. Although FF and FB inputs are excitatory, their influences on pyramidal neurons also depend on the outputs of GABAergic neurons, which receive FF and FB inputs. Rat visual cortex contains at least three different families of GABAergic neurons that express parvalbumin (PV), calretinin (CR), and somatostatin (SOM) (Gonchar and Burkhalter, 1997). To examine whether pathway-specific inhibition (Shao and Burkhalter, 1996) is attributable to distinct connections with GABAergic neurons, we traced FF and FB inputs to PV, CR, and SOM neurons in layers 1-2/3 of area 17 and the secondary lateromedial area in rat visual cortex. We found that in layer 2/3 maximally 2% of FF and FB inputs go to CR and SOM neurons. This contrasts with 12-13% of FF and FB inputs onto layer 2/3 PV neurons. Unlike inputs to layer 2/3, connections to layer 1, which contains CR but lacks SOM and PV somata, are pathway-specific: 21% of FB inputs go to CR neurons, whereas FF inputs to layer 1 and its CR neurons are absent. These findings suggest that FF and FB influences on layer 2/3 pyramidal neurons mainly involve disynaptic connections via PV neurons that control the spike outputs to axons and proximal dendrites. Unlike FF input, FB input in addition makes a disynaptic link via CR neurons, which may influence the excitability of distal pyramidal cell dendrites in layer 1.

Reduced steroidogenesis in patients with PCDH19-female limited epilepsy.

PubMed

Trivisano, Marina; Lucchi, Chiara; Rustichelli, Cecilia; Terracciano, Alessandra; Cusmai, Raffaella; Ubertini, Grazia Maria; Giannone, Germana; Bertini, Enrico Silvio; Vigevano, Federico; Gecz, Jozef; Biagini, Giuseppe; Specchio, Nicola

2017-06-01

Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays. Apart from estradiol and progesterone, all the considered hormones were evaluated in basal condition and after stimulation with adrenocorticotropic hormone (ACTH). A generalized decrease in blood levels of almost all measured neuroactive steroids was found. When considering sexual development, cortisol and pregnenolone sulfate basal levels were significantly reduced in postpubertal girls affected by PCDH19-FE. Of interest, ACTH administration did not recover pregnenolone sulfate serum levels but restored cortisol to control levels. In prepubertal girls with PCDH19-FE, by challenging adrenal function with ACTH we disclosed defects in the production of cortisol, pregnenolone sulfate, and 17OH-progesterone, which were not apparent in basal condition. These findings point to multiple defects in peripheral steroidogenesis associated with and potentially relevant to PCDH19-FE. Some of these defects could be addressed by stimulating adrenocortical activity. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Comparisons of steroid, acyclovir, lipoprostoglandin E1 and steroid + acyclovir treatments in facial paralysis: a rat study.

PubMed

Gök, Uzeyir; Alpay, Hayrettin Cengiz; Akpolat, Nusret; Yoldaş, Tahir; Kilic, Abdullah; Yilmaz, Bayram; Kabakuş, Nimet

2005-09-01

To induce experimental peripheral facial paralysis by inoculation of HSV1 and to compare the effects of steroid, acyclovir, lipoprostoglandin E2 and steroid + acyclovir treatments in terms of clinical recovery, electrophysiologically and histopathologically. A total of 132 adult female rats were used in this study. HSV type 1 strain was inoculated at the back of the left ear by using 27 gauge needle. Of all animals, 70 (53%) rats which developed facial paralysis were divided into five groups (n = 14 for each group) as control, steroid + acyclovir, lipoprostaglandin E1, steroid only and acyclovir only. At the end of the 21 days period, the rats were clinically examined and electrophysiological tests were performed, then decapitated and the nerve specimens were obtained. A modified electroneurography (ENoG) test was performed and the latencies and the amplitudes were compared. The findings of the intact side were better, but with no significant difference. Histopathologicaly edema was significantly smaller in all groups compared to the controls (p < 0.05). Similarly, no difference was seen in terms of vacuolar degeneration and Schwann cell hyperchromatisation among the groups and no significant difference in recovery period and rate of facial paralysis when all groups were compared. Facial paralysis induced by HSV1 recovered spontaneously within a week. In the treatment of facial paralysis, steroid alone, acyclovir alone, steroid + acyclovir, or lipoprostaglandin E1 all reduced edema in the infected facial nerve but there was no statistical difference in of the rate or degree of recovery.

Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon.

PubMed

Zhao, Yangu; Flandin, Pierre; Vogt, Daniel; Blood, Alexander; Hermesz, Edit; Westphal, Heiner; Rubenstein, John L R

2014-01-01

The progenitor zones of the embryonic mouse ventral telencephalon give rise to GABAergic and cholinergic neurons. We have shown previously that two LIM-homeodomain (LIM-HD) transcription factors, Lhx6 and Lhx8, that are downstream of Nkx2.1, are critical for the development of telencephalic GABAergic and cholinergic neurons. Here we investigate the role of Ldb1, a nuclear protein that binds directly to all LIM-HD factors, in the development of these ventral telencephalon derived neurons. We show that Ldb1 is expressed in the Nkx2.1 cell lineage during embryonic development and in mature neurons. Conditional deletion of Ldb1 causes defects in the expression of a series of genes in the ventral telencephalon and severe impairment in the tangential migration of cortical interneurons from the ventral telencephalon. Similar to the phenotypes observed in Lhx6 or Lhx8 mutant mice, the Ldb1 conditional mutants show a reduction in the number of both GABAergic and cholinergic neurons in the telencephalon. Furthermore, our analysis reveals defects in the development of the parvalbumin-positive neurons in the globus pallidus and striatum of the Ldb1 mutants. These results provide evidence that Ldb1 plays an essential role as a transcription co-regulator of Lhx6 and Lhx8 in the control of mammalian telencephalon development. © 2013 Published by Elsevier Inc.

Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon

PubMed Central

Zhao, Yangu; Flandin, Pierre; Vogt, Daniel; Blood, Alexander; Hermesz, Edit; Westphal, Heiner; Rubenstein, John

2013-01-01

The progenitor zones of the embryonic mouse ventral telencephalon give rise to GABAergic and cholinergic neurons. We have shown previously that two LIM-homeodomain (LIM-HD) transcription factors, Lhx6 and Lhx8, that are downstream of Nkx2.1, are critical for the development of telencephalic GABAergic and cholinergic neurons. Here we investigate the role of Ldb1, a nuclear protein that binds directly to all LIM-HD factors, in the development of these ventral telencephalon derived neurons. We show that Ldb1 is expressed in the Nkx2.1 cell lineage during embryonic development and in mature neurons. Conditional deletion of Ldb1 causes defects in the expression of a series of genes in the ventral telencephalon and severe impairment in the tangential migration of cortical interneurons from the ventral telencephalon. Similar to the phenotypes observed in Lhx6 or Lhx8 mutant mice, the Ldb1 conditional mutants show a reduction in the number of both GABAergic and cholinergic neurons in the telencephalon. Furthermore, our analysis reveals defects in the development of the parvalbumin-positive neurons in the globus pallidus and striatum of the Ldb1 mutants. These results provide evidence that Ldb1 plays an essential role as a transcription co-regulator of Lhx6 and Lhx8 in the control of mammalian telencephalon development. PMID:24157949

Psychological Characteristics of Adolescent Steroid Users.

ERIC Educational Resources Information Center

Burnett, Kent F.; Kleiman, Mark E.

1994-01-01

Used Millon Adolescent Personality Inventory and Profile of Mood States to assess psychological characteristics in 72 adolescent males: 24 adolescent athletes who reported steroid use, 24 athletes with no steroid use, and 24 nonathletes. Although some personality variables differentiated between athletes and nonathletes, no personality variables…

Metabolite profiling of sex developmental steroid conjugates reveals an association between decreased levels of steroid sulfates and adiposity in obese girls.

PubMed

Lee, Su Hyeon; Kim, Shin Hye; Lee, Won-Yong; Chung, Bong Chul; Park, Mi Jung; Choi, Man Ho

2016-09-01

Free and conjugated steroids coexist in a dynamic equilibrium due to complex biosynthetic and metabolic processes. This may have clinical significance related to various physiological conditions, including sex development involving the reproductive system. Therefore, we performed quantitative profiling of 16 serum steroids conjugated with glucuronic and sulfuric acids using liquid chromatography-mass spectrometry (LC-MS). All steroid conjugates were purified by solid-phase extraction and then separated through a 3-μm particle size C18 column (150mm×2.1mm) at a flow rate of 0.3 mL/min in the negative ionization mode. The LC-MS-based analysis was found to be linear (r(2)>0.99), and all steroid conjugates had a limit-of-quantification (LOQ) of 10ng/mL, except for cholesterol sulfate and 17β-estradiol-3,17-disulfate (20ng/mL). The extraction recoveries of all steroid conjugates ranged from 97.9% to 110.7%, while the overall precision (% CV) and accuracy (% bias) ranged from 4.8% to 10.9% and from 94.4% to 112.9% at four different concentrations, respectively. Profiling of steroid conjugates corrected by adiposity revealed decreased levels of steroid sulfates (P<0.01) in overweight and obese girls compared to normal girls. The suggested technique can be used for evaluating metabolic changes in steroid conjugates and for understanding the pathophysiology and relative contributions of adiposity in childhood obesity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Physiological concentrations of anabolic steroids in human hair.

PubMed

Shen, Min; Xiang, Ping; Shen, Baohua; Bu, Jun; Wang, Mengye

2009-01-30

Doping with endogenous anabolic steroids is one of the most serious issues in sports today. The measurement of anabolic steroid levels in human hair is necessary in order to distinguish between pharmaceutical steroids and natural steroids. This is the first investigation into the physiological concentrations of anabolic steroids in human hair in Chinese subjects. A gas chromatography-tandem mass spectrometry (GC/MS/MS) method was developed for the simultaneous identification and quantitation of five endogenous anabolic steroids (testosterone, epitestosterone, androsterone, etiocholanolone and dehydroepiandrosterone) in hair. After basic hydrolysis, hair samples were extracted with diethyl ether, derivatized and then detected using GC/MS/MS in the multiple-reaction monitoring mode (MRM). The one precursor/two product ion transitions for each anabolic steroid were monitored. The limits of detection for the five endogenous anabolic steroids were in the 0.1-0.2 pg/mg range. All analytes showed good linearity and the extraction recoveries were 74.6-104.5%. Within-day and between-day precisions were less than 20%. This method was applied to the analysis of testosterone, epitestosterone, androsterone, etiocholanolone, and dehydroepiandrosterone in human hair. Full-length hair samples were taken at the skin surface from the vertex of 39 males, 30 females and 11 children from China. None of the subjects were professional athletes. Testosterone and dehydroepiandrosterone were detected in all the hair segments. The physiological concentrations of testosterone were in the range 0.8-24.2 pg/mg, 0.1-16.8 pg/mg and 0.2-11.5 pg/mg in males, females and children, respectively, however, the mean values of dehydroepiandrosterone were much higher than the concentrations of testosterone. These data are suitable reference values and are the basis for the interpretation of results from investigations into the abuse of endogenous anabolic steroids.

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

Glutamate spillover modulates GABAergic synaptic transmission in the rat midbrain periaqueductal grey via metabotropic glutamate receptors and endocannabinoid signaling.

PubMed

Drew, Geoffrey M; Mitchell, Vanessa A; Vaughan, Christopher W

2008-01-23

Glutamate spillover regulates GABAergic synaptic transmission at several CNS synapses via presynaptic ionotropic and metabotropic glutamate receptors (mGluRs). We have previously demonstrated that activation of group I-III mGluRs inhibits GABAergic transmission in the midbrain periaqueductal gray (PAG), a region involved in organizing behavioral responses to threat, stress, and pain. Here, we examined the role of glutamate spillover in the modulation of GABAergic transmission in the PAG. Using whole-cell recordings from rat PAG slices, we found that evoked IPSCs were reduced by the nonspecific glutamate transport blockers DL-threo-beta-benzyloxyaspartic acid (TBOA) and L-trans-pyrrolidine-2,4-dicarboxylic acid, but not by the glial GLT1-specific blocker dihydrokainate. In contrast, TBOA had no effect on evoked IPSCs when glutamate uptake into the postsynaptic neuron was selectively impaired. TBOA increased the paired-pulse ratio of evoked IPSCs and reduced the rate but not the amplitude of spontaneous miniature IPSCs. The effect of TBOA on evoked IPSCs was abolished by the broad-spectrum mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (100 microM), reduced by the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and mimicked by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the effects of both TBOA and DHPG were reduced by the cannabinoid CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251). Finally, although MPEP and AM251 had no effect on single evoked IPSCs, they increased evoked IPSCs during repetitive stimulation. These results indicate that neuronal glutamate transporters limit mGluR5 activation and endocannabinoid signaling, but may be overwhelmed during conditions of elevated glutamate release. Thus, neuronal glutamate transporters play a key role in regulating endocannabinoid

Steroids and Other Ergogenic Aids: A Resource Guide.

ERIC Educational Resources Information Center

Virginia State Dept. of Education, Richmond.

Steroids have become one of society's "short cuts" to athletic prowess and success. This guide includes information and teaching materials for educators and others who work with youth on how to teach that steroids are drugs, that drugs can harm and kill, and that a "no-use" policy applies to steroids as well as to alcohol and…

Quest for steroidomimetics: Amino acids derived steroidal and nonsteroidal architectures.

PubMed

Shagufta; Ahmad, Irshad; Panda, Gautam

2017-06-16

The chiral pool amino acids have been utilized for the construction of steroidal and non-steroidal architectures in the quest for steroidomimetics. Chirality derived from amino acid-based architectures provides new and easy to incorporate chiral chemical space, which is otherwise very difficult to introduce and comprised of several synthetic steps for asymmetric steroids. The different and exciting ligand-receptor interactions may arise from the use of each amino acid enantiomer that was introduced into the chiral steroidal backbone. The A and D rings of steroidal architectures can be mimicked by the phenyl group of the amino acid tyrosine. The Mitsunobu reaction, nucleophilic substitution and elimination, etc. were utilized for constructing diverse tri- and tetracyclic steroidal skeletons as well as benzofused seco-steroids from amino acids. These benzofused, amino acid-derived steroidal and nonsteroidal molecules had promising biological activity in hormonal related disorders. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.

PubMed

Warejko, Jillian K; Tan, Weizhen; Daga, Ankana; Schapiro, David; Lawson, Jennifer A; Shril, Shirlee; Lovric, Svjetlana; Ashraf, Shazia; Rao, Jia; Hermle, Tobias; Jobst-Schwan, Tilman; Widmeier, Eugen; Majmundar, Amar J; Schneider, Ronen; Gee, Heon Yung; Schmidt, J Magdalena; Vivante, Asaf; van der Ven, Amelie T; Ityel, Hadas; Chen, Jing; Sadowski, Carolin E; Kohl, Stefan; Pabst, Werner L; Nakayama, Makiko; Somers, Michael J G; Rodig, Nancy M; Daouk, Ghaleb; Baum, Michelle; Stein, Deborah R; Ferguson, Michael A; Traum, Avram Z; Soliman, Neveen A; Kari, Jameela A; El Desoky, Sherif; Fathy, Hanan; Zenker, Martin; Bakkaloglu, Sevcan A; Müller, Dominik; Noyan, Aytul; Ozaltin, Fatih; Cadnapaphornchai, Melissa A; Hashmi, Seema; Hopcian, Jeffrey; Kopp, Jeffrey B; Benador, Nadine; Bockenhauer, Detlef; Bogdanovic, Radovan; Stajić, Nataša; Chernin, Gil; Ettenger, Robert; Fehrenbach, Henry; Kemper, Markus; Munarriz, Reyner Loza; Podracka, Ludmila; Büscher, Rainer; Serdaroglu, Erkin; Tasic, Velibor; Mane, Shrikant; Lifton, Richard P; Braun, Daniela A; Hildebrandt, Friedhelm

2018-01-06

Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1 , PLCE1 , NPHS2 , and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences

Delineation of Steroid-Degrading Microorganisms through Comparative Genomic Analysis

PubMed Central

Bergstrand, Lee H.; Cardenas, Erick; Holert, Johannes; Van Hamme, Jonathan D.

2016-01-01

ABSTRACT Steroids are ubiquitous in natural environments and are a significant growth substrate for microorganisms. Microbial steroid metabolism is also important for some pathogens and for biotechnical applications. This study delineated the distribution of aerobic steroid catabolism pathways among over 8,000 microorganisms whose genomes are available in the NCBI RefSeq database. Combined analysis of bacterial, archaeal, and fungal genomes with both hidden Markov models and reciprocal BLAST identified 265 putative steroid degraders within only Actinobacteria and Proteobacteria, which mainly originated from soil, eukaryotic host, and aquatic environments. These bacteria include members of 17 genera not previously known to contain steroid degraders. A pathway for cholesterol degradation was conserved in many actinobacterial genera, particularly in members of the Corynebacterineae, and a pathway for cholate degradation was conserved in members of the genus Rhodococcus. A pathway for testosterone and, sometimes, cholate degradation had a patchy distribution among Proteobacteria. The steroid degradation genes tended to occur within large gene clusters. Growth experiments confirmed bioinformatic predictions of steroid metabolism capacity in nine bacterial strains. The results indicate there was a single ancestral 9,10-seco-steroid degradation pathway. Gene duplication, likely in a progenitor of Rhodococcus, later gave rise to a cholate degradation pathway. Proteobacteria and additional Actinobacteria subsequently obtained a cholate degradation pathway via horizontal gene transfer, in some cases facilitated by plasmids. Catabolism of steroids appears to be an important component of the ecological niches of broad groups of Actinobacteria and individual species of Proteobacteria. PMID:26956583

CONTAMINANT INTERACTIONS WITH STEROID RECEPTORS: EVIDENCE FOR RECEPTOR BINDING.

EPA Science Inventory

Steroid receptors are important determinants of endocrine disrupter consequences. As the most frequently proposed mechanism of endocrine-disrupting contaminant (EDC) action, steroid receptors are not only targets of natural steroids but are also commonly sites of nonsteroidal com...

Steroids in teleost fishes: A functional point of view.

PubMed

Tokarz, Janina; Möller, Gabriele; Hrabě de Angelis, Martin; Adamski, Jerzy

2015-11-01

Steroid hormones are involved in the regulation of a variety of processes like embryonic development, sex differentiation, metabolism, immune responses, circadian rhythms, stress response, and reproduction in vertebrates. Teleost fishes and humans show a remarkable conservation in many developmental and physiological aspects, including the endocrine system in general and the steroid hormone related processes in particular. This review provides an overview of the current knowledge about steroid hormone biosynthesis and the steroid hormone receptors in teleost fishes and compares the findings to the human system. The impact of the duplicated genome in teleost fishes on steroid hormone biosynthesis and perception is addressed. Additionally, important processes in fish physiology regulated by steroid hormones, which are most dissimilar to humans, are described. We also give a short overview on the influence of anthropogenic endocrine disrupting compounds on steroid hormone signaling and the resulting adverse physiological effects for teleost fishes. By this approach, we show that the steroidogenesis, hormone receptors, and function of the steroid hormones are reasonably well understood when summarizing the available data of all teleost species analyzed to date. However, on the level of a single species or a certain fish-specific aspect of physiology, further research is needed. Copyright © 2015 Elsevier Inc. All rights reserved.

Steroid-Responsive Recurrent Encephalopathy Associated with Subacute Thyroiditis

PubMed Central

Chung, Yun Jae; Ahn, Jihyun; Ha, Sam-Yeol; Youn, Young Chul

2008-01-01

Background Steroid-responsive encephalopathy associated with subacute thyroiditis has, to our knowledge, not been reported previously. Case Report A 49-year-old woman was found collapsed and brought to our institution with decreased mentality, dysarthria, and gait disturbance. Brain magnetic resonance imaging and angiography were normal but blood tests revealed thyroid-autoantibody-negative thyrotoxicosis. Results of a 99mtechnetium-pertechnetate scan were compatible with the thyrotoxic phase of subacute thyroiditis. 14-3-3 proteins were detected in cerebrospinal fluid. Her mental status began to improve from the day following steroid administration. Recurrent encephalopathy was found 2 months after the initial admission, which was also effectively treated with steroid. Conclusions We speculate that steroid-responsive recurrent encephalopathy associated with subacute thyroiditis is a subtype of Hashimoto's encephalopathy, and consider that steroid treatment should not be delayed in suspected patients. PMID:19513293

The effect of propofol postconditioning on the expression of K(+)-Cl(-)-co-transporter 2 in GABAergic inhibitory interneurons of acute ischemia/reperfusion injury rats.

PubMed

Wang, Hongbai; Liu, Shuying; Wang, Haiyun; Wang, Guolin; Zhu, Ai

2015-02-09

It has been shown in our previous study that propofol postconditioning enhanced the activity of phosphatidylinositol-3-kinase (PI3K) and prevented the internalization of GluR2 subunit of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, thus provided neuroprotection in cerebral ischemia/reperfusion (I/R) injury. Regarding inhibitory system in CNS, K(+)-Cl(-)-co-transporter 2 (KCC2), a Cl(-) extruder, plays a critical role in gamma-aminobutyric acid (GABA) inhibitory effect in mature central neurons. However, the effect of propofol postconditioning on the expression of KCC2 in GABAergic interneurons is unclear. Therefore, in this article we describe the role of KCC2 in GABAergic interneurons in the ipsilateral hippocampal CA1 region of adult rats and the effects of propofol postconditioning on this region. Herein we demonstrate that propofol postconditioning (20mg/kg/h, 2h) improved rats' neurobehavioral abilities, increased the number of survival neurons, and up-regulated neuronal KCC2 expression in glutamic acid decarboxylase 67 (GAD67) expressing GABAergic interneurons in hippocampal CA1 region at 24h after I/R. In contrast, when rats were injected with the KCC2 antagonist, [(dihydroindenyl)oxy] alkanoic acid (DIOA), the neuroprotective effects induced by propofol postconditioning were reversed. Our study indicated that propofol postconditioning increased the expression of KCC2 in inhibitory GABAergic interneurons, thus providing acute neuroprotection to rats who had undergone cerebral I/R injury. Copyright © 2014 Elsevier B.V. All rights reserved.

Kv2.2: a novel molecular target to study the role of basal forebrain GABAergic neurons in the sleep-wake cycle.

PubMed

Hermanstyne, Tracey O; Subedi, Kalpana; Le, Wei Wei; Hoffman, Gloria E; Meredith, Andrea L; Mong, Jessica A; Misonou, Hiroaki

2013-12-01

The basal forebrain (BF) has been implicated as an important brain region that regulates the sleep-wake cycle of animals. Gamma-aminobutyric acidergic (GABAergic) neurons are the most predominant neuronal population within this region. However, due to the lack of specific molecular tools, the roles of the BF GABAergic neurons have not been fully elucidated. Previously, we have found high expression levels of the Kv2.2 voltage-gated potassium channel on approximately 60% of GABAergic neurons in the magnocellular preoptic area and horizontal limb of the diagonal band of Broca of the BF and therefore proposed it as a potential molecular target to study this neuronal population. In this study, we sought to determine the functional roles of the Kv2.2-expressing neurons in the regulation of the sleep-wake cycle. Sleep analysis between two genotypes and within each genotype before and after sleep deprivation. Animal sleep research laboratory. Adult mice. Wild-type and Kv2.2 knockout mice with C57/BL6 background. EEG/EMG recordings from the basal state and after sleep-deprivation which was induced by mild agitation for 6 h. Immunostaining of a marker of neuronal activity indicates that these Kv2.2-expressing neurons appear to be preferentially active during the wake state. Therefore, we tested whether Kv2.2-expressing neurons in the BF are involved in arousal using Kv2.2-deficient mice. BF GABAergic neurons exhibited augmented expression of c-Fos. These knockout mice exhibited longer consolidated wake bouts than wild-type littermates, and that phenotype was further exacerbated by sleep deprivation. Moreover, in-depth analyses of their cortical electroencephalogram revealed a significant decrease in the delta-frequency activity during the nonrapid eye movement sleep state. These results revealed the significance of Kv2.2-expressing neurons in the regulation of the sleep-wake cycle.

Prolonged withdrawal from cocaine self-administration affects prefrontal cortex- and basolateral amygdala-nucleus accumbens core circuits but not accumbens GABAergic local interneurons.

PubMed

Purgianto, Anthony; Weinfeld, Michael E; Wolf, Marina E

2017-11-01

Withdrawal from extended-access cocaine self-administration leads to progressive intensification ('incubation') of cocaine craving. After prolonged withdrawal (1-2 months), when craving is high, expression of incubation depends on strengthening of excitatory inputs to medium spiny neurons (MSN) of the nucleus accumbens (NAc). These excitatory inputs interact with the intra-NAc GABAergic 'microcircuit', composed of MSN axon collaterals and GABAergic interneurons. Here, we investigated whether the increased glutamatergic neurotransmission observed after prolonged withdrawal is accompanied by altered GABAergic neurotransmission, focusing on NAc core. Rats self-administered cocaine or saline (6 hours/day) and then underwent >40 days of withdrawal. First, we investigated parvalbumin positive (PV+) interneurons, GABAergic fast-spiking interneurons that regulate MSN activity. Immunohistochemical studies revealed no significant change in PV signal intensity or the number of PV+ cells in cocaine rats versus saline controls. We then screened PV and other interneuron markers using immunoblotting. We detected no changes in levels of PV, calretinin, calbindin or neuronal nitric oxide synthase. Because expression of these markers is activity dependent, our results suggest no marked changes in interneuron activity. Finally, we utilized local field potential recording, which can detect GABA-mediated alterations at the circuit level, to investigate potential changes in two circuits implicated in cocaine craving: prelimbic prefrontal cortex to NAc core and basolateral amygdala to NAc core. We detected differential adaptations in these circuits, some of which may involve GABA. Overall, our results suggest that alterations in GABA transmission may accompany incubation of cocaine craving, but they are circuit specific and less pronounced than alterations in glutamate transmission. © 2016 Society for the Study of Addiction.

The interaction of central nitrergic and GABAergic systems on food intake in neonatal layer-type chicks.

PubMed

Mokhtarpouriani, Kasra; Zendehdel, Morteza; Jonaidi, Hossein; Babapour, Vahab; Shayan, Parviz

2016-05-01

Most physiological behaviors such as food intake are controlled by the hypothalamus and its nuclei. It has been demonstrated that injection of the paraventricular nucleus of the hypothalamus with nitric oxide (NO) donors elicited changes in the concentration of some amino acids, including GABA. Also, central nitrergic and GABAergic systems are known to provide inputs to the paraventricular nucleus and are involved in food intake control. Therefore, the present study examines the probable interaction of central nitrergic and GABAergic systems on food intake in neonatal layer-type chicks. The results of this study showed that intracerebroventricular (ICV) injection of L-arginine (400 and 800 nmol), as a NO donor, significantly decreased food intake (P < 0.001), but ICV injection of Nω-Nitro-L-arginine methyl ester (L-NAME) (200 and 400 nmol), a NO synthesis inhibitor, increased food intake (P < 0.001). In addition, the orexigenic effect of gaboxadol (0.2 µg), a GABAA agonist, was significantly attenuated in ICV co-injection of L-arginine (200 nmol) and gaboxadol (0.2 µg) (P < 0.001), but it was significantly amplified in ICV co-injection of L-NAME (100 nmol) and gaboxadol (0.2 µg) (P < 0.001). On the other hand, the orexigenic effect of baclofen (0.2 µg), a GABAB agonist, did not change in ICV co-injection of L-arginine (200 nmol) or L-NAME (100 nmol) with baclofen (0.2 µg) (P > 0.05). Also, the hypophagic effect of L-arginine (800 nmol) was significantly amplified in ICV co-injection of picrotoxin (0.5 µg), a GABAA antagonist, or CGP54626 (21 ng), a GABAB antagonist, with L-arginine (800 nmol) (P < 0.001). These results probably suggest an interaction of central nitrergic and GABAergic systems on food intake in neonatal layer-type chicks and GABAA receptors play a major role in this interaction.

Hypothalamic Non-AgRP, Non-POMC GABAergic Neurons Are Required for Postweaning Feeding and NPY Hyperphagia

PubMed Central

Kim, Eun Ran; Wu, Zhaofei; Sun, Hao; Xu, Yuanzhong; Mangieri, Leandra R.; Xu, Yong

2015-01-01

The hypothalamus is critical for feeding and body weight regulation. Prevailing studies focus on hypothalamic neurons that are defined by selectively expressing transcription factors or neuropeptides including those expressing proopiomelanocortin (POMC) and agouti-related peptides (AgRP). The Cre expression driven by the pancreas-duodenum homeobox 1 promoter is abundant in several hypothalamic nuclei but not in AgRP or POMC neurons. Using this line, we generated mice with disruption of GABA release from a major subset of non-POMC, non-AgRP GABAergic neurons in the hypothalamus. These mice exhibited a reduction in postweaning feeding and growth, and disrupted hyperphagic responses to NPY. Disruption of GABA release severely diminished GABAergic input to the paraventricular hypothalamic nucleus (PVH). Furthermore, disruption of GABA-A receptor function in the PVH also reduced postweaning feeding and blunted NPY-induced hyperphagia. Given the limited knowledge on postweaning feeding, our results are significant in identifying GABA release from a major subset of less appreciated hypothalamic neurons as a key mediator for postweaning feeding and NPY hyperphagia, and the PVH as one major downstream site that contributes significantly to the GABA action. SIGNIFICANCE STATEMENT Prevalent studies on feeding in the hypothalamus focus on well characterized, selective groups neurons [e.g., proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons], and as a result, the role of the majority of other hypothalamic neurons is largely neglected. Here, we demonstrated an important role for GABAergic projections from non-POMC non-AgRP neurons to the paraventricular hypothalamic nucleus in promoting postweaning (mainly nocturnal) feeding and mediating NPY-induced hyperphagia. Thus, these results signify an importance to study those yet to be defined hypothalamic neurons in the regulation of energy balance and reveal a neural basis for postweaning (nocturnal) feeding and NPY

Hypothalamic Non-AgRP, Non-POMC GABAergic Neurons Are Required for Postweaning Feeding and NPY Hyperphagia.

PubMed

Kim, Eun Ran; Wu, Zhaofei; Sun, Hao; Xu, Yuanzhong; Mangieri, Leandra R; Xu, Yong; Tong, Qingchun

2015-07-22

The hypothalamus is critical for feeding and body weight regulation. Prevailing studies focus on hypothalamic neurons that are defined by selectively expressing transcription factors or neuropeptides including those expressing proopiomelanocortin (POMC) and agouti-related peptides (AgRP). The Cre expression driven by the pancreas-duodenum homeobox 1 promoter is abundant in several hypothalamic nuclei but not in AgRP or POMC neurons. Using this line, we generated mice with disruption of GABA release from a major subset of non-POMC, non-AgRP GABAergic neurons in the hypothalamus. These mice exhibited a reduction in postweaning feeding and growth, and disrupted hyperphagic responses to NPY. Disruption of GABA release severely diminished GABAergic input to the paraventricular hypothalamic nucleus (PVH). Furthermore, disruption of GABA-A receptor function in the PVH also reduced postweaning feeding and blunted NPY-induced hyperphagia. Given the limited knowledge on postweaning feeding, our results are significant in identifying GABA release from a major subset of less appreciated hypothalamic neurons as a key mediator for postweaning feeding and NPY hyperphagia, and the PVH as one major downstream site that contributes significantly to the GABA action. Significance statement: Prevalent studies on feeding in the hypothalamus focus on well characterized, selective groups neurons [e.g., proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons], and as a result, the role of the majority of other hypothalamic neurons is largely neglected. Here, we demonstrated an important role for GABAergic projections from non-POMC non-AgRP neurons to the paraventricular hypothalamic nucleus in promoting postweaning (mainly nocturnal) feeding and mediating NPY-induced hyperphagia. Thus, these results signify an importance to study those yet to be defined hypothalamic neurons in the regulation of energy balance and reveal a neural basis for postweaning (nocturnal) feeding and

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

PubMed

Abekawa, Tomohiro; Ito, Koki; Nakagawa, Shin; Koyama, Tsukasa

2007-06-01

Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: relationships to resting-state functional connectivity

PubMed Central

Moeller, Scott J.; London, Edythe D.; Northoff, Georg

2015-01-01

Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications. PMID:26657968

An efficient route for annulation of pyrimidines to steroids and non-steroids via a base catalyzed one-pot three component reaction.

PubMed

Saikia, Pallabi; Gogoi, Shyamalee; Gogoi, Sanjib; Boruah, Romesh C

2014-10-01

A facile strategy for the synthesis of steroidal A- and D-ring fused pyrimidines has been accomplished in high yields via a one-pot reaction of steroidal ketones, aromatic aldehydes and amidine derivatives in presence of potassium tert-butoxide in refluxing ethanol. The generality of the reaction was also extended to non-steroidal ketones. Copyright © 2014 Elsevier Inc. All rights reserved.

Steroids: To Test or to Educate?

ERIC Educational Resources Information Center

LaFee, Scott

2006-01-01

In February 2005, The Dallas Morning News published a multipart series on steroid use among high school students in Texas. The paper's four-month investigation was wide-ranging, but shined a particular spotlight upon alleged abuses in the 13,700-student Grapevine-Colleyville Independent School District, north of Dallas. Use of steroids and other…

Use of postoperative steroids to reduce pain and inflammation.

PubMed

Fleischli, J W; Adams, W R

1999-01-01

Postoperative injection of a steroid is used by many podiatric surgeons to reduce pain and inflammation after foot surgery. The authors present a review of the literature on postoperative steroid use from many medical specialties as well as a review of wound and bone healing. The literature indicates that using a steroid is a safe and effective means to reduce postoperative pain and edema. Studies have shown steroids to delay healing, inhibit collagen synthesis, and increase the risk of postoperative infection. No author reported a delay in wound or bone healing or increased infection rate in patients in which a steroid was used. Although there is literature to support this practice, many questions remain and further investigation is needed.

Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons.

PubMed

Sullivan, Chelsea S; Gotthard, Ingo; Wyatt, Elliott V; Bongu, Srihita; Mohan, Vishwa; Weinberg, Richard J; Maness, Patricia F

2018-04-18

Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.

Do mollusks use vertebrate sex steroids as reproductive hormones? Part I: Critical appraisal of the evidence for the presence, biosynthesis and uptake of steroids.

PubMed

Scott, Alexander P

2012-11-01

The consensus view is that vertebrate-type steroids are present in mollusks and perform hormonal roles which are similar to those that they play in vertebrates. Although vertebrate steroids can be measured in molluscan tissues, a key question is 'Are they formed endogenously or they are picked up from their environment?'. The present review concludes that there is no convincing evidence for biosynthesis of vertebrate steroids by mollusks. Furthermore, the 'mollusk' genome does not contain the genes for key enzymes that are necessary to transform cholesterol in progressive steps into vertebrate-type steroids; nor does the mollusk genome contain genes for functioning classical nuclear steroid receptors. On the other hand, there is very strong evidence that mollusks are able to absorb vertebrate steroids from the environment; and are able to store some of them (by conjugating them to fatty acids) for weeks to months. It is notable that the three steroids that have been proposed as functional hormones in mollusks (i.e. progesterone, testosterone and 17β-estradiol) are the same as those of humans. Since humans (and indeed all vertebrates) continuously excrete steroids not just via urine and feces, but via their body surface (and, in fish, via the gills), it is impossible to rule out contamination as the sole reason for the presence of vertebrate steroids in mollusks (even in animals kept under supposedly 'clean laboratory conditions'). Essentially, the presence of vertebrate steroids in mollusks cannot be taken as reliable evidence of either endogenous biosynthesis or of an endocrine role. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Sensitivity of thalamic GABAergic currents to clonazepam does not differ between control and genetic absence epilepsy rats.

PubMed

Badiu, Carmen-Ionela

2004-11-12

Mutations in GABA-A receptor subunits have been reported in a number of idiopathic generalized epilepsies including childhood absence epilepsy. One of these mutations is located within a high-affinity benzodiazepine-binding domain, and clonazepam is clinically used as an anti-absence drug. The intrathalamic loop consisting of the GABAergic neurons of the nucleus reticularis thalami (NRT) and the thalamocortical (TC) neurons of sensory thalamic nuclei plays an essential role in spike and wave discharges. In a well-established genetic model of absence epilepsy (Genetic Absence Epilepsy rat from Strasbourg, GAERS), systemic injections of benzodiazepines have been shown to suppress spike-and-waves discharges. The aim of this study, therefore, was to determine whether the sensitivity of GABAergic synaptic currents to clonazepam in NRT and TC neurons was different in GAERS and non-epileptic control (NEC) rats. In both pre-seizure GAERS and NEC clonazepam (100 nM) had no effect on the mIPSCs recorded from TC neurons while it increased the decay time constant of the mIPSCs recorded in NRT neurons by a similar amount in GAERS (54.5+/-5%) and NEC (50.7+/-5%). Similar results have been obtained in the presence of 100 microM Cd2+, showing that the effect of clonazepam did not occur via modulation of voltage-activated Ca2+ currents. These results are relevant to understand that in GAERS, the clonazepam anti-absence actions cannot be fully explained by the enhancement of the intra-NRT inhibition and the modulation of the GABAergic synaptic currents in other brain areas, in particular the cortex, must be taken into consideration.

Enhancement of extinction memory consolidation: the role of the noradrenergic and GABAergic systems within the basolateral amygdala.

PubMed

Berlau, Daniel J; McGaugh, James L

2006-09-01

Evidence from previous studies indicates that the noradrenergic and GABAergic influences within the basolateral amygdala (BLA) modulate the consolidation of memory for fear conditioning. The present experiments investigated whether the same modulatory influences are involved in regulating the extinction of fear-based learning. To investigate this issue, male Sprague Dawley rats implanted with unilateral or bilateral cannula aimed at the BLA were trained on a contextual fear conditioning (CFC) task and 24 and 48 h later were given extinction training. Immediately following each extinction session they received intra-BLA infusions of the GABAergic antagonist bicuculline (50 ng), the beta-adrenocepter antagonist propranolol (500 ng), bicuculline with propranolol, norepinephrine (NE) (0.3, 1.0, and 3.0 microg), the GABAergic agonist muscimol (125 ng), NE with muscimol or a control solution. To investigate the involvement of the dorsal hippocampus (DH) as a possible target of BLA activation during extinction, other animals were given infusions of muscimol (500 ng) via an ipsilateral cannula implanted in the DH. Bilateral BLA infusions of bicuculline significantly enhanced extinction, as did infusions into the right, but not left BLA. Propranolol infused into the right BLA together with bicuculline blocked the bicuculline-induced memory enhancement. Norepinephrine infused into the right BLA also enhanced extinction, and this effect was not blocked by co-infusions of muscimol. Additionally, muscimol infused into the DH did not attenuate the memory enhancing effects of norepinephrine infused into the BLA. These findings provide evidence that, as with original CFC learning, noradrenergic activation within the BLA modulates the consolidation of CFC extinction. The findings also suggest that the BLA influence on extinction is not mediated by an interaction with the dorsal hippocampus.

Steroid and sterol 7-hydroxylation: ancient pathways.

PubMed

Lathe, Richard

2002-11-01

B-ring hydroxylation is a major metabolic pathway for cholesterols and some steroids. In liver, 7 alpha-hydroxylation of cholesterols, mediated by CYP7A and CYP39A1, is the rate-limiting step of bile acid synthesis and metabolic elimination. In brain and other tissues, both sterols and some steroids including dehydroepiandrosterone (DHEA) are prominently 7 alpha-hydroxylated by CYP7B. The function of extra-hepatic steroid and sterol 7-hydroxylation is unknown. Nevertheless, 7-oxygenated cholesterols are potent regulators of cell proliferation and apoptosis; 7-oxygenated derivatives of DHEA, pregnenolone, and androstenediol can have major effects in the brain and in the immune system. The receptor targets involved remain obscure. It is argued that B-ring modification predated steroid evolution: non-enzymatic oxidation of membrane sterols primarily results in 7-oxygenation. Such molecules may have provided early growth and stress signals; a relic may be found in hydroxylation at the symmetrical 11-position of glucocorticoids. Early receptor targets probably included intracellular sterol sites, some modern steroids may continue to act at these targets. 7-Hydroxylation of DHEA may reflect conservation of an early signaling pathway.

Anemarrhena asphodeloides Non-Steroidal Saponin Components Alter the Pharmacokinetic Profile of Its Steroidal Saponins in Rat.

PubMed

Tang, Zhishu; Li, Guolong; Yang, Jie; Duan, Jinao; Qian, Dawei; Guo, Jianming; Zhu, Zhenhua; Song, Zhongxing

2015-06-26

A rapid, selective and sensitive UPLC-MS/MS assay was established to determine the plasma concentrations of four steroidal saponins. Sprague-Dawley rats were allocated to four groups which were orally administered Anemarrhena asphodeloides extracts (ASE), ASE combined with macromolecular fraction (ASE-MF), ASE combined with small molecule fraction (ASE-SF) and ASE combined with small molecule and macromolecular fraction (ASE-SF-MF) containing approximately the same dose of ASE. At different time points, the concentration of timosaponin BII, anemarsaponin BIII, timosaponin AIII and timosaponin E1 in rat plasma were determined and main pharmacokinetic parameters including Cmax, Tmax, T1/2, AUC were calculated using the DAS 3.2 software package. The statistical analysis was performed using the Student's t-test with p < 0.05 as the level of significance. MF had no effect on the pharmacokinetic behaviors and parameters of four steroidal saponins. It was found that Cmax and AUC of four steroidal saponins in group ASE-SF and ASE-SF-MF, were significantly increased compared with those in group ASE. These results indicate that SF in A. asphodeloides extracts could increase the absorption and improve the bioavailability of the steroidal saponins.

Gym and tonic: a profile of 100 male steroid users.

PubMed Central

Evans, N A

1997-01-01

OBJECTIVE: To identify unsupervised anabolic steroid regimens used by athletes. METHODS: 100 athletes attending four gymnasia were surveyed using an anonymous self administered questionnaire. RESULTS: Anabolic steroid doses ranged from 250 to 3200 mg per week and users combined different drugs to achieve these doses. Injectable and oral preparations were used in cycles lasting four to 12 weeks. Eighty six per cent of users admitted to the regular use of drugs other than steroids for various reasons, including additional anabolic effects, the minimisation of steroid related side effects, and withdrawal symptoms. Acne, striae, and gynaecomastia were the most commonly reported subjective side effects. CONCLUSIONS: Multiple steroids are combined in megadoses and self administered in a cyclical fashion. Polypharmacy is practised by over 80% of steroid users. Skeletal muscle hypertrophy along with acne, striae, and gynaecomastia are frequent physical signs associated with steroid use. Images Figure 2 PMID:9132214

A very large number of GABAergic neurons are activated in the tuberal hypothalamus during paradoxical (REM) sleep hypersomnia.

PubMed

Sapin, Emilie; Bérod, Anne; Léger, Lucienne; Herman, Paul A; Luppi, Pierre-Hervé; Peyron, Christelle

2010-07-26

We recently discovered, using Fos immunostaining, that the tuberal and mammillary hypothalamus contain a massive population of neurons specifically activated during paradoxical sleep (PS) hypersomnia. We further showed that some of the activated neurons of the tuberal hypothalamus express the melanin concentrating hormone (MCH) neuropeptide and that icv injection of MCH induces a strong increase in PS quantity. However, the chemical nature of the majority of the neurons activated during PS had not been characterized. To determine whether these neurons are GABAergic, we combined in situ hybridization of GAD(67) mRNA with immunohistochemical detection of Fos in control, PS deprived and PS hypersomniac rats. We found that 74% of the very large population of Fos-labeled neurons located in the tuberal hypothalamus after PS hypersomnia were GAD-positive. We further demonstrated combining MCH immunohistochemistry and GAD(67)in situ hybridization that 85% of the MCH neurons were also GAD-positive. Finally, based on the number of Fos-ir/GAD(+), Fos-ir/MCH(+), and GAD(+)/MCH(+) double-labeled neurons counted from three sets of double-staining, we uncovered that around 80% of the large number of the Fos-ir/GAD(+) neurons located in the tuberal hypothalamus after PS hypersomnia do not contain MCH. Based on these and previous results, we propose that the non-MCH Fos/GABAergic neuronal population could be involved in PS induction and maintenance while the Fos/MCH/GABAergic neurons could be involved in the homeostatic regulation of PS. Further investigations will be needed to corroborate this original hypothesis.

Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization.

PubMed

Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

2014-08-01

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

Glutamic Acid Decarboxylase 65: A Link Between GABAergic Synaptic Plasticity in the Lateral Amygdala and Conditioned Fear Generalization

PubMed Central

Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

2014-01-01

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders. PMID:24663011

Steroid plant hormones: effects outside plant kingdom.

PubMed

Zhabinskii, Vladimir N; Khripach, Natalia B; Khripach, Vladimir A

2015-05-01

Brassinosteroids (BS) are the first group of steroid-hormonal compounds isolated from and acting in plants. Among numerous physiological effects of BS growth stimulation and adaptogenic activities are especially remarkable. In this review, we provide evidence that BS possess similar types of activity also beyond plant kingdom at concentrations comparable with those for plants. This finding allows looking at steroids from a new point of view: how common are the mechanisms of steroid bioregulation in different types of organisms from protozoa to higher animals. Copyright © 2014 Elsevier Inc. All rights reserved.

Hypercholesterolemia in Male Power Lifters Using Anabolic-Androgenic Steroids.

ERIC Educational Resources Information Center

Cohen, Jonathan C.; And Others

1988-01-01

Measurement of serum cholesterol concentrations in male power lifters who used anabolic-androgenic steroids for eight weeks, three years, or eight years indicated that mean serum cholesterol levels increased with drug use, but decreased promptly to near pre-steroid levels after steroid use ended. (Author/CB)

Anabolic steroid abuse causing recurrent hepatic adenomas and hemorrhage.

PubMed

Martin, Nicole M; Abu Dayyeh, Barham K; Chung, Raymond T

2008-07-28

Anabolic steroid abuse is common among athletes and is associated with a number of medical complications. We describe a case of a 27-year-old male bodybuilder with multiple hepatic adenomas induced by anabolic steroids. He initially presented with tumor hemorrhage and was treated with left lateral hepatic segmentectomy. Regression of the remaining tumors was observed with cessation of steroid use. However, 3 years and a half after his initial hepatic segmentectomy, he presented with recurrent tumor enlargement and intraperitoneal hemorrhage in the setting of steroid abuse relapse. Given his limited hepatic reserve, he was conservatively managed with embolization of the right accessory hepatic artery. This is the first reported case of hepatic adenoma re-growth with recidivistic steroid abuse, complicated by life-threatening hemorrhage. While athletes and bodybuilders are often aware of the legal and social ramifications of steroid abuse, they should continue to be counseled about its serious medical risks.

[Body cult and use of anabolic steroids by bodybuilders].

PubMed

Iriart, Jorge Alberto Bernstein; Chaves, José Carlos; Orleans, Roberto Ghignone de

2009-04-01

This study focused on the reasons for practicing bodybuilding and the use of anabolic steroids, as well as the social representations and uses of the body among bodybuilding steroid users. This ethnographic study involved participant observation in middle and lower-class bodybuilding gyms in Salvador, Bahia State, Brazil, and 43 in-depth interviews with steroid users. Aesthetic reasons are the main motivation for bodybuilding and steroid use in both middle and lower-class users. Dissatisfaction with one's real body as compared to the ideal standard flaunted by the mass media, fear of being devalued or shunned by one's peer groups, the symbolic capital associated with a 'pumped-up' body, and the sense of immediacy in obtaining results all contributed to steroid use. Preventive campaigns are needed, targeting young people and combining a critical view and deconstruction of the values assigned to the body by consumer society, counteracted by high-quality information on the health risks associated with anabolic steroid use.

Effective prescribing in steroid allergy: controversies and cross-reactions.

PubMed

Browne, Fiona; Wilkinson, S Mark

2011-01-01

Contact allergy to topical corticosteroids should be considered in all patients who do not respond to, or are made worse by, the use of topical steroids. The incidence of steroid allergy in such patients is reported as 9% to 22% in adult patients and in 25% of children. It can often go undiagnosed for a long time in patients with a long history of dermatologic conditions and steroid use. Although rare, both immediate and delayed-type hypersensitivity reactions have been reported to systemic corticosteroids with an incidence of 0.3%. Reported reactions range from localized eczematous eruptions to systemic reactions, anaphylaxis, and even death. Delayed type reactions to systemically administered steroids may present as a generalized dermatitis, an exanthematous eruption, or occasionally, with blistering or purpura. In this contribution, we clarify the issues surrounding the pathogenesis of steroid allergy, cover the importance of cross-reactions, and describe strategies for the investigation and management for patients with suspected steroid allergy. Copyright © 2011 Elsevier Inc. All rights reserved.

Review of Androgenic Anabolic Steroid Use

DOE Office of Scientific and Technical Information (OSTI.GOV)

T. Borges; G. Eisele; C. Byrd

An area that has been overlooked within personnel security evaluations is employee use of androgenic-anabolic steroids (AAS). Current drug testing within the federal government does not include testing for anabolic steroids, and the difficulties to implement such testing protocols-not to mention the cost involved-make AAS testing highly improbable. The basis of this report is to bring to the forefront the damage that anabolic steroids can cause from both a physical and a psychological standpoint. Most individuals who use AASs do so to increase their muscle mass because they wish to gain some type of competitive edge during athletic competition ormore » they wish to enhance their physical features for self-satisfaction and self-esteem (i.e., body building). Security officers are one group of men who often take high doses of anabolic steroids, according to the Second Report of the Senate Standing Committee (1990). The negative psychological characteristics for AAS use is extensive and includes prominent hostility, aggressiveness, irritability, euphoria, grandiose beliefs, hyperactivity, reckless behavior, increased sexual appetite, unpredictability, poor impulse control, mood fluctuations, and insomnia. The drug may invoke a sense of power and invincibility (Leckman and Scahill, 1990). Depressive symptoms, such as anhedonia, fatigue, impaired concentration, decreased libido, and even suicidality (Pope and Katz, 1992) have been noted with steroid withdrawal. It appears that long-term users of AAS experience similar characteristics as other substance abusers (i.e., craving, dependence, and withdrawal symptoms).« less

Thawing frozen shoulder by steroid injection.

PubMed

Pushpasekaran, Narendran; Kumar, Narender; Chopra, R K; Borah, Diganta; Arora, Sumit

2017-01-01

Frozen shoulder is not an uncommon disorder, and steroid injection into the glenohumeral (GH) joint is one of the most well-known approaches for the frozen shoulder. However, their results have been varied with beneficial effects or no additional advantage. With the understanding about the pathological changes taking place in frozen shoulder and the biomechanics involved, we wanted to evaluate the short- and long-term efficacy of steroid injection by a novel three-site (NTS) injection technique and compare it with the single-site injection (SSI). This was a prospective study with 85 patients including all stages and randomized into two groups. SSI group received steroid injection through posterior approach. NTS group received the same dose of steroid in diluted doses at three sites (posterior capsule, subacromial and subcoracoid). Second sitting was repeated after 3 weeks. Both groups had received the same physiotherapy. The patients were evaluated by CONSTANT score at initial, 3 week, 6 week and 6 month. NTS group patients had significant pain relief and early improvement in activities of daily living ( p < 0.005). Both groups had improvement in shoulder movements but with NTS group, early near-normal scores were attained and sustained after 6 months. About 43% in SSI group could not attain near-normal levels and had relapses. The three-site approach to steroid instillation in frozen shoulder is a safe method and provides early recovery and better improvement in shoulder function with less relapses.

The cholinergic agonist carbachol increases the frequency of spontaneous GABAergic synaptic currents in dorsal raphe serotonergic neurons in the mouse.

PubMed

Yang, C; Brown, R E

2014-01-31

Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons play an important role in feeding, mood control and stress responses. One important feature of their activity across the sleep-wake cycle is their reduced firing during rapid-eye-movement (REM) sleep which stands in stark contrast to the wake/REM-on discharge pattern of brainstem cholinergic neurons. A prominent model of REM sleep control posits a reciprocal interaction between these cell groups. 5-HT inhibits cholinergic neurons, and activation of nicotinic receptors can excite DRN 5-HT neurons but the cholinergic effect on inhibitory inputs is incompletely understood. Here, in vitro, in DRN brain slices prepared from GAD67-GFP knock-in mice, a brief (3 min) bath application of carbachol (50 μM) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in GFP-negative, putative 5-HT neurons but did not affect miniature (tetrodotoxin-insensitive) IPSCs. Carbachol had no direct postsynaptic effect. Thus, carbachol likely increases the activity of local GABAergic neurons which synapse on 5-HT neurons. Removal of dorsal regions of the slice including the ventrolateral periaqueductal gray (vlPAG) region where GABAergic neurons projecting to the DRN have been identified, abolished the effect of carbachol on sIPSCs whereas the removal of ventral regions containing the oral region of the pontine reticular nucleus (PnO) did not. In addition, carbachol directly excited GFP-positive, GABAergic vlPAG neurons. Antagonism of both muscarinic and nicotinic receptors completely abolished the effects of carbachol. We suggest cholinergic neurons inhibit DRN 5-HT neurons when acetylcholine levels are lower i.e. during quiet wakefulness and the beginning of REM sleep periods, in part via excitation of muscarinic and nicotinic receptors located on local vlPAG and DRN GABAergic neurons. Higher firing rates or burst firing of cholinergic neurons associated with attentive wakefulness or phasic REM sleep periods

The Cholinergic Agonist Carbachol Increases the Frequency of Spontaneous GABAergic Synaptic Currents in Dorsal Raphe Serotonergic Neurons in the Mouse

PubMed Central

Yang, Chun; Brown, Ritchie E.

2013-01-01

Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons play an important role in feeding, mood control and stress responses. One important feature of their activity across the sleep-wake cycle is their reduced firing during rapid-eye-movement (REM) sleep which stands in stark contrast to the wake/REM-on discharge pattern of brainstem cholinergic neurons. A prominent model of REM sleep control posits a reciprocal interaction between these cell groups. 5-HT inhibits cholinergic neurons, and activation of nicotinic receptors can excite DRN 5-HT neurons but the cholinergic effect on inhibitory inputs is incompletely understood. Here, in vitro, in DRN brain slices prepared from GAD67-GFP knock-in mice, a brief (3 min) bath application of carbachol (50 μM) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in GFP-negative, putative serotonin neurons but did not affect miniature (tetrodotoxin-insensitive) IPSCs. Carbachol had no direct postsynaptic effect. Thus, carbachol likely increases the activity of local GABAergic neurons which synapse on 5-HT neurons. Removal of dorsal regions of the slice including the ventrolateral periaqueductal gray (vlPAG) region where GABAergic neurons projecting to the DRN have been identified, abolished the effect of carbachol on sIPSCs whereas removal of ventral regions containing the oral region of the pontine reticular nucleus (PnO) did not. In addition, carbachol directly excited GFP-positive, GABAergic vlPAG neurons. Antagonism of both muscarinic and nicotinic receptors completely abolished the effects of carbachol. We suggest cholinergic neurons inhibit DRN 5-HT neurons when acetylcholine levels are lower i.e. during quiet wakefulness and the beginning of REM sleep periods, in part via excitation of muscarinic and nicotinic receptors located on local vlPAG and DRN GABAergic neurons. Higher firing rates or burst firing of cholinergic neurons associated with attentive wakefulness or phasic REM sleep periods

The current state of knowledge on the neuroactive compounds that affect the development, mating and reproduction of spiders (Araneae) compared to insects.

PubMed

Sawadro, Marta; Bednarek, Agata; Babczyńska, Agnieszka

2017-06-01

The neuroendocrine system of insects, including the presence of the main neuroactive compounds, and their role in ontogenesis are probably best understood of all the arthropods. Development, metamorphosis, the maturation of the gonads, vitellogenesis and egg production are regulated by hormones (juvenile hormones, ecdysteroids) and neuropeptides. However, knowledge about their presence and functions in spiders is fragmentary. In this paper, we present a summary of the current data about the juvenile hormones, ecdysteroids and neuropeptides in selected groups of arthropods, with particular emphasis on spiders. This is the first article that takes into account the occurrence, action and role of hormones and neuropeptides in spiders. In addition, the suggestions for possible ways to study these compounds in Araneomorphae spiders are unique and cannot be found in the arachnological literature.

Ptosis induced by topical steroid eye drops: Two cases reports.

PubMed

Zhu, Yanan; Sun, Chaohui; Zhang, Xin; Shentu, Xingchao

2017-12-01

Ptosis is a rare complication of periocular steroid use. Studies report that local injections of steroids produce ptosis. We describe the first 2 cases of ptosis because of long-term treatment with topical steroid eye drops. Two cases admitted to our hospital because of ptosis of their right eye after long-term treatment with topical steroid eye drops. Both of them had uncontrolled Posner-Schlossman syndrome. Two cases were diagnosed as steroid-related ptosis. Regulatory anti-inflammation therapy was prescribed for case 1, and after inflammation control, phacoemulsification was done for her. Six months after steroid withdrawal, the levator resection of the right eye was performed. Case 2 refused our advice of steroid reduction and ptosis surgery. After surgery, case 1 retained a symmetrical appearance during a 1-year follow-up. In the surgery, we found thin levator muscles and slack levator palpebrae superioris aponeurosis (LPSA) in the affected eye. Postoperative transmission electron microscopy revealed typical signs of apoptosis in levator muscle cells. We suggest topical application of steroids induces levator muscle apoptosis and LPSA weakness, and results in ptosis. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Epidural Steroid Injections

MedlinePlus

... slipped vertebrae’, also known as spondylolisthesis). The epidural space is a fat filled ‘sleeve’ that surrounds the ... spinal cord. Steroids (‘cortisone’) placed into the epidural space have a very potent anti-inflammatory action that ...

Do mollusks use vertebrate sex steroids as reproductive hormones? II. Critical review of the evidence that steroids have biological effects.

PubMed

Scott, Alexander P

2013-02-01

In assessing the evidence as to whether vertebrate sex steroids (e.g. testosterone, estradiol, progesterone) have hormonal actions in mollusks, ca. 85% of research papers report at least one biological effect; and 18 out of 21 review papers (published between 1970 and 2012) express a positive view. However, just under half of the research studies can be rejected on the grounds that they did not actually test steroids, but compounds or mixtures that were only presumed to behave as steroids (or modulators of steroids) on the basis of their effects in vertebrates (e.g. Bisphenol-A, nonylphenol and sewage treatment effluents). Of the remaining 55 papers, some can be criticized for having no statistical analysis; some for using only a single dose of steroid; others for having irregular dose-response curves; 40 out of the 55 for not replicating the treatments; and 50 out of 55 for having no within-study repetition. Furthermore, most studies had very low effect sizes in comparison to fish-based bioassays for steroids (i.e. they had a very weak 'signal-to-noise' ratio). When these facts are combined with the fact that none of the studies were conducted with rigorous randomization or 'blinding' procedures (implying the possibility of 'operator bias') one must conclude that there is no indisputable bioassay evidence that vertebrate sex steroids have endocrinological or reproductive roles in mollusks. The only observation that has been independently validated is the ability of estradiol to trigger rapid (1-5 min) lysosomal membrane breakdown in hemocytes of Mytilus spp. This is a typical 'inflammatory' response, however, and is not proof that estradiol is a hormone - especially when taken in conjunction with the evidence (discussed in a previous review) that mollusks have neither the enzymes necessary to synthesize vertebrate steroids nor nuclear receptors with which to respond to them. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Anabolic-Androgenic Steroid Use Among 1,010 College Men.

ERIC Educational Resources Information Center

Pope, Harrison G., Jr.; And Others

1988-01-01

Two percent of 1,010 male college students responding to a questionnaire about anabolic-androgenic steroid use reported using steroids; most of the users were competitive athletes, although some used steroids to improve their physical appearance. Users were not distinguished from non-users in terms of academic achievement or use of other illicit…

Would Controlled Substance Status Affect Steroid Trafficking?

PubMed

Cowart, V S

1987-05-01

Loss of control over anabolic steroids has prompted the federal government to take steps to stem the black market manufacture and distribution of these drugs. But-at least for now-these steps are likely to stop short of bestowing controlled substance status on steroids.

GABAergic inhibition shapes frequency tuning and modifies response properties in the superior olivary nucleus of the leopard frog.

PubMed

Zheng, W; Hall, J C

2000-01-01

The role of gamma-aminobutyric acid (GABA)ergic inhibition in shaping the excitatory frequency tuning of 74 neurons in the superior olivary nucleus of the leopard frog, Rana pipiens, was studied using iontophoretic application of the GABA(A) receptor antagonist, bicuculline methiodide. For 37 neurons, bicuculline application broadened and/or changed the configuration of the excitatory frequency-tuning curve. Results indicate that GABA-mediated inhibition not only sharpens the tuning curves of neurons but also plays a critical role in creating new frequency tuning properties in the superior olivary nucleus. Bicuculline application affected other neuronal response properties as well. Spontaneous firing rate increased 11-338% for 18 of 59 neurons. For 32 of 58 neurons there was an increase in stimulus-evoked discharge rate and a change in rate-level function. There was no qualitative effect on the discharge pattern of 60 neurons, though 2 tonically responding neurons did show an increase (> 30%) in response duration. Additional roles for GABAergic inhibition in monaural signal analysis are discussed.

Endometrium and steroids, a pathologic overview.

PubMed

Plaza-Parrochia, Francisca; Romero, Carmen; Valladares, Luis; Vega, Margarita

2017-10-01

Normal endometrial function requires of cell proliferation and differentiation; therefore, disturbances in these processes could lead to pathological entities such as hyperplasia and endometrial adenocarcinoma, where cell proliferation is increased. The development of these pathologies is highly related to alterations in the levels and/or action of sexual steroids. In the present review, it has been analyzed how steroids, particularly estrogens, androgens and progestagens are involved in the etiopathogenesis of hyperplasia and endometrial endometrioid adenocarcinoma. The emphasis is given on pathological and pharmacological conditions that are presented as risk factors for endometrial pathologies, such as obesity, polycystic ovarian syndrome and hormone replacement postmenopausal women therapy, among others. Steroids alterations may promote changes at molecular level that enhance the development of hyperplasia and endometrioid cancer. In fact, there are solid data that indicate that estrogens stimulate cell-proliferation in this tissue; meanwhile, progestagens are able to stop cell proliferation and to increase differentiation. Nevertheless, the role of androgens is less clear, since there is contradictory information. It is most likely that the major contribution of steroids to the development of cell proliferation pathologies in endometria would be in early stages, where there is a high sensitivity to these molecules. This phenomenon is present even in stages previous to the occurrence of hyperplasia, like in the condition of polycystic ovarian syndrome, where the endometria have a greater sensitivity to steroids and high expression of cell cycle molecules. These abnormalities would contribute to the pathogenesis of hyperplasia and then in the progression to endometrioid adenocarcinoma. Copyright © 2017. Published by Elsevier Inc.

The Incidence of Anabolic Steroid Use among Competitive Bodybuilders.

ERIC Educational Resources Information Center

Tricker, Ray; And Others

1989-01-01

Investigated incidence of anabolic steroid use among 380 competitive male and female bodybuilders in Kansas and Missouri. Results indicated more than half (54 percent) of the male bodybuilders were using steroids on a regular basis compared to 10 percent of the female competitors. Found main reason for use of steroids was desire to win. (Author/TE)

Sex-Steroid Hormone Manipulation Reduces Brain Response to Reward.

PubMed

Macoveanu, Julian; Henningsson, Susanne; Pinborg, Anja; Jensen, Peter; Knudsen, Gitte M; Frokjaer, Vibe G; Siebner, Hartwig R

2016-03-01

Mood disorders are twice as frequent in women than in men. Risk mechanisms for major depression include adverse responses to acute changes in sex-steroid hormone levels, eg, postpartum in women. Such adverse responses may involve an altered processing of rewards. Here, we examine how women's vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo or the gonadotropin-releasing hormone agonist (GnRHa) goserelin, which causes a net decrease in sex-steroid levels. Fifty-eight women performed a gambling task while undergoing functional MRI at baseline, during the mid-follicular phase, and again following the intervention. The gambling task enabled us to map regional brain activity related to the magnitude of risk during choice and to monetary reward. The GnRHa intervention caused a net reduction in ovarian sex steroids (estradiol and testosterone) and increased depression symptoms. Compared with placebo, GnRHa reduced amygdala's reactivity to high monetary rewards. There was a positive association between the individual changes in testosterone and changes in bilateral insula response to monetary rewards. Our data provide evidence for the involvement of sex-steroid hormones in reward processing. A blunted amygdala response to rewarding stimuli following a rapid decline in sex-steroid hormones may reflect a reduced engagement in positive experiences. Abnormal reward processing may constitute a neurobiological mechanism by which sex-steroid fluctuations provoke mood disorders in susceptible women.

Occurrence and fate of hormone steroids in the environment.

PubMed

Yin, Guang-Guo; Kookana, Rai S; Ru, Ying-Jun

2002-12-01

Hormone steroids are a group of endocrine disruptors, which are excreted by humans and animals. In this paper, we briefly review the current knowledge on the fate of these steroids in the environment. Natural estrogenic steroids estrone (E1), 17beta-estradiol (E2) and estriol (E3) all have a solubility of approximately 13 mg/l, whereas synthetic steroids 17alpha-ethynylestradiol (EE2) and mestranol (MeEE2) have a solubility of 4.8 and 0.3 mg/l, respectively. These steroids have a moderate binding on sediments and are reported to degrade rapidly in soil and water. Estrogenic steroids have been detected in effluents of sewage treatment plants (STPs) in different countries at concentrations ranging up to 70 ng/l for E1, 64 ng/l for E2, 18 ng/l for E3 and 42 ng/l for EE2. E2 concentrations in river waters from Japan, Germany, Italy and the Netherlands ranged up to 27 ng/l. In addition, E2 concentrations ranging from 6 to 66 ng/l have also been measured in mantled karst aquifers in northwest Arkansas. This contamination of ground water has been associated with poultry litter and cattle manure waste applied on the land. Although hormone steroids have been detected at a number of sources worldwide, currently, there is limited data on the environmental behaviour and fate of these hormone steroids in different environmental media. Consequently, the exposure and risk associated with these chemicals are not adequately understood.

Synthesis and Cytotoxic Evaluation of Steroidal Copper (Cu (II)) Complexes

PubMed Central

Huang, Yanmin; Kong, Erbin; Zhan, Junyan; Chen, Shuang; Gan, Chunfang; Liu, Zhiping; Pang, Liping

2017-01-01

Using estrone and pregnenolone as starting materials, some steroidal copper complexes were synthesized by the condensation of steroidal ketones with thiosemicarbazide or diazanyl pyridine and then complexation of steroidal thiosemicarbazones or steroidal diazanyl pyridines with Cu (II). The complexes were characterized by IR, NMR, and HRMS. The synthesized compounds were screened for their cytotoxicity against HeLa, Bel-7404, and 293T cell lines in vitro. The results show that all steroidal copper (II) complexes display obvious antiproliferative activity against the tested cancer cells. The IC50 values of complexes 5 and 12 against Bel-7404 (human liver carcinoma) are 5.0 and 7.0 μM. PMID:29180937

Electrical and chemical transmission between striatal GABAergic output neurones in rat brain slices

PubMed Central

Venance, Laurent; Glowinski, Jacques; Giaume, Christian

2004-01-01

Basal ganglia are interconnected subcortical nuclei, connected to the thalamus and all cortical areas involved in sensory motor control, limbic functions and cognition. The striatal output neurones (SONs), the major striatal population, are believed to act as detectors and integrators of distributed patterns of cerebral cortex inputs. Despite the key role of SONs in cortico-striatal information processing, little is known about their local interactions. Here, we report the existence and characterization of electrical and GABAergic transmission between SONs in rat brain slices. Tracer coupling (biocytin) incidence was high during the first two postnatal weeks and then decreased (postnatal days (P) 5–25, 60%; P25–30, 29%; n = 61). Electrical coupling was observed between 27% of SON pairs (coupling coefficient: 3.1 ± 0.3%, n = 89 at P15) and as shown by single-cell RT-PCR, several connexin (Cx) mRNAs were found to be expressed (Cx31.1, Cx32, Cx36 and Cx47). GABAergic synaptic transmission (abolished by bicuculline, a GABAA receptor antagonist) observed in 19% of SON pairs (n = 62) was reliable (mean failure rate of 6 ± 3%), precise (variation coefficient of latency, 0.06), strong (IPSC amplitudes of 38 ± 12 pA) and unidirectional. Interestingly, electrical and chemical transmission were mutually exclusive. These results suggest that preferential networks of electrically and chemically connected SONs, might be involved in the channelling of cortico-basal ganglia information processing. PMID:15235091

Actions of Steroids: New Neurotransmitters

PubMed Central

Cornil, Charlotte A.; Mittelman-Smith, Melinda A.; Rainville, Jennifer R.; Remage-Healey, Luke; Sinchak, Kevin; Micevych, Paul E.

2016-01-01

Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane progesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain. PMID:27911748

Sex steroids: beyond conventional dimorphism.

PubMed

Lavranos, Giagkos; Angelopoulou, Roxani; Manolakou, Panagiota; Katsiki, Evangelia

2013-09-01

Sexual dimorphism is a characteristic of a large number of species, ranging from lower invertebrates to mammals and, last but not least, humans. Recognition of the various factors regulating sexual dimorphism initial establishment (i.e. sex determination and differentiation) and subsequent life-long adaptation to distinct functional and behavioural patterns has remained a hot topic for several decades. As our understanding of the various molecular pathways involved in this process increases, the significant role of sex steroids becomes more evident. At the same time, the recognition of new sites of steroid production (e.g. parts of the brain) and aromatization, as well as new target cells (owing to the proposed presence of additional receptors to those classically considered as primary steroid receptors) has lead to the need to revisit their spectrum of actions within a novel, multifactorial context. Thus, anthropology and medicine are presented with the challenge to unravel a major mystery, i.e. that of sexual orientation and differentiation and its potential contribution in human evolution and civilization development, taking advantage of the high-tech research tools provided by modern biotechnology. This short review summarizes the basic principles of sex determination and sex steroid function as they have been classically described in the literature and then proceeds to present examples of how modern research methods have started to offer a new insight on the more subtle details of this process, stressing that it is extending to virtually every single part and system of the body.

Does Steroid Abuse Cause--Or Excuse--Violence?

ERIC Educational Resources Information Center

Lubell, Adele

1989-01-01

Use of anabolic steroids is believed to increase the odds of violent antisocial behavior, thus posing risks to consumers and the general public. Some research shows the danger of steroids in inducing severe adverse psychiatric effects. Certain lawyers use this abuse to plead insanity for their clients. (SM)

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

PubMed Central

Buckmaster, Paul S.; Abrams, Emily; Wen, Xiling

2018-01-01

Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31–61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24–36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy. PMID:28425097

A Reorganized GABAergic Circuit in a Model of Epilepsy: Evidence from Optogenetic Labeling and Stimulation of Somatostatin Interneurons

PubMed Central

Peng, Zechun; Zhang, Nianhui; Wei, Weizheng; Huang, Christine S.; Cetina, Yliana; Otis, Thomas S.

2013-01-01

Axonal sprouting of excitatory neurons is frequently observed in temporal lobe epilepsy, but the extent to which inhibitory interneurons undergo similar axonal reorganization remains unclear. The goal of this study was to determine whether somatostatin (SOM)-expressing neurons in stratum (s.) oriens of the hippocampus exhibit axonal sprouting beyond their normal territory and innervate granule cells of the dentate gyrus in a pilocarpine model of epilepsy. To obtain selective labeling of SOM-expressing neurons in s. oriens, a Cre recombinase-dependent construct for channelrhodopsin2 fused to enhanced yellow fluorescent protein (ChR2-eYFP) was virally delivered to this region in SOM-Cre mice. In control mice, labeled axons were restricted primarily to s. lacunosum-moleculare. However, in pilocarpine-treated animals, a rich plexus of ChR2-eYFP-labeled fibers and boutons extended into the dentate molecular layer. Electron microscopy with immunogold labeling demonstrated labeled axon terminals that formed symmetric synapses on dendritic profiles in this region, consistent with innervation of granule cells. Patterned illumination of ChR2-labeled fibers in s. lacunosum-moleculare of CA1 and the dentate molecular layer elicited GABAergic inhibitory responses in dentate granule cells in pilocarpine-treated mice but not in controls. Similar optical stimulation in the dentate hilus evoked no significant responses in granule cells of either group of mice. These findings indicate that under pathological conditions, SOM/GABAergic neurons can undergo substantial axonal reorganization beyond their normal territory and establish aberrant synaptic connections. Such reorganized circuitry could contribute to functional deficits in inhibition in epilepsy, despite the presence of numerous GABAergic terminals in the region. PMID:24005292

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy.

PubMed

Buckmaster, Paul S; Abrams, Emily; Wen, Xiling

2017-08-01

Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31-61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24-36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy. © 2017 Wiley Periodicals, Inc.

Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice.

PubMed

Aligny, C; Roux, C; Dourmap, N; Ramdani, Y; Do-Rego, J-C; Jégou, S; Leroux, P; Leroux-Nicollet, I; Marret, S; Gonzalez, B J

2014-07-03

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, widely used as an anesthetic in neonatal pediatrics, is also an illicit drug named Super K or KitKat consumed by teens and young adults. In the immature brain, despite several studies indicating that NMDA antagonists are neuroprotective against excitotoxic injuries, there is more and more evidence indicating that these molecules exert a deleterious effect by suppressing a trophic function of glutamate. In the present study, we show using Gad67-GFP mice that prenatal exposure to ketamine during a time-window in which GABAergic precursors are migrating results in (i) strong apoptotic death in the ganglionic eminences and along the migratory routes of GABAergic interneurons; (ii) long-term deficits in interneuron density, dendrite numbers and spine morphology; (iii) a sex-dependent deregulation of γ-aminobutyric acid (GABA) levels and GABA transporter expression; (iv) sex-dependent changes in the response to glutamate-induced calcium mobilization; and (v) the long-term sex-dependent behavioral impairment of locomotor activity. In conclusion, using a preclinical approach, the present study shows that ketamine exposure during cortical maturation durably affects the integration of GABAergic interneurons by reducing their survival and differentiation. The resulting molecular, morphological and functional modifications are associated with sex-specific behavioral deficits in adults. In light of the present data, it appears that in humans, ketamine could be deleterious for the development of the brain of preterm neonates and fetuses of addicted pregnant women.

Learning-Dependent Plasticity of the Barrel Cortex Is Impaired by Restricting GABA-Ergic Transmission.

PubMed

Posluszny, Anna; Liguz-Lecznar, Monika; Turzynska, Danuta; Zakrzewska, Renata; Bielecki, Maksymilian; Kossut, Malgorzata

2015-01-01

Experience-induced plastic changes in the cerebral cortex are accompanied by alterations in excitatory and inhibitory transmission. Increased excitatory drive, necessary for plasticity, precedes the occurrence of plastic change, while decreased inhibitory signaling often facilitates plasticity. However, an increase of inhibitory interactions was noted in some instances of experience-dependent changes. We previously reported an increase in the number of inhibitory markers in the barrel cortex of mice after fear conditioning engaging vibrissae, observed concurrently with enlargement of the cortical representational area of the row of vibrissae receiving conditioned stimulus (CS). We also observed that an increase of GABA level accompanied the conditioning. Here, to find whether unaltered GABAergic signaling is necessary for learning-dependent rewiring in the murine barrel cortex, we locally decreased GABA production in the barrel cortex or reduced transmission through GABAA receptors (GABAARs) at the time of the conditioning. Injections of 3-mercaptopropionic acid (3-MPA), an inhibitor of glutamic acid decarboxylase (GAD), into the barrel cortex prevented learning-induced enlargement of the conditioned vibrissae representation. A similar effect was observed after injection of gabazine, an antagonist of GABAARs. At the behavioral level, consistent conditioned response (cessation of head movements in response to CS) was impaired. These results show that appropriate functioning of the GABAergic system is required for both manifestation of functional cortical representation plasticity and for the development of a conditioned response.

[Effects of neuroactive substances on intracellular free Ca2+ concentration in isolated outer hair cells of the guinea pig cochlea].

PubMed

Yang, J; Wang, J; Wei, S

1998-10-01

To measure the effects of neuro-active substances on intracellular free Ca2+ concentration ([Ca2+]i) in isolated outer hair cells(OHCs) of the guinea pig cochlea. The fura-2 microfluorimetry was used to measure changes of [Ca2+]i in OHCs of the guinea pig cochlea after application of acetylcholine, ATP and carbacholine. Acetylcholine, ATP and carbacholine increased [Ca2+]i (acetylcholine: 0.74 +/- 0.12 mumol/L, ATP: 0.65 +/- 0.11 mumol/L, carbacholine: 1.16 +/- 0.27 mumol/L) in OHCs in the presence of extracellular Ca2+. In the absence of extracellular Ca2+, however, only ATP induced a gradual and small [Ca2+]i elevation, whereas other substances did not. Acetylcholine and carbacholine, the cholinergic mascarinic agonists, increased [Ca2+]i in OHCs by acting at receptor-induced ion channel resulting in Ca2+ efflux. ATP-induced elevation of [Ca2+]i without Ca2+ in extracellular medium is due to a release of Ca2+ from an intracellular reservoir.

Enhancement of GABAergic transmission by zolpidem, an imidazopyridine with preferential affinity for type I benzodiazepine receptors.

PubMed

Biggio, G; Concas, A; Corda, M G; Serra, M

1989-02-28

The effect of zolpidem, an imidazopyridine derivative with high affinity at the type I benzodiazepine recognition site, on the function of the GABAA/ionophore receptor complex was studied in vitro. Zolpidem, mimicking the action of diazepam, increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced [35S]TBPS binding in rat cortical membrane preparations. Zolpidem was less effective than diazepam on the above parameters. Zolpidem induced a lower increase of [3H]GABA binding (23 vs. 35%) and muscimol-stimulated 36Cl- uptake (22 vs. 40%) and a smaller decrease of [35S]TBPS binding (47 vs. 77%) than diazepam. The finding that zolpidem enhanced the function of GABAergic synapses with an efficacy qualitatively and quantitatively different from that of diazepam suggests that this compound is a partial agonist at the benzodiazepine recognition site. Thus, our results are consistent with the view that the biochemical and pharmacological profile of a benzodiazepine recognition site ligand reflects its efficacy to enhance GABAergic transmission. Whether the preferential affinity of zolpidem at the type I site is involved in its atypical biochemical and pharmacological profile remains to be clarified.

Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity.

PubMed

Moeller, Scott J; London, Edythe D; Northoff, Georg

2016-02-01

Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinical value of transforaminal epidural steroid injection in lumbar radiculopathy.

PubMed

Leung, S M; Chau, W W; Law, S W; Fung, K Y

2015-10-01

To identify the diagnostic, therapeutic, and prognostic values of transforaminal epidural steroid injection as interventional rehabilitation for lumbar radiculopathy. Regional hospital, Hong Kong. A total of 232 Chinese patients with lumbar radiculopathy attributed to disc herniation or spinal stenosis received transforaminal epidural steroid injection between 1 January 2007 and 31 December 2011. Transforaminal epidural steroid injection. Patients' immediate response, response duration, proportion of patients requiring surgery, and risk factors affecting the responses to transforaminal epidural steroid injection for lumbar radiculopathy. Of the 232 patients, 218 (94.0%) had a single level of radiculopathy and 14 (6.0%) had multiple levels. L5 was the most commonly affected level. The immediate response rate to transforaminal epidural steroid injection was 80.2% in 186 patients with clinically diagnosed lumbar radiculopathy and magnetic resonance imaging of the lumbar spine suggesting nerve root compression. Of patients with single-level radiculopathy and multiple-level radiculopathy, 175 (80.3%) and 11 (78.6%) expressed an immediate response to transforaminal epidural steroid injection, respectively. The analgesic effect lasted for 1 to <3 weeks in 35 (15.1%) patients, for 3 to 12 weeks in 37 (15.9%) patients, and for more than 12 weeks in 92 (39.7%) patients. Of the 232 patients, 106 (45.7%) were offered surgery, with 65 (61.3%) undergoing operation, and with 42 (64.6%) requiring spinal fusion in addition to decompression surgery. Symptom chronicity was associated with poor immediate response to transforaminal epidural steroid injection, but not with duration of pain reduction. Poor response to transforaminal epidural steroid injection was not associated with a preceding industrial injury. The immediate response to transforaminal epidural steroid injection was approximately 80%. Transforaminal epidural steroid injection is a useful diagnostic, prognostic, and

Anabolic steroid use among students at a British college of technology.

PubMed Central

Williamson, D J

1993-01-01

To determine the rate of current or previous use of anabolic steroids by students at a UK college of technology, a questionnaire survey of 687 day students was conducted. The questionnaire began with a general section for all of the students, which ended with the question 'Have you ever used anabolic steroids?'. A further section specifically for anabolic steroid users examined patterns of use, and how certain circumstances might affect the individual's decision to use anabolic steroids. The response rate to the questionnaire was 92%. The overall rate of current or previous use of anabolic steroids was 2.8% (4.4% in males, 1.0% in females). Of these, 56% had first used anabolic steroids at age 15 or less. Anabolic steroid users were more likely to be male, under 17 years of age, and participating in bodybuilding, weight-lifting or rugby. The results of this survey, if confirmed in other groups of young people, would suggest that use of anabolic steroids may be widespread in the UK. PMID:8242280

Anabolic steroid use among students at a British college of technology.

PubMed

Williamson, D J

1993-09-01

To determine the rate of current or previous use of anabolic steroids by students at a UK college of technology, a questionnaire survey of 687 day students was conducted. The questionnaire began with a general section for all of the students, which ended with the question 'Have you ever used anabolic steroids?'. A further section specifically for anabolic steroid users examined patterns of use, and how certain circumstances might affect the individual's decision to use anabolic steroids. The response rate to the questionnaire was 92%. The overall rate of current or previous use of anabolic steroids was 2.8% (4.4% in males, 1.0% in females). Of these, 56% had first used anabolic steroids at age 15 or less. Anabolic steroid users were more likely to be male, under 17 years of age, and participating in bodybuilding, weight-lifting or rugby. The results of this survey, if confirmed in other groups of young people, would suggest that use of anabolic steroids may be widespread in the UK.

Endocrinology of sex steroid hormones and cell dynamics in the periodontium.

PubMed

Mariotti, Angelo; Mawhinney, Michael

2013-02-01

Numerous scientific studies assert the existence of hormone-sensitive periodontal tissues. Tissue specificity of hormone localization, identification of hormone receptors and the metabolism of hormones are evidence that periodontal tissues are targets for sex steroid hormones. Although the etiologies of periodontal endocrinopathies are diverse, periodontal pathologies are primarily the consequence of the actions and interactions of sex steroid hormones on specific cells found in the periodontium. This review provides a broad overview of steroid hormone physiology, evidence for the periodontium being a target tissue for sex steroid hormones and theories regarding the roles of sex steroid hormones in periodontal pathogenesis. Using this information, a teleological argument for the actions of steroid hormones in the periodontium is assessed.

Nuclear receptor coactivators: regulators of steroid action in brain and behaviour.

PubMed

Tetel, M J; Acharya, K D

2013-11-01

Steroid hormones act in specific regions of the brain to alter behaviour and physiology. Although it has been well established that the bioavailability of the steroid and the expression of its receptor is critical for understanding steroid action in the brain, the importance of nuclear receptor coactivators in the brain is becoming more apparent. The present review focuses on the function of the p160 family of coactivators, which includes steroid receptor coactivator-1 (SRC-1), SRC-2 and SRC-3, in steroid receptor action in the brain. The expression, regulation and function of these coactivators in steroid-dependent gene expression in both brain and behaviour are discussed. © 2013 British Society for Neuroendocrinology.

Reproductive Steroid Regulation of Mood and Behavior.

PubMed

Schiller, Crystal Edler; Johnson, Sarah L; Abate, Anna C; Schmidt, Peter J; Rubinow, David R

2016-06-13

In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive-related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135-1160, 2016e. Copyright © 2016 John Wiley & Sons, Inc.

Sugammadex Improves Neuromuscular Function in Patients Receiving Perioperative Steroids.

PubMed

Ozer, A B; Bolat, E; Erhan, O L; Kilinc, M; Demirel, I; Toprak, G Caglar

2018-02-01

Sugammadex has steroid-encapsulating effect. This study was undertaken to assess whether the clinical efficacy of sugammadex was altered by the administration of steroids. Sixty patients between 18 and 60 years of age with the American Society of Anesthesiologists I-IV and undergoing elective direct laryngoscopy/biopsy were included in this study. Patients were assigned to two groups based on the intraoperative steroid use: those who received steroid (Group S) and who did not (Group C). After standard general anesthesia, patients were monitored with the train of four (TOF) monitoring. The preferred steroid and its dose, timing of steroid administration, and TOF value before and after sugammadex as well as the time to recovery (TOF of 0.9) were recorded. SPSS software version 17.0 was used for statistical analysis. There is no statistically significant difference between groups in terms of age, gender, preoperative medication use, and TOF ratio just before administering sugammadex. The reached time to TOF 0.9 after sugammadex administration was significantly shorter in Group S than Group C (P < 0.05). A within-group comparison in Group S showed no difference in TOF ratio immediately before sugammadex as well as the dose of sugammadex in those who received prednisolone; time to TOF 0.9 was higher in prednisolone receivers as compared to dexamethasone receivers (P < 0.05). In patients receiving steroids, and particularly dexamethasone, an earlier reversal of neuromuscular block by sugammadex was found, in contrast with what one expect. Further studies are required to determine the cause of this effect which is probably due to a potential interaction between sugammadex and steroids.

What is the role of steroids in pneumonia therapy?

PubMed

Póvoa, Pedro; Salluh, Jorge I F

2012-04-01

This review evaluates the potential benefits as well as adverse effects from adjunctive therapy with systemic steroids in patients with pneumonia: either mild-to-moderate or severe, community-acquired or hospital-acquired, of bacterial or of viral origin (in particular H1N1 viral infection). Steroids potentially modulate the marked and persistent activation of the immune system in pneumonia. However, several recent randomized controlled trials and large prospective observational studies have repeatedly shown that steroids had no impact on survival, the clinical event of interest, but in severe pneumonia some studies pointed to potential harmful effect. In addition, adverse effects, namely hyperglycemia, superinfections, as well as increased length-of-stay, were frequent findings in the steroid-treated patients. According to the current evidence, there are no data to support the well tolerated use of systemic steroids as a standard of care in pneumonia, neither in mild-to-moderate and severe, nor in bacterial and viral infection. Clinical and basic research should work together to improve trial designs to identify reliable surrogate markers of outcome, in particular of mortality. This may improve the patient selection and facilitate the identification of subgroups that can benefit from adjunctive steroid therapy.

What goes on behind closed doors: physiological vs. pharmacological steroid hormone actions

PubMed Central

Simons, S. Stoney

2009-01-01

Summary Steroid hormone-activated receptor proteins are among the best understood class of factors for altering gene transcription in cells. Steroid receptors are of major importance in maintaining normal human physiology by responding to circulating concentrations of steroid in the nM range. Nonetheless, most studies of steroid receptor action have been conducted using the supra-physiological conditions of saturating concentrations (≥100 nM) of potent synthetic steroid agonists. Here we summarize the recent developments arising from experiments using two clinically relevant conditions: subsaturating concentrations of agonist (to mimic the circulating concentrations in mammals) and saturating concentrations of antagonists (which are employed in endocrine therapies to block the actions of endogenous steroids). These studies have revealed new facets of steroid hormone action that could not be uncovered by conventional experiments with saturating concentrations of agonist steroids, such as a plethora of factors/conditions for the differential control of gene expression by physiological levels of steroid, a rational approach for examining the gene-specific variations in partial agonist activity of antisteroids, and a dissociation of steroid potency and efficacy that implies the existence of separate, and possibly novel, mechanistic steps and cofactors. PMID:18623071

Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus.

PubMed

Chen, Z L; Huang, R Q

2014-06-20

Changes in extracellular pH have a modulatory effect on GABAA receptor function. It has been reported that pH sensitivity of the GABA receptor is dependent on subunit composition and GABA concentration. Most of previous investigations focused on GABA-evoked currents, which only reflect the postsynaptic receptors. The physiological relevance of pH modulation of GABAergic neurotransmission is not fully elucidated. In the present studies, we examined the influence of extracellular pH on the GABAA receptor-mediated inhibitory neurotransmission in rat hypothalamic neurons. The inhibitory postsynaptic currents (IPSCs), tonic currents, and the GABA-evoked currents were recorded with whole-cell patch techniques on the hypothalamic slices from Sprague-Dawley rats at 15-26 postnatal days. The amplitude and frequency of spontaneous GABA IPSCs were significantly increased while the external pH was changed from 7.3 to 8.4. In the acidic pH (6.4), the spontaneous GABA IPSCs were reduced in amplitude and frequency. The pH induced changes in miniature GABA IPSCs (mIPSCs) similar to that in spontaneous IPSCs. The pH effect on the postsynaptic GABA receptors was assessed with exogenously applied varying concentrations of GABA. The tonic currents and the currents evoked by sub-saturating concentration of GABA ([GABA]) (10 μM) were inhibited by acidic pH and potentiated by alkaline pH. In contrast, the currents evoked by saturating [GABA] (1mM) were not affected by pH changes. We also investigated the influence of pH buffers and buffering capacity on pH sensitivity of GABAA receptors on human recombinant α1β2γ2 GABAA receptors stably expressed in HEK 293 cells. The pH influence on GABAA receptors was similar in HEPES- and MES-buffered media, and not dependent on protonated buffers, suggesting that the observed pH effect on GABA response is a specific consequence of changes in extracellular protons. Our data suggest that the hydrogen ions suppress the GABAergic neurotransmission

Steroids Update, Part 1 and Part 2.

ERIC Educational Resources Information Center

Miller, Calvin; Duda, Marty

1986-01-01

Part 1 of this two-part article describes the views of a physician who believes that athletes who want to take steroids are best protected by receiving a prescription and monitoring. Part 2 discusses the more general view of physicians that steroids should not be prescribed but perhaps should be monitored. (MT)

Preoperative steroids for hearing preservation cochlear implantation: A review.

PubMed

Kuthubutheen, Jafri; Smith, Leah; Hwang, Euna; Lin, Vincent

2016-01-01

Preoperative steroids have been shown to be beneficial in reducing the hearing loss associated with cochlear implantation. This review article discusses the mechanism of action, effects of differing routes of administration, and side effects of steroids administered to the inner ear. Studies on the role of preoperative steroids in animal and human studies are also examined and future directions for research in this area are discussed.

Sex steroids and cervical cancer.

PubMed

Hellberg, Dan

2012-08-01

During the 19th century, studies indicated that reproductive events were involved in cervical cancer. Human papillomavirus (HPV) infection is a prerequisite for development of cancer, but co-factors, among them the action of sexual steroid hormones, are necessary. Childbirth has been an important risk factor but now probably plays a minor role in the industrialized world, where parity is low. Long-term oral contraceptive use has been thoroughly studied epidemiologically, and correlates to cervical cancer in most studies. In vitro studies on cervical cell lines transfected with HPV and animal studies indicate that sex steroid hormones are capable to induce cancer. In in vivo cervical cancer tissue studies there have been observations that endogenous progesterone in serum correlates to a negative pattern of expression of cellular and extracellular proteins, tumor markers. Immune response could be another mechanism. Estradiol might be associated with a positive pattern and high estradiol and low progesterone levels increase duration of survival in cervical cancer. Studies where treatment of compounds that influence sex steroid hormones have been given are rare and have been disappointing.

Drug Facts: Anabolic Steroids

MedlinePlus

Skip to main content En español Researchers Medical & Health Professionals Patients & ... Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine ...

Steroid profiling in H295R cells to identify chemicals potentially disrupting the production of adrenal steroids.

PubMed

Strajhar, Petra; Tonoli, David; Jeanneret, Fabienne; Imhof, Raphaella M; Malagnino, Vanessa; Patt, Melanie; Kratschmar, Denise V; Boccard, Julien; Rudaz, Serge; Odermatt, Alex

2017-04-15

The validated OECD test guideline 456 based on human adrenal H295R cells promotes measurement of testosterone and estradiol production as read-out to identify potential endocrine disrupting chemicals. This study aimed to establish optimal conditions for using H295R cells to detect chemicals interfering with the production of key adrenal steroids. H295R cells' supernatants were characterized by liquid chromatography-mass spectrometry (LC-MS)-based steroid profiling, and the influence of experimental conditions including time and serum content was assessed. Steroid profiles were determined before and after incubation with reference compounds and chemicals to be tested for potential disruption of adrenal steroidogenesis. The H295R cells cultivated according to the OECD test guideline produced progestins, glucocorticoids, mineralocorticoids and adrenal androgens but only very low amounts of testosterone. However, testosterone contained in Nu-serum was metabolized during the 48h incubation. Thus, inclusion of positive and negative controls and a steroid profile of the complete medium prior to the experiment (t=0h) was necessary to characterize H295R cells' steroid production and indicate alterations caused by exposure to chemicals. Among the tested chemicals, octyl methoxycinnamate and acetyl tributylcitrate resembled the corticosteroid induction pattern of the positive control torcetrapib. Gene expression analysis revealed that octyl methoxycinnamate and acetyl tributylcitrate enhanced CYP11B2 expression, although less pronounced than torcetrapib. Further experiments need to assess the toxicological relevance of octyl methoxycinnamate- and acetyl tributylcitrate-induced corticosteroid production. In conclusion, the extended profiling and appropriate controls allow detecting chemicals that act on steroidogenesis and provide initial mechanistic evidence for prioritizing chemicals for further investigations. Copyright © 2017 Elsevier B.V. All rights reserved.

The use and abuse of anabolic steroids in Olympic-caliber athletes.

PubMed

Bergman, R; Leach, R E

1985-09-01

Self-medication with anabolic steroids by athletes, particularly in the sports of weight lifting and track and field, has become increasingly popular. In the 1983 Pan American Games, 15 athletes were disqualified for taking anabolic steroids. Athletes take steroids believing the steroids will allow increased periods of intensive training and will increase muscle strength with proper weight training. The athletes assume this increased strength and training will translate into better athletic performance. Most athletes taking anabolic steroids are taking very large doses with no thought as to the potential adverse side effects. They ignore the possibility of long-term problems relating to hypertension, liver dysfunction, and atherosclerosis for what they see as the immediate performance benefits. In an attempt to keep sports competition "clean" and to help protect athletes from harmful drugs, the International Olympic Committee (IOC) and the United States Olympic Committee have rules stating that the use of anabolic steroids is illegal. Drug testing is performed in Olympic and in many international competitions. Those people found using anabolic steroids are disqualified. This use of anabolic steroids indicates that for some athletes the need to win or to maximize performance supersedes any worries about future health.

Striae and Their Relation to Topical Steroid Therapy

PubMed Central

Adam, J. E.; Craig, Gibson

1965-01-01

Atrophic striae have been reported to occur normally in 35% of adolescents and abnormally in a variety of medical conditions. Recently, the occurrence of striae has been observed in adults after the use of potent topical steroids with occlusion. Pre-existing striae have been found to enlarge after topical steroid therapy, even without occlusion. The mechanism of striae formation appears to be due to the action of the steroids on the dermal connective tissue and/or dermal matrix rather than to mechanical tension. ImagesFig. 1Fig. 2 PMID:14270214

Seventeen steroids from the pith of Tetrapanax papyriferus.

PubMed

Xu, Jing-Lan; Gu, Li-Hua; Wang, Zheng-Tao; Bligh, Annie; Han, Zhu-Zhen; Liu, Shou-Jin

2016-12-01

Two new steroidal ketones (1, 2), together with 10 known steroids (3-12) and five known steroidal saponins (13-17), have been obtained from the pitch of Tetrapanax papyrierus. The structures of 1 and 2 were elucidated as 3β-hydroxystigmast-8, 22-diene-7,11-dione and 3β-hydroxystigmast-8-ene-7,11-dione by IR, HR-ESI-MS, 1D and 2D NMR techniques. Except for 4, 14, 15, 16, 13 compounds reported in this paper were isolated from Tetrapanax papyriferus for the first time.

Non-reproductive effects of sex steroids: their immunoregulatory role.

PubMed

Arroyo, Ignácio Camacho; Montor, Jorge Morales

2011-01-01

In this special issue of Current Topics in Medicinal Chemistry, the reader will find reviewed some of the hottest topics in the field of the non-reproductive effects of sex steroids. Cabrera-Muñoz et al., show that progesterone participates in the regulation of human brain tumors growth. The contribution of Martocchia suggests that sex steroid receptor modulating drugs provide new therapeutic approaches to autoimmune diseases. The role of sex steroid participation in the differentiation of stem cells to neurones is discussed by I. Velasco. Pérez-Torres and collaborators demonstrate that sex steroids play an important role in the appearance and development of renal diseases and the metabolic syndrome, the new epidemics of our century. Paris and Frye hypthetize that gestational stress, have effects on cognitive performance and/or neuronal integrity in the fetus, and that exposure to variable stress during gestation can perturb cognitive performance, concomitant with dendrite development in hippocampus and diencephalon. Muñoz-Cruz et al. thoroughly review the growing body of evidence that shows reciprocal relationship between sex steroids and the immune system, and conclude that understanding the mechanisms of action of sex steroids on immune cells is important for further progress in the development of novel therapies for chronic diseases associated to immune dysregulation. Besides, the effects of sexual steroids on pancreatic function and diabetes are reviewed by Morimoto et al. Yanes et al. review some of the contradictions raised in the context of the recently proposed critical period hypothesis, which takes into account the frame-time after cessation of ovarian function. Finally, another vey intetresting aspect of the non-reproductive effects of sex-steroids, is the related to some cognition-related aspects, which is reviewed by Picazo et al.

School and Parent Factors Associated with Steroid Use among Adolescents

ERIC Educational Resources Information Center

Elkins, Rebecca L.; King, Keith; Nabors, Laura; Vidourek, Rebecca

2017-01-01

Background: Steroid use among adolescents is an increasing health concern. Literature examining factors related to steroid use is limited. Methods: We investigated steroid use among 9th through 12th grade adolescents in the Greater Cincinnati area. A total of 38,414 adolescents completed the PRIDE Questionnaire. Associations between demographics,…

Mass Spectrometry Combinations for Structural Characterization of Sulfated-Steroid Metabolites

NASA Astrophysics Data System (ADS)

Yan, Yuetian; Rempel, Don L.; Holy, Timothy E.; Gross, Michael L.

2014-05-01

Steroid conjugates, which often occur as metabolites, are challenging to characterize. One application is female-mouse urine, where steroid conjugates serve as important ligands for the pheromone-sensing neurons. Although the two with the highest abundance in mouse urine were previously characterized with mass spectrometry (MS) and NMR to be sulfated steroids, many more exist but remain structurally unresolved. Given that their physical and chemical properties are similar, they are likely to have a sulfated steroid ring structure. Because these compounds occur in trace amounts in mouse urine and elsewhere, their characterization by NMR will be difficult. Thus, MS methods become the primary approach for determining structure. Here, we show that a combination of MS tools is effective for determining the structures of sulfated steroids. Using 4-pregnene analogs, we explored high-resolving power MS (HR-MS) to determine chemical formulae; HD exchange MS (HDX-MS) to determine number of active, exchangeable hydrogens (e.g., OH groups); methoxyamine hydrochloride (MOX) derivatization MS, or reactive desorption electrospray ionization with hydroxylamine to determine the number of carbonyl groups; and tandem MS (MSn), high-resolution tandem MS (HRMS/MS), and GC-MS to obtain structural details of the steroid ring. From the fragmentation studies, we deduced three major fragmentation rules for this class of sulfated steroids. We also show that a combined MS approach is effective for determining structure of steroid metabolites, with important implications for targeted metabolomics in general and for the study of mouse social communication in particular.

Learning and memory: Steroids and epigenetics.

PubMed

Colciago, Alessandra; Casati, Lavinia; Negri-Cesi, Paola; Celotti, Fabio

2015-06-01

Memory formation and utilization is a complex process involving several brain structures in conjunction as the hippocampus, the amygdala and the adjacent cortical areas, usually defined as medial temporal lobe structures (MTL). The memory processes depend on the formation and modulation of synaptic connectivity affecting synaptic strength, synaptic plasticity and synaptic consolidation. The basic neurocognitive mechanisms of learning and memory are shortly recalled in the initial section of this paper. The effect of sex hormones (estrogens, androgens and progesterone) and of adrenocortical steroids on several aspects of memory processes are then analyzed on the basis of animal and human studies. A specific attention has been devoted to the different types of steroid receptors (membrane or nuclear) involved and on local metabolic transformations when required. The review is concluded by a short excursus on the steroid activated epigenetic mechanisms involved in memory formation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clarithromycin increases neuronal excitability in CA3 pyramidal neurons through a reduction in GABAergic signaling

PubMed Central

Elder, Courtney C.; García, Paul S.

2016-01-01

Antibiotics are used in the treatment and prevention of bacterial infections, but effects on neuron excitability have been documented. A recent study demonstrated that clarithromycin alleviates daytime sleepiness in hypersomnia patients (Trotti LM, Saini P, Freeman AA, Bliwise DL, García PS, Jenkins A, Rye DB. J Psychopharmacol 28: 697–702, 2014). To explore the potential application of clarithromycin as a stimulant, we performed whole cell patch-clamp recordings in rat pyramidal cells from the CA3 region of hippocampus. In the presence of the antibiotic, rheobase current was reduced by 50%, F-I relationship (number of action potentials as a function of injected current) was shifted to the left, and the resting membrane potential was more depolarized. Clarithromycin-induced hyperexcitability was dose dependent; doses of 30 and 300 μM clarithromycin significantly increased the firing frequency and membrane potential compared with controls (P = 0.003, P < 0.0001). We hypothesized that clarithromycin enhanced excitability by reducing GABAA receptor activation. Clarithromycin at 30 μM significantly reduced (P = 0.001) the amplitude of spontaneous miniature inhibitory GABAergic currents and at 300 μM had a minor effect on action potential width. Additionally, we tested the effect of clarithromycin in an ex vivo seizure model by evaluating its effect on spontaneous local field potentials. Bath application of 300 μM clarithromycin enhanced burst frequency twofold compared with controls (P = 0.0006). Taken together, these results suggest that blocking GABAergic signaling with clarithromycin increases cellular excitability and potentially serves as a stimulant, facilitating emergence from anesthesia or normalizing vigilance in hypersomnia and narcolepsy. However, the administration of clarithromycin should be carefully considered in patients with seizure disorders. NEW & NOTEWORTHY Clinical administration of the macrolide antibiotic clarithromycin has been associated

Nociceptive vocalization response in guinea pigs modulated by opioidergic, GABAergic and serotonergic neurotransmission in the dorsal raphe nucleus.

PubMed

Ferreira, Mateus Dalbem; Menescal-de-Oliveira, Leda

2014-07-01

The dorsal raphe nucleus (DRN) is involved in the control of several physiological functions, including nociceptive modulation. This nucleus is one of the main sources of serotonin to the CNS and neuromodulators such as opioids and GABA may be are important for its release. This study evaluated the influence of serotonergic, GABAergic and opioidergic stimulation, as well as their interactions in the DRN, on vocalization nociceptive response during a peripheral noxious stimulus application in guinea pigs. Morphine (1.1 nmol), bicuculline (0.50 nmol) and alpha-methyl-5-HT (1.6 nmol) microinjection on the DRN produces antinociception. The antinociception produced by morphine (1.1 nmol) and alpha-methyl-5-HT (1.6 nmol) into the DRN was blocked by prior microinjection of naloxone (0.7 nmol). The alpha-methyl-5-HT effect blocked by naloxone may indicate the existence of 5-HT2A receptors on enkephalinergic interneurons within the dorsal raphe. Pretreatment with muscimol (0.26 nmol) also prevented the antinociceptive effect caused by morphine (1.1 nmol) when administered alone at the same site, indicating an interaction between GABAergic and opioidergic interneurons. The antinociception produced by bicuculline (0.5 nmol) in the DRN was blocked by prior administration of 8-OH-DPAT (0.5 nmol), a 5-HT1A agonist. This may indicate that the 5-HT autoreceptor activation by 8-OH-DPAT at DRN effector neurons can oppose the bicuculline disinhibition effect applied to the same effectors. Thus, we suggest that 5-HT2 receptor activation in the DRN promotes endorphin/enkephalin release that may disinhibit efferent serotonergic neurons of this present structure by inhibiting GABAergic interneurons, resulting in antinociception. Copyright © 2014 Elsevier Inc. All rights reserved.

Should we ever give steroids to ARDS patients?

PubMed Central

Hough, Catherine L.

2014-01-01

The development and severity of ARDS are closely related to dysregulated inflammation, and the duration of ARDS and eventual outcomes are related to persistent inflammation and abnormal fibroproliferation. Corticosteroids are potent modulators of inflammation and inhibitors of fibrosis that have been used since the description of the acute respiratory distress syndrome in attempts to improve outcomes. Randomized controlled trials of steroids for ARDS have answered some, but not all, questions regarding efficacy for prevention and treatment. First, there is no evidence that corticosteroids prevent the development of ARDS among patients at risk. Second, high dose and short course treatment with steroids does not improve the outcomes of patients with ARDS. And third, while there is compelling data that low dose and prolonged treatment with steroids improves pulmonary physiology in patients with ARDS, additional studies are needed to recommend treatment with steroids for ARDS. PMID:25453425

Confounding factors and genetic polymorphism in the evaluation of individual steroid profiling

PubMed Central

Kuuranne, Tiia; Saugy, Martial; Baume, Norbert

2014-01-01

In the fight against doping, steroid profiling is a powerful tool to detect drug misuse with endogenous anabolic androgenic steroids. To establish sensitive and reliable models, the factors influencing profiling should be recognised. We performed an extensive literature review of the multiple factors that could influence the quantitative levels and ratios of endogenous steroids in urine matrix. For a comprehensive and scientific evaluation of the urinary steroid profile, it is necessary to define the target analytes as well as testosterone metabolism. The two main confounding factors, that is, endogenous and exogenous factors, are detailed to show the complex process of quantifying the steroid profile within WADA-accredited laboratories. Technical aspects are also discussed as they could have a significant impact on the steroid profile, and thus the steroid module of the athlete biological passport (ABP). The different factors impacting the major components of the steroid profile must be understood to ensure scientifically sound interpretation through the Bayesian model of the ABP. Not only should the statistical data be considered but also the experts in the field must be consulted for successful implementation of the steroidal module. PMID:24764553

[Effect of activation and blockade of the GABA-ergic system of the substantia nigra in the midbrain on the realization of conditioned food reflexes in dogs].

PubMed

Iakimovskiĭ, A F

1988-01-01

Bilateral injection of 45 mcg of GABA into substantia nigra pars compacta produced in dogs a manifested improvement of parameters of the conditioned differentiation inhibition but failed to influence the positive Pavlovian alimentary conditioned reflex. Injection of GABA synaptic antagonist--picrotoxin impaired conditioned alimentary behaviour. Numerous injections of the GABAergic pharmacological agents resulted in motor disturbance--rotatory movements--and skin trophic deviations. The data obtained and literature references give ground for discussion of the role of striato-nigral and internal GABAergic substantia nigra systems in the positive modulation of adaptive alimentary behaviour and conditioned stimuli differentiation.

A bibliometric analysis of research updates and tendencies on steroid biotransformation

NASA Astrophysics Data System (ADS)

Song, Zhaoyu

2018-03-01

Steroid biotransformation, as a powerful tool for generation of steroid active pharmaceutical ingredients and key intermediates, has received widespread attention with increasing market demand for steroid-based drugs. In our study, a bibliometric analysis of steroid biotransformation was performed to trace the research updates and tendencies from 1993 to 2016, based on the Science Citation Index Expanded (SCIE) database. Results showed a notable growth trend in publication outputs. Although the USA was the most productive country between 1993 and 2016, developing nations, including China and India, contributed the prominent growth in recent years (2005–2016). Steroids was the leading journal in this field, and the research outputs had notably increased in the field of ‘Chemistry’, ‘Pharmacology and Pharmacy’ and ‘Biotechnology and Applied Microbiology’. Finally, research focused mainly on the efficient production of novel steroid active pharmaceutical ingredients and key intermediates through steroid biotransformation. Furthermore, cytochrome P450 involved in the side-chain oxidation of sterols has gradually become a hotspot issue in recent years.

Epidural steroid injections: update on efficacy, safety, and newer medications for injection.

PubMed

Kozlov, N; Benzon, H T; Malik, K

2015-08-01

The best evidence for epidural injection appears to be in the setting of radicular pain with epidural steroid and non-steroid injections more efficacious than non-epidural injections. Studies showed the efficacy of non-particulate steroid to approach the efficacy of particulate steroid and very limited comparisons demonstrated no significant difference between epidural steroid and epidural non-steroid (local anesthetic) injection. Preliminary studies evaluating epidural injection of disease modifying anti-rheumatic drugs such etanercept and tocilizumab showed conflicting results and had significant limitations. Randomized studies support better efficacy of transforaminal injection due to greater incidence of ventral epidural spread of injectate when compared to interlaminar injection. Thus, the transforaminal approach is recommended when unilateral radicular pain is limited to one nerve root. However, the transforaminal approach is associated with greater incidence of central nervous system injury, including paraplegia, attributed to embolization of the particulate steroid. Recent studies showed that non-particulate steroids potentially last as long as particulate steroids. Therefore non-particulate steroid should be used in initial transforaminal epidural injection. Future studies should look into the role of adjunct diagnostic aids, including digital subtraction angiography, in detecting intravascular injection and the ideal site of needle placement, whether it is the safe triangle or the triangle of Kambin. Finally, the role of epidural disease -modifying antirheumatic drugs in the management of back pain needs to be better elucidated.

Mass spectrometry combinations for structural characterization of sulfated-steroid metabolites.

PubMed

Yan, Yuetian; Rempel, Don L; Holy, Timothy E; Gross, Michael L

2014-05-01

Steroid conjugates, which often occur as metabolites, are challenging to characterize. One application is female-mouse urine, where steroid conjugates serve as important ligands for the pheromone-sensing neurons. Although the two with the highest abundance in mouse urine were previously characterized with mass spectrometry (MS) and NMR to be sulfated steroids, many more exist but remain structurally unresolved. Given that their physical and chemical properties are similar, they are likely to have a sulfated steroid ring structure. Because these compounds occur in trace amounts in mouse urine and elsewhere, their characterization by NMR will be difficult. Thus, MS methods become the primary approach for determining structure. Here, we show that a combination of MS tools is effective for determining the structures of sulfated steroids. Using 4-pregnene analogs, we explored high-resolving power MS (HR-MS) to determine chemical formulae; HD exchange MS (HDX-MS) to determine number of active, exchangeable hydrogens (e.g., OH groups); methoxyamine hydrochloride (MOX) derivatization MS, or reactive desorption electrospray ionization with hydroxylamine to determine the number of carbonyl groups; and tandem MS (MS(n)), high-resolution tandem MS (HRMS/MS), and GC-MS to obtain structural details of the steroid ring. From the fragmentation studies, we deduced three major fragmentation rules for this class of sulfated steroids. We also show that a combined MS approach is effective for determining structure of steroid metabolites, with important implications for targeted metabolomics in general and for the study of mouse social communication in particular.

Mass spectrometry combinations for structural characterization of sulfated-steroid metabolites

PubMed Central

Yan, Yuetian; Rempel, Don; Holy, Timothy E.; Gross, Michael L.

2015-01-01

Steroid conjugates, which often occur as metabolites, are challenging to characterize. One application is female-mouse urine, where steroid conjugates serve as important ligands for the pheromone-sensing neurons. Although the two with the highest abundance in mouse urine were previously characterized with mass spectrometry (MS) and NMR to be sulfated steroids, many more exist but remain structurally unresolved. Given that their physical and chemical properties are similar, they are likely to have a sulfated steroid ring structure. Because these compounds occur in trace amounts in mouse urine and elsewhere, their characterization by NMR will be difficult. Thus, MS methods become the primary approach for determining structure. Here, we show that a combination of MS tools is effective for determining the structures of sulfated steroids. Using 4-pregnene analogs, we explored high-resolving power MS (HR-MS) to determine chemical formulae; HD exchange MS (HDX-MS) to determine number of active, exchangeable hydrogens (e.g., OH groups); methoxyamine hydrochloride (MOX) derivatization MS, or reactive desorption electrospray ionization with hydroxylamine to determine the number of carbonyl groups; and tandem MS (MSn), high-resolution tandem MS (HRMS/MS), and GC-MS to obtain structural details of the steroid ring. From the fragmentation studies, we deduced three major fragmentation rules for this class of sulfated steroids. We also show that a combined MS approach is effective for determining structure of steroid metabolites, with important implications for targeted metabolomics in general and for the study of mouse social communication in particular. PMID:24658800

Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat.

PubMed

Zhang, Min; Balmadrid, Christian; Kelley, Ann E

2003-04-01

The current studies were designed to evaluate whether incentive motivation for palatable food is altered after manipulations of opioid, GABAergic, and dopaminergic transmission within the nucleus accumbens. A progressive ratio schedule was used to measure lever-pressing for sugar pellets after microinfusion of drugs into the nucleus accumbens in non-food-deprived rats. The mu opioid agonist D-Ala2, NMe-Phe4, Glyo15-enkephalin and the indirect dopamine agonist amphetamine induced a marked increase in break point and correct lever-presses; the GABA(A) agonist muscimol did not affect breakpoint or lever-presses. The data suggest that opioid, dopaminergic, and GABAergic systems within the accumbens differentially modulate food-seeking behavior through mechanisms related to hedonic evaluation of food, incentive salience, and control of motor feeding circuits, respectively.

Cytotoxic Oxygenated Steroids from the Soft Coral Nephthea erecta.

PubMed

Tsai, Tsung-Chang; Huang, Yu-Ting; Chou, Shih-Kai; Shih, Ming-Cheng; Chiang, Ching-Ying; Su, Jui-Hsin

2016-10-01

A new 10-demethylated steroid, nephtheasteroid A (1), a new 19-oxygenated steroid, nephtheasteroid B (2) as well as five known steroids 3-7 were isolated from the organic extract of a Taiwanese soft coral Nephthea erecta. The structure was determined by means of IR, MS, and NMR techniques. Among these metabolites, 1 is rarely found in steroids possessing a 19-norergostane skeleton. In vitro cytotoxicity study using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that compounds 3 and 4 exhibited cytotoxicity against human chronic myelogenous leukemia (K562), human acute lymphoblastic leukemia (Molt-4), human T lymphoblastoid (Sup-T1), and human leukemic monocyte lymphoma (U937), with IC 50 of 6.5-14.0 µM.

Steroid-induced hyperglycaemia in hospitalised patients: does it matter?

PubMed

Cheung, N Wah

2016-12-01

Steroid-induced hyperglycaemia is a common problem faced by endocrinologists in hospital wards. In this issue of Diabetologia, Popovic and colleagues (DOI 10.1007/s00125-016-4091-4 ) have conducted a subanalysis within a randomised controlled trial of prednisone therapy for community-acquired pneumonia. The authors found that the presence of diabetes or hyperglycaemia related to steroid therapy did not attenuate the clinical benefits of steroid therapy. The relevance and possible implications of these findings are discussed.

Tandem mass spectrometry approach for the investigation of the steroidal metabolism: structure-fragmentation relationship (SFR) in anabolic steroids and their metabolites by ESI-MS/MS analysis.

PubMed

Musharraf, Syed Ghulam; Ali, Arslan; Khan, Naik Tameem; Yousuf, Maria; Choudhary, Muhammad Iqbal; Atta-ur-Rahman

2013-02-01

Electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to investigate the effect of different substitutions introduced during metabolism on fragmentation patterns of four anabolic steroids including methyltestosterone, methandrostenolone, cis-androsterone and adrenosterone, along with their metabolites. Collision-induced dissociation (CID) analysis was performed to correlate the major product ions of 19 steroids with structural features. The analysis is done to portray metabolic alteration, such as incorporation or reduction of double bonds, hydroxylations, and/or oxidation of hydroxyl moieties to keto functional group on steroidal skeleton which leads to drastically changed product ion spectra from the respective classes of steroids, therefore, making them difficult to identify. The comparative ESI-MS/MS study also revealed some characteristic peaks to differentiate different steroidal metabolites and can be useful for the unambiguous identification of anabolic steroids in biological fluid. Moreover, LC-ESI-MS/MS analysis of fermented extract of methyltestosterone, obtained by Macrophomina phaseolina was also investigated. Copyright © 2012 Elsevier Inc. All rights reserved.

Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic Inhibition.

PubMed

Chiu, Chiayu Q; Martenson, James S; Yamazaki, Maya; Natsume, Rie; Sakimura, Kenji; Tomita, Susumu; Tavalin, Steven J; Higley, Michael J

2018-01-17

Preservation of a balance between synaptic excitation and inhibition is critical for normal brain function. A number of homeostatic cellular mechanisms have been suggested to play a role in maintaining this balance, including long-term plasticity of GABAergic inhibitory synapses. Many previous studies have demonstrated a coupling of postsynaptic spiking with modification of perisomatic inhibition. Here, we demonstrate that activation of NMDA-type glutamate receptors leads to input-specific long-term potentiation of dendritic inhibition mediated by somatostatin-expressing interneurons. This form of plasticity is expressed postsynaptically and requires both CaMKIIα and the β2 subunit of the GABA-A receptor. Importantly, this process may function to preserve dendritic inhibition, as genetic deletion of NMDAR signaling results in a selective weakening of dendritic inhibition. Overall, our results reveal a new mechanism for linking excitatory and inhibitory input in neuronal dendrites and provide novel insight into the homeostatic regulation of synaptic transmission in cortical circuits. Copyright © 2017 Elsevier Inc. All rights reserved.

Regulation of Microglia by Ionotropic Glutamatergic and GABAergic Neurotransmission

PubMed Central

Wong, Wai T.; Wang, Minhua; Li, Wei

2015-01-01

Recent studies have indicated that constitutive functions of microglia in the healthy adult CNS involve immune surveillance, synapse maintenance, and trophic support. These functions have been related to the ramified structure of “resting” microglia and the prominent motility in their processes that provide extensive coverage of the entire extracellular milleu. In this review, we examine how external signals, and in particular, ionotropic neurotransmission, regulate features of microglial morphology and process motility. Taken together, current findings indicate that microglial physiology in the healthy CNS is constitutively and reciprocally regulated by endogenous ionotropic glutamatergic and GABAergic neurotransmission. These influences do not act directly on microglial cells but indirectly via the activity-dependent release of ATP, likely through a mechanism involving pannexin channels. Microglia in the “resting” state are not only dynamically active, but are constantly engaged in ongoing communication with neuronal and macroglial components of the CNS in a functionally relevant way. PMID:22166726

Total synthesis of steroids and heterosteroids from BISTRO.

PubMed

Ibrahim-Ouali, Malika

2015-06-01

Due to their high profile biological activity, the steroids are among the most important secondary metabolites. A review of literature on the total synthesis of steroids starting from BISTRO (1,8-bis(trimethylsilyl)-2,6-octadiene) is presented. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of composting on the fate of steroids in beef cattle manure.

PubMed

Bartelt-Hunt, Shannon L; Devivo, Shannon; Johnson, Leslie; Snow, Daniel D; Kranz, William L; Mader, Terry L; Shapiro, Charles A; van Donk, Simon J; Shelton, David P; Tarkalson, David D; Zhang, Tian C

2013-07-01

In this study, the fate of steroid hormones in beef cattle manure composting is evaluated. The fate of 16 steroids and metabolites was evaluated in composted manure from beef cattle administered growth promotants and from beef cattle with no steroid hormone implants. The fate of estrogens (primary detected as estrone), androgens, progesterone, and the fusarium metabolite and implant α-zearalanol was monitored in manure compost piles. First-order decay rates were calculated for steroid half-lives in compost and ranged from 8 d for androsterone to 69 d for 4-androstenedione. Other steroid concentration data could not be fit to first-order decay models, which may indicate that microbial processes may result in steroid production or synthesis in composting systems. We demonstrate that composting is an effective strategy to remove steroid hormones from manure. Total steroid hormone removal in composted beef cattle manure ranged from 79 to 87%. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Sox and Drugs: Baseball, Steroids and Physics

NASA Astrophysics Data System (ADS)

Tobin, Roger

2008-03-01

The sports world is in an uproar over performance-enhancing drugs. In the United States steroids in baseball have received the most attention, in part because the purported effects are much more dramatic than in any other sport. From 1995-2003 a few players hit home runs at rates 20-50% higher than the best sluggers of the preceding century. Could steroids really increase home-run performance that much? I will describe a model that combines estimates of the physiological effects of steroids, known baseball physics, and reasonable models of batting effectiveness for highly skilled hitters. A 10% increase in muscle mass, which can reasonably be expected from steroid use, increases the speed of a batted ball by 3%. Because home runs are relatively rare events on the tail of a batter's range distribution, even this modest change in ball speed can increase the proportion of batted balls that result in home runs by 30 -- 70%, enough to account for the record-shattering performances of the recent past. I will also describe some of the attention -- both welcome and not -- that comes to the unsuspecting physicist who wades into such emotionally troubled waters.

1-Ene-steroid reductase of Mycobacterium sp. NRRL B-3805.

PubMed

Goren, T; Harnik, M; Rimon, S; Aharonowitz, Y

1983-12-01

The microbial enzymatic reduction of 1,4-androstadiene-3,17-dione (ADD) to 4-androstene-3,17-dione (AD), testosterone and 1-dehydrotestosterone (DHT) is described. Two reducing activities observed in washed cell suspensions and cell free extracts of Mycobacterium sp. NRRL B-3805 were found to account for these bioconversions. One was a 1-ene-steroid reductase and the other a 17-keto steroid reductase. The first reducing activity was found to appear in the soluble cell fraction whereas the latter could be precipitated by centrifugation. Maximum 1-ene-steroid reductase specific activity was achieved during the exponential growth phase of the organism and significantly increased upon induction with ADD. The 1-ene-steroid reductase was partially purified (30-fold) by ammonium sulfate fractionation, gel-filtration and ion-exchange chromatography, and was eluted from a Sephacryl S-300 column with an Mr = 115,000. The 1-ene-steroid reductase activity was NADPH-dependent and had specificity towards steroid compounds containing C-1,2 double bond with an apparent Km for ADD of 2.2 X 10(-5) M. The reverse reaction catalyzing C-1,2 dehydrogenation could not be detected in our preparations. The results suggest that in Mycobacterium sp NRRL B-3805 and B-3683 the steroid C-1,2 dehydrogenation and 1-ene reduction are two separable activities.

Recurrence of IgA nephropathy after kidney transplantation in steroid continuation versus early steroid-withdrawal regimens: a retrospective analysis of the UNOS/OPTN database.

PubMed

Leeaphorn, Napat; Garg, Neetika; Khankin, Eliyahu V; Cardarelli, Francesca; Pavlakis, Martha

2018-02-01

In the past 20 years, there has been an increase in use of steroid-withdrawal regimens in kidney transplantation. However, steroid withdrawal may be associated with an increased risk of recurrent IgA nephropathy (IgAN). Using United Network of (Organ Sharing/Organ Procurement and Transplantation Network) UNOS/OPTN data, we analyzed adult patients with end-stage renal disease (ESRD) due to IgAN who received their first kidney transplant between 2000 and 2014. For the primary outcome, we used a competing risk analysis to compare the cumulative incidence of graft loss due to IgAN recurrence between early steroid-withdrawal (ESW) and steroid continuation groups. The secondary outcomes were patient survival and death-censored graft survival (DCGS). A total of 9690 recipients were included (2831 in ESW group and 6859 in steroid continuation group). In total, 1238 recipients experienced graft loss, of which 191 (15.43%) were due to IgAN recurrence. In multivariable analysis, steroid use was associated with a decreased risk of recurrence (subdistribution hazard ratio 0.666, 95% CI 0.482-0.921; P = 0.014). Patient survival and DCGS were not different between the two groups. In the USA, ESW in transplant for ESRD due to IgAN is associated with a higher risk of graft loss due to disease recurrence. Future prospective studies are warranted to further address which patients with IgAN would benefit from steroid continuation. © 2017 Steunstichting ESOT.

Steroids and endocrine disruptors--History, recent state of art and open questions.

PubMed

Hampl, Richard; Kubátová, Jana; Stárka, Luboslav

2016-01-01

This introductory chapter provides an overview of the levels and sites at which endocrine disruptors (EDs) affect steroid actions. In contrast to the special issue of Journal of Steroid Biochemistry and Molecular Biology published three years ago and devoted to EDs as such, this paper focuses on steroids. We tried to point to more recent findings and opened questions. EDs interfere with steroid biosynthesis and metabolism either as inhibitors of relevant enzymes, or at the level of their expression. Particular attention was paid to enzymes metabolizing steroid hormones to biologically active products in target cells, such as aromatase, 5α-reductase and 3β-, 11β- and 17β-hydroxysteroid dehydrogenases. An important target for EDs is also steroid acute regulatory protein (StAR), responsible for steroid precursor trafficking to mitochondria. EDs influence receptor-mediated steroid actions at both genomic and non-genomic levels. The remarkable differences in response to various steroid-receptor ligands led to a more detailed investigation of events following steroid/disruptor binding to the receptors and to the mapping of the signaling cascades and nuclear factors involved. A virtual screening of a large array of EDs with steroid receptors, known as in silico methods (≡computer simulation), is another promising approach for studying quantitative structure activity relationships and docking. New data may be expected on the effect of EDs on steroid hormone binding to selective plasma transport proteins, namely transcortin and sex hormone-binding globulin. Little information is available so far on the effects of EDs on the major hypothalamo-pituitary-adrenal/gonadal axes, of which the kisspeptin/GPR54 system is of particular importance. Kisspeptins act as stimulators for hormone-induced gonadotropin secretion and their expression is regulated by sex steroids via a feed-back mechanism. Kisspeptin is now believed to be one of the key factors triggering puberty in

Cardiotoxic effects of cocaine and anabolic-androgenic steroids in the athlete.

PubMed

Welder, A A; Melchert, R B

1993-04-01

Cocaine and anabolic-androgenic steroid abuse have become major drug problems in the United States. Cocaine has been designated as "the drug of greatest national health concern" while as many as 1 million Americans have used or are currently using anabolic-androgenic steroids to promote athletic performance and/or improve physical appearance. Unfavorable cardiovascular events have been linked to both cocaine and anabolic-androgenic steroid abuse in healthy, physically active individuals. Deaths of several United States athletes in 1986 focused attention on the life-threatening cardiovascular consequences of cocaine abuse. Reports of myocardial injury with anabolic-androgenic steroid abuse are anecdotal. Nevertheless, case reports have illustrated the alarming cardiotoxic potential of these steroids in athletes. Anabolic-androgenic steroids were correlated to myocardial infarction in weight lifters and cardiomyopathy in a former professional football player. From the total emergency room episodes where cocaine was mentioned in 1990, approximately 66% of these episodes occurred in young individuals 18-29 years of age. Over 500,000 of the individuals currently taking anabolic-androgenic steroids for nonmedical purposes are high-school children. Because cocaine and anabolic-androgenic steroids are used improperly, more focus needs to be paid to the toxic mechanisms of their adverse effects. Therefore, the purpose of this review is to discuss mechanisms whereby exercise and/or exercise training may alter the cardiovascular responses to these drugs. Furthermore, we would like to illustrate that contrary to the popular belief, acute and chronic abuse of cocaine and anabolic-androgenic steroids have a negative impact on exercise performance.

Retropharyngeal Steroids and Dysphagia Following Multilevel Anterior Cervical Surgery.

PubMed

Koreckij, Theodore D; Davidson, Abigail A; Baker, Kevin C; Park, Daniel K

2016-05-01

A retrospective case-control study. The aim of this study was to determine the effect of retropharyngeal steroids on postoperative dysphagia scores and clinical outcomes following multilevel anterior cervical discectomy and fusion (ACDF). Dysphagia is a well-known complication following ACDF surgery and increased rates of dysphagia are seen with increased levels of surgery. Retropharyngeal steroids have been shown to decrease painful swallowing and prevertebral soft tissue (PSTS) swelling in 1- and 2-level anterior cervical surgery. A retrospective review of 44 patients undergoing multilevel (2-, 3-, 4-level) ACDF. Twenty-two patients who received retropharyngeal steroids (methylprednisone) placed on a collagen sponge at the time of surgery were compared with a matched cohort of controls who did not receive local steroids. Postoperative day 1 and 6-week radiographs were analyzed for differences in PSTS. Clinical outcomes were measured pre-operatively, 6 weeks, and 3 months postoperatively utilizing the Neck Disability Index (NDI), the Bazaz-Yoo Dysphagia Scoring System, and Eat Assessment Tool (EAT-10). Significant improvement in dysphagia scores were seen utilizing both outcome measures. Bazaz-Yoo scores were significantly better at both 6 weeks and 3 months in patients receiving local steroids compared with controls (P = 0.008 and P = 0.022, respectively). EAT-10 showed similar improvement of the steroid group versus control at 6 weeks and 3 months (P = 0.067 and P = 0.012, respectively). A trend toward decreased PSTS was found with locally delivered steroids on initial postoperative radiographs (P = 0.07), but was no longer evident at 6 weeks. NDI, although improved from pre-operative scores, failed to demonstrate significant differences between groups. No differences in length of stay or complications were observed between the groups. The use of retropharyngeal steroids resulted in decreased rates of dysphagia following multilevel ACDF

A Study of Steroid Use among Athletes: Knowledge, Attitude and Use.

ERIC Educational Resources Information Center

Chng, Chwee Lye; Moore, Alan

1990-01-01

The relationship of knowledge, attitudes, and prevalence of steroid use among college athletes and nonathletes was investigated. Results indicated that the more individuals knew about steroids, the more favorable was their attitude toward use. Powerlifters and bodybuilders were found most likely to use steroids. (JD)

Endogenous steroid profiling in the athlete biological passport.

PubMed

Sottas, Pierre-Edouard; Saugy, Martial; Saudan, Christophe

2010-03-01

The Athlete Biological Passport (ABP) is an individual electronic document that collects data regarding a specific athlete that is useful in differentiating between natural physiologic variations of selected biomarkers and deviations caused by artificial manipulations. A subsidiary of the endocrine module of the ABP, that which here is called Athlete Steroidal Passport (ASP), collects data on markers of an altered metabolism of endogenous steroidal hormones measured in urine samples. The ASP aims to identify not only doping with anabolic-androgenic steroids, but also most indirect steroid doping strategies such as doping with estrogen receptor antagonists and aromatase inhibitors. Development of specific markers of steroid doping, use of the athlete's previous measurements to define individual limits, with the athlete becoming his or her own reference, the inclusion of heterogeneous factors such as the UDPglucuronosyltransferase B17 genotype of the athlete, the knowledge of potentially confounding effects such as heavy alcohol consumption, the development of an external quality control system to control analytical uncertainty, and finally the use of Bayesian inferential methods to evaluate the value of indirect evidence have made the ASP a valuable alternative to deter steroid doping in elite sports. The ASP can be used to target athletes for gas chromatography/combustion/ isotope ratio mass spectrometry (GC/C/IRMS) testing, to withdraw temporarily the athlete from competing when an abnormality has been detected, and ultimately to lead to an antidoping infraction if that abnormality cannot be explained by a medical condition. Although the ASP has been developed primarily to ensure fairness in elite sports, its application in endocrinology for clinical purposes is straightforward in an evidence-based medicine paradigm. Copyright 2010 Elsevier Inc. All rights reserved.

Nitric oxide facilitates GABAergic neurotransmission in the cat oculomotor system: a physiological mechanism in eye movement control

PubMed Central

Moreno-López, Bernardo; Escudero, Miguel; Estrada, Carmen

2002-01-01

Nitric oxide (NO) synthesis by prepositus hypoglossi (PH) neurons is necessary for the normal performance of horizontal eye movements. We have previously shown that unilateral injections of NO synthase (NOS) inhibitors into the PH nucleus of alert cats produce velocity imbalance without alteration of the eye position control, both during spontaneous eye movements and the vestibulo-ocular reflex (VOR). This NO effect is exerted on the dorsal PH neuropil, whose fibres increase their cGMP content when stimulated by NO. In an attempt to determine whether NO acts by modulation of a specific neurotransmission system, we have now compared the oculomotor effects of NOS inhibition with those produced by local blockade of glutamatergic, GABAergic or glycinergic receptors in the PH nucleus of alert cats. Both glutamatergic antagonists used, 2-amino-5-phosphonovaleric acid (APV) and 2,3-dihydro-6-nitro-7-sulphamoyl-benzo quinoxaline (NBQX), induced a nystagmus contralateral to that observed upon NOS inhibition, and caused exponential eye position drift. In contrast, bicuculline and strychnine induced eye velocity alterations similar to those produced by NOS inhibitors, suggesting that NO oculomotor effects were due to facilitation of some inhibitory input to the PH nucleus. To investigate the anatomical location of the putative NO target neurons, the retrograde tracer Fast Blue was injected in one PH nucleus, and the brainstem sections containing Fast Blue-positive neurons were stained with double immunohistochemistry for NO-sensitive cGMP and glutamic acid decarboxylase. GABAergic neurons projecting to the PH nucleus and containing NO-sensitive cGMP were found almost exclusively in the ipsilateral medial vestibular nucleus and marginal zone. The results suggest that the nitrergic PH neurons control their own firing rate by a NO-mediated facilitation of GABAergic afferents from the ipsilateral medial vestibular nucleus. This self-control mechanism could play an important role

Sex steroids effects in normal endocrine pancreatic function and diabetes.

PubMed

Morimoto, Sumiko; Jiménez-Trejo, Francisco; Cerbón, Marco

2011-01-01

Traditionally the role of sexual steroid hormones was focused primarily on reproductive organs: the breast, female reproductive tract (uterus, mammary gland, and ovary), and male reproductive tract (testes, epididymis and prostate), however our current understanding of tissue-specific effects of sex steroids has elucidated new aspects in its functionality. Recent data have shown that many other tissues are targets of those hormones in addition to classical reproductive organs. The pancreas (which performs both endocrine and exocrine functions), has proven to be an extragonadal target of sexual steroid hormone action. The endocrine pancreas has a pivotal role on carbohydrate homeostasis and deterioration in function produces diabetes. Diabetes is a metabolic disorder that has high prevalence worldwide, particularly in developing countries. It has been shown that steroid hormones have an important role in susceptibility and development of diabetes in animal models, in humans its role is less clear, however the most evident effect is on the perimenopausal women, in this stage the decrease in gonadal steroids produces an increase on susceptibility to develop diabetes mellitus; in men, hypoandrogenism is associated with an increased prevalence of insulin resistance. This review focused on the effects of sexual steroids on pancreatic function and diabetes.

Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks

PubMed Central

Pennucci, Roberta; Talpo, Francesca; Astro, Veronica; Montinaro, Valentina; Morè, Lorenzo; Cursi, Marco; Castoldi, Valerio; Chiaretti, Sara; Bianchi, Veronica; Marenna, Silvia; Cambiaghi, Marco; Tonoli, Diletta; Leocani, Letizia; Biella, Gerardo; D'Adamo, Patrizia; de Curtis, Ivan

2016-01-01

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons. PMID:26582364

The Central Effects of Androgenic-anabolic Steroid Use.

PubMed

Mędraś, Marek; Brona, Anna; Jóźków, Paweł

: Millions of men use androgenic-anabolic steroids (AAS) to stimulate muscle growth and improve physical appearance. Although 1 out of 3 people who uses androgenic-anabolic steroids develops a steroid use disorder, the effects of the drugs on the central nervous system and the psyche are still not well understood. Although most addictive substances improve mood immediately after administration, AAS exert less pronounced euphoric effects. Instead, they are primarily taken for the delayed gratification of increased muscle mass. Withdrawal from AAS may lead to a range of somatic and psychiatric symptoms, and, in many cases, comprehensive treatment supervised by an endocrinologist and a psychiatrist is required.

21 CFR 1308.33 - Exemption of certain anabolic steroid products; application.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Exemption of certain anabolic steroid products... SCHEDULES OF CONTROLLED SUBSTANCES Exempt Anabolic Steroid Products § 1308.33 Exemption of certain anabolic steroid products; application. (a) The Administrator, upon the recommendation of Secretary of Health and...

Steroid hormones in environmental matrices: extraction method comparison.

PubMed

Andaluri, Gangadhar; Suri, Rominder P S; Graham, Kendon

2017-11-09

The U.S. Environmental Protection Agency (EPA) has developed methods for the analysis of steroid hormones in water, soil, sediment, and municipal biosolids by HRGC/HRMS (EPA Method 1698). Following the guidelines provided in US-EPA Method 1698, the extraction methods were validated with reagent water and applied to municipal wastewater, surface water, and municipal biosolids using GC/MS/MS for the analysis of nine most commonly detected steroid hormones. This is the first reported comparison of the separatory funnel extraction (SFE), continuous liquid-liquid extraction (CLLE), and Soxhlet extraction methods developed by the U.S. EPA. Furthermore, a solid phase extraction (SPE) method was also developed in-house for the extraction of steroid hormones from aquatic environmental samples. This study provides valuable information regarding the robustness of the different extraction methods. Statistical analysis of the data showed that SPE-based methods provided better recovery efficiencies and lower variability of the steroid hormones followed by SFE. The analytical methods developed in-house for extraction of biosolids showed a wide recovery range; however, the variability was low (≤ 7% RSD). Soxhlet extraction and CLLE are lengthy procedures and have been shown to provide highly variably recovery efficiencies. The results of this study are guidance for better sample preparation strategies in analytical methods for steroid hormone analysis, and SPE adds to the choice in environmental sample analysis.

Morphofunctional evidence for the involvement of hypothalamic dopaminergic and GABAergic neurons in the mechanisms of photoperiod-dependent prolactin release in the mink.

PubMed

Boissin-Agasse, L; Tappaz, M; Roch, G; Gril, C; Boissin, J

1991-06-01

This study was designed to examine possible relationships between the photoperiodic regulation of prolactin secretion and the activity of dopaminergic and GABAergic neurons projecting to the external layer of the median eminence. The study was carried out on the mink whose remarkable photosensitivity has been clearly demonstrated. The animals were reared in short (4L:20D) or long (20L:4D) photoperiods. The experiment began in November when day length is short (9.5 h). Dopaminergic and GABAergic neurons were studied using immunocytochemical methods allowing evaluation of the immunoreactivities of tyrosine hydroxylase (TH) and glutamate decarboxylase (GAD), which are respective markers of these neurons. The results were quantified by image analysis. The plasma prolactin level of animals maintained in 4L:20D decreased after 60 days and TH and GAD immunoreactivity were strongly stimulated. After 110 days, the prolactin concentration and TH and GAD immunoreactivity recovered their starting levels. In animals maintained in 20L:4D, the prolactin level was 3 times higher than at the beginning of the photoperiodic treatment but only dopaminergic neurons showed a change, i.e. a decrease in immunoreactivity. At the end of the experiment, prolactin secretion was no longer affected by the stimulatory effect of long-day treatment, and TH immunoreactivity remained low. These results confirm the generally accepted concept that dopaminergic neurons are potent PIF-producing components. GABAergic hypothalamic system appears to be implicated in photoperiodic PRL regulation, but this remains to be clearly demonstrated.

Interactions between hormones and epilepsy.

PubMed

Taubøll, Erik; Sveberg, Line; Svalheim, Sigrid

2015-05-01

There is a complex, bidirectional interdependence between sex steroid hormones and epilepsy; hormones affect seizures, while seizures affect hormones thereby disturbing reproductive endocrine function. Both female and male sex steroid hormones influence brain excitability. For the female sex steroid hormones, progesterone and its metabolites are anticonvulsant, while estrogens are mainly proconvulsant. The monthly fluctuations in hormone levels of estrogen and progesterone are the basis for catamenial epilepsy described elsewhere in this issue. Androgens are mainly anticonvulsant, but the effects are more varied, probably because of its metabolism to, among others, estradiol. The mechanisms for the effects of sex steroid hormones on brain excitability are related to both classical, intracellularly mediated effects, and non-classical membrane effects due to binding to membrane receptors. The latter are considered the most important in relation to epilepsy. The different sex steroids can also be further metabolized within the brain to different neurosteroids, which are even more potent with regard to their effect on excitability. Estrogens potentiate glutamate responses, primarily by potentiating NMDA receptor activity, but also by affecting GABA-ergic mechanisms and altering brain morphology by increasing dendritic spine density. Progesterone and its main metabolite 5α-pregnan-3α-ol-20-one (3α-5α-THP) act mainly to enhance postsynaptic GABA-ergic activity, while androgens enhance GABA-activated currents. Seizures and epileptic discharges also affect sex steroid hormones. There are close anatomical connections between the temporolimbic system and the hypothalamus controlling the endocrine system. Several studies have shown that epileptic activity, especially mediated through the amygdala, alters reproductive function, including reduced ovarian cyclicity in females and altered sex steroid hormone levels in both genders. Furthermore, there is an asymmetric

Effect of anabolic steroids on skeletal muscle mass during hindlimb suspension

NASA Technical Reports Server (NTRS)

Tsika, R. W.; Herrick, R. E.; Baldwin, K. M.

1987-01-01

The effect of treatment with an anabolic steroid (nandrolone decanoate) on the muscle mass of plantaris and soleus of a rats in hindlimb suspension, and on the isomyosin expression in these muscles, was investigated in young female rats divided into four groups: normal control (NC), normal steroid (NS), normal suspension (N-sus), and suspension steroid (sus-S). Steroid treatment of suspended animals (sus-S vs N-sus) was found to partially spare body weight and muscle weight, as well as myofibril content of plantaris (but not soleus), but did not modify the isomyosin pattern induced by suspension. In normal rats (NS vs NC), steroid treatment did enhance body weight and plantaris muscle weight; the treatment did not alter isomyosin expression in either muscle type.

Conserved steroid hormone homology converges on NFκB to modulate inflammation in asthma

PubMed Central

Payne, Asha S.; Freishtat, Robert J.

2012-01-01

Asthma is a complex, multifactorial disease comprising multiple different subtypes, rather than a single disease entity [1], yet has a consistent clinical phenotype: recurring episodes of chest tightness, wheezing, and difficulty breathing. Despite the complex pathogenesis of asthma, steroid hormones (e.g. glucocorticoids) are ubiquitous in the acute and chronic management of all types of asthma. Overall, steroid hormones are a class of widely-relevant, biologically-active compounds originating from cholesterol and altered in a stepwise fashion, but maintain a basic 17-carbon, 4-ring structure. Steroids are lipophilic molecules that diffuse readily through cell membranes to directly and/or indirectly affect gene transcription. In addition, they employ rapid, non-genomic actions to affect cellular products. Steroid hormones are comprised of several groups (including glucocorticoids, sex steroid hormones, and secosteroids) with critical divergent biological and physiological functions relevant to health and disease. However, the conserved homology of steroid hormone molecules, receptors, and signaling pathways suggest that each of these is part of dynamic system of hormone interaction, likely involving overlap of downstream signaling mechanisms. Therefore, we will review the similarities and differences of these three groups of steroid hormones (i.e. glucocorticoids, sex steroid hormones, and secosteroids), identifying NFκB as a common inflammatory mediator. Despite our understanding of the impact of individual steroids (e.g. glucocorticoids, sex steroids and secosteroids) on asthma, research has yet to explain the interplay of the dynamic system in which these hormones function. To do so, there needs to be better understanding of the interplay of classical, non-classical, and non-genomic steroid hormone function. However, clues from the conserved homology steroid hormone structure and function and signaling pathways, offer insight into a possible model of steroid

Collision Cross Section (CCS) Database: An Additional Measure to Characterize Steroids.

PubMed

Hernández-Mesa, Maykel; Le Bizec, Bruno; Monteau, Fabrice; García-Campaña, Ana M; Dervilly-Pinel, Gaud

2018-04-03

Ion mobility spectrometry enhances the performance characteristics of liquid chromatography-mass spectrometry workflows intended to steroid profiling by providing a new separation dimension and a novel characterization parameter, the so-called collision cross section (CCS). This work proposes the first CCS database for 300 steroids (i.e., endogenous, including phase I and phase II metabolites, and exogenous synthetic compounds), which involves 1080 ions and covers the CCS of 127 androgens, 84 estrogens, 50 corticosteroids, and 39 progestagens. This large database provides information related to all the ionized species identified for each steroid in positive electrospray ionization mode as well as for estrogens in negative ionization mode. CCS values have been measured using nitrogen as drift gas in the ion mobility cell. Generally, direct correlation exists between mass-to-charge ratio ( m/ z) and CCS because both are related parameters. However, several steroids mainly steroid glucuronides and steroid esters have been characterized as more compact or elongated molecules than expected. In such cases, CCS results in additional relevant information to retention time and mass spectral data for the identification of steroids. Moreover, several isomeric steroid pairs (e.g., 5β-androstane-3,17-dione and 5α-androstane-3,17-dione) have been separated based on their CCS differences. These results indicate that adding the CCS to databases in analytical workflows increases selectivity, thus improving the confidence in steroids analysis. Consequences in terms of identification and quantification are discussed. Quality criteria and a construction of an interlaboratory reproducibility approach are also reported for the obtained CCS values. The CCS database described here is made publicly available.

Regulation of TRP channels by steroids: Implications in physiology and diseases.

PubMed

Kumar, Ashutosh; Kumari, Shikha; Majhi, Rakesh Kumar; Swain, Nirlipta; Yadav, Manoj; Goswami, Chandan

2015-09-01

While effects of different steroids on the gene expression and regulation are well established, it is proven that steroids can also exert rapid non-genomic actions in several tissues and cells. In most cases, these non-genomic rapid effects of steroids are actually due to intracellular mobilization of Ca(2+)- and other ions suggesting that Ca(2+) channels are involved in such effects. Transient Receptor Potential (TRP) ion channels or TRPs are the largest group of non-selective and polymodal ion channels which cause Ca(2+)-influx in response to different physical and chemical stimuli. While non-genomic actions of different steroids on different ion channels have been established to some extent, involvement of TRPs in such functions is largely unexplored. In this review, we critically analyze the literature and summarize how different steroids as well as their metabolic precursors and derivatives can exert non-genomic effects by acting on different TRPs qualitatively and/or quantitatively. Such effects have physiological repercussion on systems such as in sperm cells, immune cells, bone cells, neuronal cells and many others. Different TRPs are also endogenously expressed in diverse steroid-producing tissues and thus may have importance in steroid synthesis as well, a process which is tightly controlled by the intracellular Ca(2+) concentrations. Tissue and cell-specific expression of TRP channels are also regulated by different steroids. Understanding of the crosstalk between TRP channels and different steroids may have strong significance in physiological, endocrinological and pharmacological context and in future these compounds can also be used as potential biomedicine. Copyright © 2014 Elsevier Inc. All rights reserved.

GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid schizophrenia: A post-mortem study.

PubMed

Steiner, Johann; Brisch, Ralf; Schiltz, Kolja; Dobrowolny, Henrik; Mawrin, Christian; Krzyżanowska, Marta; Bernstein, Hans-Gert; Jankowski, Zbigniew; Braun, Katharina; Schmitt, Andrea; Bogerts, Bernhard; Gos, Tomasz

2016-11-01

Glutamic acid decarboxylase (GAD) is a key enzyme in GABA synthesis and alterations in GABAergic neurotransmission related to glial abnormalities are thought to play a crucial role in the pathophysiology of schizophrenia. This study aimed to identify potential differences regarding the neuropil expression of GAD between paranoid and residual schizophrenia. GAD65/67 immunostained histological sections were evaluated by quantitative densitometric analysis of GAD-immunoreactive (ir) neuropil. Regions of interest were the hippocampal formation (CA1 field and dentate gyrus [DG]), superior temporal gyrus (STG), and laterodorsal thalamic nucleus (LD). Data from 16 post-mortem schizophrenia patient samples (10 paranoid and 6 residual schizophrenia cases) were compared with those from 16 matched controls. Overall, schizophrenia patients showed a lower GAD-ir neuropil density (P=0.014), particularly in the right CA1 (P=0.033). However, the diagnostic subgroups differed significantly (P<0.001), mainly because of lower right CA1 GAD-ir neuropil density in paranoid versus residual patients (P=0.036) and controls (P<0.003). Significant GAD-ir neuropil reduction was also detected in the right STG layer V of paranoid versus residual schizophrenia cases (P=0.042). GAD-ir neuropil density correlated positively with antipsychotic dosage, particularly in CA1 (right: r=0.850, P=0.004; left: r=0.800, P=0.010). Our finding of decreased relative density of GAD-ir neuropil suggests hypofunction of the GABAergic system, particularly in hippocampal CA1 field and STG layer V of patients with paranoid schizophrenia. The finding that antipsychotic medication seems to counterbalance GABAergic hypofunction in schizophrenia patients suggests the possibility of exploring new treatment avenues which target this system. Copyright © 2016 Elsevier B.V. All rights reserved.