Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few and often contradictory reports exist on the long-term neurobiological consequences of cannabinoid consumption in adolescents. The endocannabinoid system plays an important role during the different stages of brain development as cannabinoids influence the release and action of different neurotransmitters and promote neurogenesis. This study tested whether long-lasting interference by cannabinoids with the developing endogenous cannabinoid system during adolescence caused persistent behavioral alterations in adult rats. Adolescent female and male rats were treated with increasing doses of Delta(9)-tetrahydrocannabinol (THC) for 11 days (postnatal day (PND) 35-45) and left undisturbed until adulthood (PND 75) when behavioral and biochemical assays were carried out. CB1 receptor level and CB1/G-protein coupling were significantly reduced by THC exposure in the amygdala (Amyg), ventral tegmental area (VTA) and nucleus accumbens (NAc) of female rats, whereas male rats had significant alterations only in the amygdala and hippocampal formation. Neither female nor male rats showed any changes in anxiety responses (elevated plus maze and open-field tests) but female rats presented significant 'behavioral despair' (forced swim test) paralleled by anhedonia (sucrose preference). In contrast, male rats showed no behavioral despair but did present anhedonia. This different behavioral picture was supported by biochemical parameters of depression, namely CREB alteration. Only female rats had low CREB activity in the hippocampal formation and prefrontal cortex and high activity in the NAc paralleled by increases in dynorphin expression. These results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimuli.
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PMID:Chronic delta 9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats: behavioral and biochemical correlates. 1817 30

Disturbed sleep is one of the hallmark signs of depression. After successful treatment, many of these signs disappear; however, changes in rapid eye movement (REM) sleep may persist and even predict recurrence of depression. High-risk studies have established these alterations to be not only biological scars but true endophenotypes for depression. REM sleep changes are mediated by the noradrenergic, serotonergic, and cholinergic systems and are under strong genetic control. REM sleep has a crucial role for brain maturation and is inhibited during ontogeny. Lack of this inhibition may predispose an individual to depression. Findings regarding the CREB gene support REM sleep's role in depression. The combination of psychopathology and neurobiological measures, such as REM sleep parameters, will help to improve genetic studies and therefore increase the knowledge of relevant pathways for depression. This could facilitate development of preventive and therapeutic measures.
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PMID:Rapid eye movement (REM) sleep: an endophenotype for depression. 1822 28

Previous research has shown that cAMP response element (CRE) binding protein (CREB) in the nucleus accumbens gates behavioral responses to emotional stimuli. For example, overexpression of CREB decreases anxiety, sucrose preference, and sensitivity to drugs of abuse and increases depression-like behavior, whereas blocking CREB via overexpression of inducible cAMP early repressor (ICER) or other dominant-negative inhibitors of CRE-mediated transcription has the opposite effects. However, CREB and ICER are but two members of a larger family of leucine zipper-containing transcription factors composed of multiple products of the creb, crem (cAMP response element modulator), and atf (activating transcription factor) genes. We demonstrate here that ATF2, ATF3, and ATF4 are each robustly induced in the nucleus accumbens and dorsal striatum by restraint stress or by amphetamine administration. In contrast, little induction is seen for ATF1 or CREM. Using viral-mediated gene transfer, we show that ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressant-like responses, a behavioral phenotype similar to that caused by dominant-negative antagonists of CREB. In contrast, ATF3 or ATF4 overexpression in nucleus accumbens decreases emotional reactivity and increases depression-like behavior, consistent with the behavioral phenotype induced by CREB. Because amphetamine and stress induce ATF2, ATF3, and ATF4 in nucleus accumbens, and overexpression of these transcription factors in this brain region in turn alters behavioral responsiveness to amphetamine and stress, our findings support novel roles for these ATF family members in regulating emotional behavior.
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PMID:Induction of activating transcription factors (ATFs) ATF2, ATF3, and ATF4 in the nucleus accumbens and their regulation of emotional behavior. 1830 37

Recent clinical neuroimaging studies have revealed the possible relation between morphological brain changes, and memory, cognitive impairment in the course of alcoholism and depression. In the previous studies, we have been analyzing the mechanism of neural network disruption by ethanol using postmortem human brain and cultured cells, and identified the sensitive effect of ethanol on the neural stem cell (NSC) differentiation rather than the influence on neuronal cell survival. Furthermore, to develop a novel method for reconstruction of the neural network damaged by ethanol, we tried to analyze the usefulness of intravenous NSC transplantation in fetal alcohol syndrome spectrum disorder (FASD) model rats. In the in vitro studies, we have found the suppressive effect of ethanol on NSC differentiation to neurons, through alteration of transcription factor, CREB and NRSF/REST activities, by the cellular signaling cascade changes including trophic factors and endoplasmic reticulum (ER) function. In the in vivo studies, we have shown the effective migration of labeled NSCs into the brain of FASD model rats, and revealed the therapeutic potential of this transplantation for the treatment of anxiety/cognitive dysfunction and behavioral abnormalities in alcohol-induced brain neural network damage. We are going to the next step for analysis of transplanted NSC dynamics in the brain, which must play a pivotal role in the effective induction of behavioral recoveries.
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PMID:[Neural network abnormalities caused by alcohol: approach for repair using neural stem cells]. 1851 85

The plasticity hypothesis of major depression states that glucocorticoids may be detrimental to neuronal plasticity while monoamines and antidepressants may reconstitute cellular plasticity. The aim of the present study was to investigate how dexamethasone, a synthetic glucocorticoid, and norepinephrine, both of which are involved in depression, interact to affect aspects of neuronal plasticity. Dexamethasone and norepinephrine administered separately oppositely affected differentiation of human neuroblastoma SH-SY5Y cells, observed by both morphological alterations and gene expression, at the level of mRNA and protein of the differentiation markers Gap-43, L1 and laminin. Norepinephrine increased differentiation, manifested as an increase in neurite length, neurite number, and gene expression, while dexamethasone reduced these parameters. Opposite effects were also observed in the expression of the transcription factor CREB with norepinephrine upregulating phosphorylated CREB (pCREB) levels, while dexamethasone downregulated CREB mRNA and protein levels, as well as pCREB levels. Interestingly, co-administration of dexamethasone and norepinephrine resulted in morphology more differentiated than control and similar to that induced by norepinephrine, albeit to a lesser degree. The alterations in the expression of the differentiation markers induced by norepinephrine or dexamethasone treatments were mostly annulled by the co-treatment. However, pCREB levels were robustly enhanced by co-treatment, as compared to both control and norepinephrine treated cells, providing a possible explanation for the morphological increase in differentiation. These results suggest that in order for cells to combat the deleterious effects of glucocorticoids, a hyperactivation of pCREB may be necessary to restore differentiation and plasticity.
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PMID:Norepinephrine-glucocorticoids interaction does not annul the opposite effects of the individual treatments on cellular plasticity in neuroblastoma cells. 1876 82

Platelet-derived growth factor (PDGF) beta receptor activation inhibits N-methyl-d-aspartate (NMDA)-evoked currents in hippocampal and cortical neurons via the activation of phospholipase Cgamma, PKC, the release of intracellular calcium, and a rearrangement of the actin cytoskeleton. In the hippocampus, the majority of NMDA receptors are heteromeric; most are composed of 2 NR1 subunits and 2 NR2A or 2 NR2B subunits. Using NR2B- and NR2A-specific antagonists, we demonstrate that PDGF-BB treatment preferentially inhibits NR2B-containing NMDA receptor currents in CA1 hippocampal neurons and enhances long-term depression in an NR2B subunit-dependent manner. Furthermore, treatment of hippocampal slices or cultures with PDGF-BB decreases the surface localization of NR2B but not of NR2A subunits. PDGFbeta receptors colocalize to a higher degree with NR2B subunits than with NR2A subunits. After neuronal injury, PDGFbeta receptors and PDGF-BB are up-regulated and PDGFbeta receptor activation is neuroprotective against glutamate-induced neuronal damage in cultured neurons. We demonstrate that the neuroprotective effects of PDGF-BB are occluded by the NR2B antagonist, Ro25-6981, and that PDGF-BB promotes NMDA signaling to CREB and ERK1/2. We conclude that PDGFbetaR signaling, by preferentially targeting NR2B receptors, provides an important mechanism for neuroprotection by growth factors in the central nervous system.
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PMID:Platelet-derived growth factor selectively inhibits NR2B-containing N-methyl-D-aspartate receptors in CA1 hippocampal neurons. 1910 10

Women in the reproductive age are more vulnerable to develop affective disorders than men. This difference may attribute to anatomical differences, hormonal influences and environmental factors such as stress. However, the higher prevalence in women normalizes once menopause is established, suggesting that ovarian hormones may play an important role in the development of depression in women. Ovarian hormones such as estrogen can pass the brain-blood barrier and bind to cytoplasmatic estrogen receptor (ER)-alpha and ER-beta in different areas of the limbic system. During stress, estrogen can modulate the behavioral and neurobiological response depending on the concentrations of estrogen. In this review we present evidence for disparate effects of chronic stress on neuroplasticity and brain activity in male and female rats. Furthermore, we will demonstrate that effects of social support on coping with stress can be mimicked by social housing of rats and that this model can be used for identification of underlying neurobiological mechanisms, including behavior, phosphorylation of CREB and ERK1/2, and brain activity changes as measured with fos expression. Using cyclic administration of estrogen in ovariectomized female rats we could specifically address effects of different plasma estrogen levels and antidepressants on stress-induced neuroplasticity and activity changes. In this model we also studied effects of estrogen on recovery after chronic stress. We conclude that the female brain has a different innate strategy to handle stress than the male brain and that female animal models are necessary for studying the underlying mechanisms and options for treatment.
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PMID:Sex differences in stress responses: focus on ovarian hormones. 1927 10

alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are responsible for excitotoxicity induced by ischemic injury in hippocampal CA1 neurons, whereas the molecular mechanisms responsible for their neurotrophic activities are much less studied. Here, we examined the neuroprotective effect of positive modeulation of AMPARs by coapplication of AMPA with PEPA, an allosteric potentiator of AMPARs. We showed that coapplication of AMPA with PEPA protected hippocampal CA1 neurons from brain ischemia-induced death. Coapplication of AMPA with PEPA could prevent downregulated expression of GluR2 subunit caused by ischemia and increase BDNF expression via Lyn-ERK1/2-CREB signaling. Furthermore, TrkB receptor-mediated PI3K/Akt signal pathway was activated after coapplication of AMPA with PEPA, which was related to MAPK pathway and protected CA1 neurons against ischemic insults through depression of JNK3 activity, release of cytochrome c to cytosol and depression of capase-3 activity. Our results revealed that positive modulation of AMPARs could exert neuroprotective effects and the possible signaling pathways underlied.
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PMID:Positive modulation of AMPA receptors prevents downregulation of GluR2 expression and activates the Lyn-ERK1/2-CREB signaling in rat brain ischemia. 1933 Aug 48

We recently have found that an acute application of the neurosteroid pregnenolone sulfate (PREGS) at 50 muM to rat hippocampal slices induces a long-lasting potentiation (LLP(PREGS)) via a sustained ERK2/CREB activation at perforant-path/granule-cell synapses in the dentate gyrus. This study is a follow up to investigate whether the expression of LLP(PREGS) influences subsequent frequency-dependent synaptic plasticity. Conditioning electric stimuli (CS) at 0.1-200 Hz were given to the perforant-path of rat hippocampal slices expressing LLP(PREGS) to induce long-term potentiation (LTP) and long-term depression (LTD). The largest LTP was induced at about 20 Hz-CS, which is normally a subthreshold frequency, and the largest LTD at 0.5 Hz-CS, resulting in a leftward-shift of the LTP/LTD-frequency curve. Furthermore, the level of LTP at 100 Hz-CS was significantly attenuated to give band-pass filter characteristics of LTP induction with a center frequency of about 20 Hz. The LTP induced by 20 Hz-CS (termed 20 Hz-LTP) was found to be postsynaptic origin and dependent on L-type voltage-gated calcium channel (L-VGCC) but not on N-methyl-D-aspartate receptor (NMDAr). Moreover, the induction of 20 Hz-LTP required a sustained activation of ERK2 that had been triggered by PREGS. In conclusion, the transient elevation of PREGS is suggested to induce a modulatory metaplasticity through a sustained activation of ERK2 in an L-VGCC dependent manner.
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PMID:Modulatory metaplasticity induced by pregnenolone sulfate in the rat hippocampus: a leftward shift in LTP/LTD-frequency curve. 1947 51

Although it is a widely studied psychiatric syndrome, major depressive disorder remains a poorly understood illness, especially with regard to the disconnect between treatment initiation and the delayed onset of clinical improvement. We have recently validated chronic social defeat stress in mice as a model in which a depression-like phenotype is reversed by chronic, but not acute, antidepressant administration. Here, we use chromatin immunoprecipitation (ChIP)-chip assays--ChIP followed by genome wide promoter array analyses--to study the effects of chronic defeat stress on chromatin regulation in the mouse nucleus accumbens (NAc), a key brain reward region implicated in depression. Our results demonstrate that chronic defeat stress causes widespread and long-lasting changes in gene regulation, including alterations in repressive histone methylation and in phospho-CREB (cAMP response element-binding protein) binding, in the NAc. We then show similarities and differences in this regulation to that observed in another mouse model of depression, prolonged adult social isolation. In the social defeat model, we observed further that many of the stress-induced changes in gene expression are reversed by chronic imipramine treatment, and that resilient mice-those resistant to the deleterious effects of defeat stress-show patterns of chromatin regulation in the NAc that overlap dramatically with those seen with imipramine treatment. These findings provide new insight into the molecular basis of depression-like symptoms and the mechanisms by which antidepressants exert their delayed clinical efficacy. They also raise the novel idea that certain individuals resistant to stress may naturally mount antidepressant-like adaptations in response to chronic stress.
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PMID:Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models. 1953 94


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