Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA(A) receptor agonist 3,21-dihydropregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g., increased anxiety, an exaggerated adrenocortical secretory response to stress, impaired responsiveness to glucocorticoid feedback, and altered transcription of the genes encoding corticotropin-releasing hormone (CRH) in the hypothalamus and glucocorticoid receptors in the hippocampus. These data indicate that neuroactive steroid derivatives with GABA-agonistic properties may exert persisting stress-protective effects in the developing brain, and may form the basis for therapeutic agents which have the potential to prevent mental disorders resulting from adverse experience during neonatal life.
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PMID:Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events. 906 54

The involvement of endogenous benzodiazepine octadecaneuropeptide in the regulation of corticotropin-releasing hormone messenger RNA expression has been studied using in situ hybridization technique. Intracerebroventricular injection of octadecaneuropeptide (4 microg/kg) induced a 26% decrease in the corticotropin-releasing hormone messenger RNA expression in the hypothalamic paraventricular nucleus. Concomitant injection of octadecaneuropeptide and i.p. injection of the GABA(A) receptor agonist muscimol (4 mg/kg) potentiated the corticotropin-releasing hormone messenger RNA decrease ( - 34%). The depressing effect of octadecaneuropeptide on corticotropin-releasing hormone gene expression was totally reversed by pretreatment of the animals with the GABA(A) receptor antagonist picrotoxin (5 mg/kg; i.p.) or by pretreatment with the benzodiazepine receptor antagonist flumazenil (4 mg/kg; i.p.). To determine the reciprocal involvement of adrenal and sexual steroids in this regulation, animals are adrenalectomized and/or castrated. Adrenalectomy reversed the effect induced by octadecaneuropeptide, which increased corticotropin-releasing hormone messenger RNA expression (+21%), while castration did not modify the negative influence of octadecaneuropeptide. When rats were adrenalectomized and castrated, the adrenalectomy influence was predominant, since octadecaneuropeptide increased significantly the hybridization signal (+18%). The involvement of neurosteroids, especially reduced metabolites of progesterone was also investigated. The concomitant injection of octadecaneuropeptide and subcutaneous injection of the 5alpha-reductase inhibitor MK-906 (14 mg/kg) to adrenalectomized and castrated rats, reduced significantly by 60% the increase of corticotropin-releasing hormone messenger RNA expression induced by octadecaneuropeptide. These results indicate that in vivo the endogenous benzodiazepine octadecaneuropeptide, via an activation of the benzodiazepine sites of the GABA(A) receptor, negatively modulates corticotropin-releasing hormone neuronal activity and that this modulation can be negatively or positively influenced by central and peripheral steroids.
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PMID:The octadecaneuropeptide-induced response of corticotropin-releasing hormone messenger RNA levels is mediated by GABA(A) receptors and modulated by endogenous steroids. 962 52

Dual hybridization histochemical studies were conducted to investigate the extent of colocalization of mRNA transcripts encoding the alpha1-2 and beta1-3 subunits of the gamma aminobutyric acid (GABA)(A) receptor with those for corticotropin-releasing hormone (CRH) within the rat hypothalamic paraventricular nucleus (PVN). A vast majority of CRH neurons (>94.5%) were found to express transcripts specific for the the alpha2, beta1 and beta3 subunits; mRNAs for the alpha1 and beta2 subunits of the GABA(A) receptor were detected within 53.3% and 65.7% of PVN CRH neurons, respectively. The results may have important implications for studies aimed at understanding GABAergic influences upon the hypothalamic-pituitary-adrenocortical (HPA) axis. Hypophysiotropic CRH neurons serve as the origin of the final common pathway for glucocorticoid secretion in response to stressful stimuli, and GABAergic afferents have been implicated in afferent control of these neurons. The subunit composition of GABA(A) receptors at this key regulatory locus may affect the efficacy of a major inhibitory input, and thus the magnitude and/or duration of stress-induced glucocorticoid secretion. The present findings reveal basal expression patterns of transcripts encoding several subunits of the GABA(A) receptor within stress-integrative CRH neurons, data which may be used to guide regulatory studies of GABAergic influences on the HPA axis under a variety of conditions.
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PMID:GABA(A) receptor subunit expression within hypophysiotropic CRH neurons: a dual hybridization histochemical study. 1072 9

1. Whole-cell patch clamp recordings were made from rat rostral ventromedial medulla (RVM) neurons in vitro to investigate the cellular actions of the opioid-like receptor ORL1 (NOP), ligand nociceptin/orphanin FQ and other putative prepronociceptin products. 2. Primary and secondary RVM neurons were identified as responding to the kappa-opioid receptor agonist U-69593 (300 nM to 1 microM) and the mu- and delta-opioid receptor agonist met-enkephalin (10 microM), respectively. Both primary and secondary RVM neurons responded to nociceptin (3 nM to 1 microM) with an outward current that reversed polarity at -115 mV in brain slices and with inhibition of Ca(2+) channel currents in acutely isolated cells. 3. The putative ORL1 antagonist J-113397 (1 microM) produced no change in membrane current and abolished the outward current produced by nociceptin (100 nM). In contrast, Phe(1)psi(CH(2)-NH)Gly(2)]-nociceptin-(1-13)NH(2) (300 nM to 1 microM) alone produced an outward current and partially reduced the outward current produced by nociceptin (300 nM) when co-applied. 4. In brain slices nociceptin (300 nM) reduced the amplitude of evoked GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) but not non-NMDA receptor-mediated excitatory postsynaptic currents (EPSCs). 5. Met-enkephalin (10 microM), but not nociceptin (300 nM), reduced the rate of spontaneous miniature IPSCs in normal external potassium solution (K(+) 2.5 mM). In high external potassium (K(+) 17.5 mM), nociceptin reduced the rate of miniature IPSCs in the presence (Ca(2+) 2.4 mM, Mg(2+) 1.2 mM) but not in the absence of external calcium (Ca(2+) 0 mM, Mg(2+) 10 mM, Cd(2+) 10 microM). Nociceptin and met-enkephalin had no effect on the amplitude of miniature IPSCs. 6. The putative nociceptin precursor products nocistatin (rat prepronociceptin(125-132)) and rat prepronociceptin(154-181) had no effect on membrane currents, evoked IPSCs and evoked EPSCs. 7. These results indicate that nociceptin acts via the ORL1 receptor to directly inhibit both primary and secondary RVM neurons by activating a potassium conductance and by inhibiting calcium conductances. In addition, nociceptin inhibits GABA release within the RVM via a presynaptic Ca(2+)-dependent mechanism. Thus, nociceptin has the potential to exert both disinhibitory and inhibitory effects on neuronal action potential firing within the RVM.
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PMID:Actions of nociceptin/orphanin FQ and other prepronociceptin products on rat rostral ventromedial medulla neurons in vitro. 1148 14

To examine the role of the GABA(A) receptor mediating systems in the control of gonadotropin-releasing hormone (GnRH) release from the ventromedial-infundibular region (VEN/IN) of anestrous ewes, the extracellular concentrations of GnRH, beta-endorphin, noradrenaline (NE), dopamine (DA), 4-hydroxy-3-methoxy-phenylglycol (MHPG) and 3,4-dihydroxy-phenylacetic acid (DOPAC) were quantified during local stimulation or blockade of GABA(A) receptors with muscimol or bicuculline respectively. In most animals stimulation of GABA(A) receptors significantly attenuates GnRH release with concomitant increase of beta-endorphin and DA release, and MHPG and DOPAC levels. Blockade of the GABA(A) receptors generally did not affect GnRH and NE release but inhibited in most animals beta-endorphin release and decreased dopaminergic activity. These results suggest, that GABA may suppress GnRH release directly by GABA(A) receptor mechanism on the axon terminal of GnRH neurons or indirectly by GABA(A) receptor processes activating beta-endorphin-ergic and dopaminergic neurons in the VEN/NI. On the basis of these results in could not be distinguish between these two events. The decrease in extracellular beta-endorphin and dopamine concentration without evident changes in the GnRH level during GABA(A) receptor blockade may suggest that other neuronal systems are involved in this effect.
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PMID:The involvement of GABA(A) receptors in the control of GnRH and beta-endorphin release, and catecholaminergic activity in the ventromedial-infundibular region of hypothalamus in anestrous ewes. 1159 66

To examine the role of GABA(A) receptor mediating systems in the control of gonadotropin-releasing hormone (GnRH) release from the ventromedial-infundibular region (VEN/NI) in ewes during luteal phase, the extracellular concentrations of GnRH, beta-endorphin, noradrenaline (NE), dopamine (DA), and their metabolites: MHPG and DOPAC were quantified by local stimulation or blockade of GABA(A) receptors with muscimol or bicuculline, respectively. Stimulation of GABA(A) receptors in the VEN/NI did not affect GnRH, beta-endorphin release or catecholaminergic system activity. Blockade of GABA(A) receptors decreased beta-endorphinergic and dopaminergic activity, and lowered the extracellular concentration of MHPG. It did not affect GnRH release or luteinizing hormone (LH) secretion. It is suggested that progesterone-induced GABAergic activity during the luteal phase may desensitize GABA(A) receptors to muscimol. Lack of changes in GnRH/LH secretion with concomitant depressed beta-endorphinergic activity corroborated the conclusion that beta-endorphin does not inhibit GnRH release from the VEN/NI during the luteal phase. The physiological significance of changes in the catecholaminergic system activity under GABA(A) receptor blockade in the control of GnRH secretion awaits to be established.
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PMID:The role of GABA(A) receptors in the neural systems of the ventromedial-infundibular region of the hypothalamus in the control of gonadotropin release during the luteal phase in ewes. 1251 Aug 67

To examine the role of gamma-aminobutyric acid (GABA)(A) receptor mediating systems in the control of gonadotropin-releasing hormone (GnRH) release from the medial preoptic area (MPOA) of ewes during the follicular phase of the estrous cycle, the extracellular concentrations of GnRH, beta-endorphin, noradrenaline (NE), dopamine (DA), 4-hydroxy-3-methoxy-phenyl-glycol (MHPG) and 3,4-dihydroxy-phenylacetic acid (DOPAC) were quantified during the local infusion of muscimol and bicuculline (agonist and antagonist of GABA(A) receptors, respectively) to this structure. Stimulation of GABA(A) receptors markedly attenuated GnRH release, increased beta-endorphin release and noradrenergic system activity in the MPOA. The decrease of the luteinizing hormone (LH) concentration in blood plasma and LH pulse amplitude suggests that a GABA(A) receptor agonist in the MPOA also suppresses GnRH release from the GnRH axon terminals in the ventromedial hypothalamus/nucleus infundibularis region (VEN/NI). Blockade of GABA(A) receptors had no evident effect on GnRH/LH secretion but decreased beta-endorphin release and increased the extracellular DOPAC concentration. The suppressive influence of muscimol in the MPOA on GnRH release might be considered a net result of its direct inhibitory effect on GnRH release, indirect inhibitory influence on GnRH release through activation of the beta-endorphinergic system, and facilitation of GnRH neurons by increasing noradrenaline release. The results obtained during bicuculline perfusion on these systems' activity are not sufficiently consistent to provide a clear understanding of the lack of changes in the GnRH/LH release under blockade of GABA(A) receptors. We conclude that the MPOA in ewes during the follicular phase is an important regulatory site where stimulation of GABA(A) receptors both decreases GnRH secretion and increases beta-endorphin release.
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PMID:The role of GABA(A) receptors in the neural systems of the medial preoptic area in the control of GnRH release in ewes during follicular phase. 1265 29

Negative energy balance inhibits fertility by decreasing GnRH release; however, the mechanisms are not well understood. GnRH neurons can be excited by activation of gamma-aminobutyric acid (GABA)(A) receptors, and GABAergic neurons provide a major synaptic input. We hypothesized that permissive metabolic signals mediated by leptin and inhibitory signals conveyed by neuropeptide Y (NPY) and opiates rapidly alter GABA(A) receptor-mediated drive to GnRH neurons. In fed and fasted female mice, GABAergic postsynaptic currents (PSCs) were recorded from GnRH neurons before and after in vitro treatment with leptin, NPY, or met-enkephalin. Leptin increased PSC frequency in fed and fasted mice, indicating that it increased presynaptic activity. Leptin also increased PSC size. Inhibiting leptin receptor signaling pathways within GnRH neurons abolished the latter effect, indicating a direct action on these cells. In fed, but not fasted, mice, NPY and met-enkephalin decreased PSC frequency in an antagonist-reversible manner, but did not alter PSC size. NPY-1 receptor antagonists alone increased frequency in fed and fasted mice, as did opiate receptor blockade in fasted animals, suggesting that endogenous NPY and opiates modulate GABAergic drive to GnRH neurons. These data suggest that GABAergic afferents integrate metabolic signals for delivery to GnRH neurons. Decreased sensitivity to NPY and opiates in fasted mice indicate that these peptides send physiologically relevant signals regarding energy balance to GnRH neurons.
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PMID:Gamma-aminobutyric acid neurons integrate and rapidly transmit permissive and inhibitory metabolic cues to gonadotropin-releasing hormone neurons. 1464 18

Neural networks controlling food intake and energy homeostasis clearly involve proopiomelanocortin (POMC) neurons and their peptide transmitters. alpha-melanocyte-stimulating hormone from arcuate POMC neurons potently reduces food intake, whereas arcuate neuropeptide Y (NPY) neurons act in opposition to stimulate food intake. In addition to orexigenic peptides, NPY neurons also release the inhibitory neurotransmitter GABA, which can act in a local circuit to inhibit POMC neuron activity. Whether or not reciprocal inhibition could occur has not yet been determined, because the presence of a rapid neurotransmitter in POMC neurons has not been demonstrated previously. Here, we used primary cultures of fluorescently labeled POMC neurons that had formed recurrent synapses (autapses) to detect the release of neurotransmitter. When an action potential was evoked in the axon of a POMC neuron with autapses, a short-latency synaptic current was recorded in the same cell. The autaptic current was abolished by GABA(A) receptor antagonists and substantially inhibited by opioids. Double-label in situ RNA hybridization for POMC and glutamic acid decarboxylase, the GABA synthetic enzyme, revealed colocalization of mRNAs in approximately one-third of POMC neurons in vivo. Our results suggest that these neurons can exert rapid inhibitory effects via the release of GABA, in addition to the more sustained actions provided by POMC peptides. However, this rapid inhibition may not play a major role within local hypothalamic circuits, but rather is likely to be important in more distant projection areas as indicated by the colocalization of vesicular GABA transporter immunoreactivity predominantly in extrahypothalamic POMC terminals.
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PMID:GABA release from proopiomelanocortin neurons. 1497 27

This review summarizes recent developments in the field of sleep regulation, particularly in the role of hormones, and of synthetic GABA(A) receptor agonists. Certain hormones play a specific role in sleep regulation. A reciprocal interaction of the neuropeptides growth hormone (GH)-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) plays a key role in sleep regulation. At least in males GHRH is a common stimulus of non-rapid-eye-movement sleep (NREMS) and GH and inhibits the hypothalamo-pituitary adrenocortical (HPA) hormones, whereas CRH exerts opposite effects. Furthermore CRH may enhance rapid-eye-movement sleep (REMS). Changes in the GHRH:CRH ratio in favor of CRH appear to contribute to sleep EEG and endocrine changes during depression and normal ageing. In women, however, CRH-like effects of GHRH were found. Besides CRH somatostatin impairs sleep, whereas ghrelin, galanin and neuropeptide Y promote sleep. Vasoactive intestinal polypeptide appears to be involved in the temporal organization of human sleep. Beside of peptides, steroids participate in sleep regulation. Cortisol appears to promote REMS. Various neuroactive steroids exert specific effects on sleep. The beneficial effect of estrogen replacement therapy in menopausal women suggests a role of estrogen in sleep regulation. The GABA(A) receptor or GABAergic neurons are involved in the action of many of these hormones. Recently synthetic GABA(A) agonists, particularly gaboxadol and the GABA reuptake inhibitor tiagabine were shown to differ distinctly in their action from allosteric modulators of the GABA(A) receptor like benzodiazepines as they promote slow-wave sleep, decrease wakefulness and do not affect REMS.
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PMID:Neurochemical regulation of sleep. 1677 43


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