1,721,025 research outputs found
Allopregnanolone modulation of HPA axis function in the adult rat
No full textRationale GABAergic neuronal circuits regulate neuroendo- crine stress response, and the most potent positive endogenous modulator of GABAA receptor function is allopregnanolone. This neurosteroid acts in a nongenomic manner to selectively increase the inhibitory signal meditated by GABAA receptors; in addition, it also induces long-lasting changes in the expres- sion of specific GABAA receptor subunits in various brain regions, with consequent changes in receptor function. Objective The objective of this review is to summarize our findings on emotional state and stress responsiveness in three animal models in which basal brain concentrations of allopregnanolone differ. It is postulated that individual differ- ences in allopregnanolone levels can influence general resilience.
Results The results showed that there is an apparent correla- tion between endogenous levels of brain allopregnanolone and basal and stress-stimulated HPA axis activity. Conclusion The relationship between endogenous brain levels of allopregnanolone and HPA axis activity and function sustains the therapeutic potential of this neurosteroid for the treatment of stress-associated disorders
Modulation of GABA(A) receptor gene expression by allopregnanolone and ethanol
No full textExpression of specific gamma-aminobutyric acid type A (GABA(A)) receptor subunit genes in neurons is affected by endogenous modulators of receptor function such as neuroactive steroids. This effect of steroids appears to be mediated through modulation of GABA(A) receptor signalling mechanisms that control the expression of specific receptor subunit genes. Furthermore, the specific outcomes of such signalling appear to differ among neurons in different regions of the brain. Neuroactive steroids such as the progesterone metabolite allopregnanolone might thus exert differential effects on GABA(A) receptor plasticity in distinct neuronal cell populations, likely accounting for some of the physiological actions of these compounds. Here we summarise experimental data obtained both in vivo and in vitro that show how fluctuations in the concentration of allopregnanolone regulate both the expression and function of GABA(A) receptors and consequently affect behaviour. Such regulation is operative both during physiological conditions such as pregnancy and lactation as well as in pharmacologically induced states such as pseudopregnancy and long-term treatment with steroid derivatives or anxiolytic-hypnotic drugs. Accordingly, long-lasting exposure of GABA(A) receptors to ethanol, as well as its withdrawal, induces marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and ethanol in modulating the functional activity of specific neuronal populations
Vagus nerve stimulation induces cell proliferation and changes in neuronal morphology in the rat hippocampus
No full textPurpose of study: Vagus nerve stimulation (VNS) is used to treat pharmacotherapy-resistant epilepsy. Observations of mood elevation during VNS therapy for epilepsy suggested that such treatment might also show efficacy for refractory major depression. The molecular mechanism(s) underlying its therapeutic action remains unclear, however. By using a rat model of VNS we previously showed that acute VNS increases the gene expression of growth factors in the rat brain as well as the release of norepinephrine. We have now examined the effects of chronic VNS on hippocampal cell proliferation as well as on the expression of DCX and BDNF in rat brain and whether such effects might be associated with behavioral changes similar to those induced by chronic antidepressant drugs.
Methods: Male Sprague-Dawley rats were used and a VNS therapy stimulator (Cyberonics, Houston, TX) was implanted. Cell proliferation in the hippocampus of rats subjected to acute (3h) or chronic (1 month) VNS was examined by injection of bromodeoxyuridine (BrdU) and immunohistochemistry. Expression of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) was evaluated by immunofluorescence staining. Behavioral effects were studied in the forced swim and elevated plus- maze tests.
Results: Acute VNS induced an increase in the number of BrdU+ cells in the dentate gyrus that was apparent 24 h (2200±159; P < 0.05) and 3 weeks (2448±129; P < 0.01) after treatment compared with that apparent in sham-operated controls (1760±74). It also induced long- lasting increases in the amount of DCX immunoreactivity (+39%; P < 0.05) and in the number of DCX+ neurons (+57%; P<0.01). Neither the number of BrdU+ cells nor the amount of DCX immunoreactivity was increased 3 weeks after the cessation of chronic VNS. Moreover, VNS induced long-lasting increases in the amount of BDNF immunoreactivity and the number of BDNF+ cells (+104% and +40% respectively; P < 0.001). VNS also affected the dendritic complexity of DCX+ neurons in the hippocampus. Nevertheless, in contrast to chronic imipramine, chronic VNS had no effect on the behavior ofratsintheforcedswimorelevatedplus-mazetests.
Conclusions: In the hippocampus VNS induced cell proliferation and persistent changes in morphology ofDCX+ neurons. These effects were accompanied by a robust increase in the expression of BDNF, which may play an important role in consolidating the changes in neuronal connections as suggested by the increased complexity of the dendritic arborization. Thus, some of the effects of chronic VNS appear to be similar to those induced by chronic treatment with antidepressant drugs but do not correlate with corresponding behavioral changes. Although further clinical and experimental studies are necessary to better understand the mechanisms of VNS, our results show that the promotion of neurogenesis and the expression of growth factors are rapidly induced by VNS differently from antidepressant. Whether such early newly generated neurons contribute to existing or de novo networks that might mediate antiepileptic or antidepressant effects remains to be determined
Voluntary ethanol consumption alters hippocampal GABAA receptor gene expression in C57BL/6J mice
No full textEffects of withdrawal of low ethanol concentrations on GABAA receptor gene expression in rat cerebellar granule neurons in colture
No full textMorphine induces the release of CCL5 from astrocytes: Potential neuroprotective mechanism against the HIV protein gp120
No full textA number of human immunodeficiency virus type-1 (HIV) positive subjects are also opiate abusers. These individuals are at high risk to develop neurological complications. However, little is still known about the molecular mechanism(s) linking opiates and HIV neurotoxicity. To learn more, we exposed rat neuronal/glial cultures prepared from different brain areas to opiate agonists and HIV envelope glycoproteins gp120IIIB or BaL. These strains bind to CXCR4 and CCR5 chemokine receptors, respectively, and promote neuronal death. Morphine did not synergize the toxic effect of gp120IIIB but inhibited the cytotoxic property of gp120BaL. This effect was blocked by naloxone and reproduced by the mu opioid receptor agonist DAMGO. To examine the potential mechanism(s) of neuroprotection, we determined the effect of morphine on the release of chemokines CCL5 and CXCL12 in neurons, astrocytes, and microglia cultures. CCL5 has been shown to prevent gp120BaL neurotoxicity while CXCL12 decreases neuronal survival. Morphine elicited a time-dependent release of CCL5 but failed to affect the release of CXCL12. This effect was observed only in primary cultures of astrocytes. To examine the role of endogenous CCL5 in the neuroprotective activity of morphine, mixed cerebellar neurons/glial cells were immunoneutralized against CCL5 prior to morphine and gp120 treatment. In these cells the neuroprotective effect of opiate agonists was blocked. Our data suggest that morphine may exhibit a neuroprotective activity against M-tropic gp120 through the release of CCL5 from astrocytes
Vagus nerve stimulation induces cells proliferation and changes in neuronal morphology in the rat hippocampus
No full textEFFECTS OF WITHDRAWAL OF LOW ETHANOL CONCENTRATIONS ON GABA(A) RECEPTOR GENE EXPRESSION IN RAT CEREBELLAR GRANULE NEURONS IN CULTURE
No full textOne of the most likely targets of ethanol (EtOH) in the central nervous system (CNS) is the GABAA receptor (GABAAR). While the effects of EtOH have been the subject of study on most common CNS GABAAR composition, many other subunit combinations have only recently been tested for their EtOH responses. The a4b2d GABAARs are very sensitive to alcohol, with a concentration of 1 mM EtOH signifcantly enhancing GABAergic currents. Moreover, a6 and a4, when combined with b3 and d-containing subunits were associated with EtOH enhancement of function. Nevertheless, other studies were not able to obtain functional effects of low (1–30 mM) concentrations of EtOH. A plethora of studies both ‘‘in vivo’’ and ‘‘in vitro’’ show that chronic EtOH and EtOH withdrawal, can modify the gene expression of the GABAAR, but in these studies large concentrations of EtOH (50–200 mM) were used. A key question is whether GABAAR gene expression can be altered also by lower concentrations (e.g., 1–50 mM) of EtOH. In order to address this question we here used rat cerebellar granule cells in culture chronically treated with EtOH (1–100 mM). We then measured the GABAAR gene expression by RNase protection assay in two experimental conditions: After chronic EtOH (5 days) or its withdrawal (3 hours). Our results demonstrated that the only subunit affected by chronic EtOH treatment was the c2, the mRNA of which resulted decreased ()20%; p < 0.01) only at concentrations of 50 mM or higher. Neither low nor high concentrations of EtOH were able to change the gene expression of the other subunits of the GABAAR (a1, a4, a6 and d). On the contrary, EtOH withdrawal at the lowest concentration
(1 mM) significantly decreased the abundance of the a1, a6 and d subunits ()36; )26 and )16% respectively; p < 0.05), but did not change the a4 subunit mRNA abundance. Similar results were observed using 10 mM EtOH for a1, a6 and d subunits ()37; )38 and 22% respectively; p < 0.05). The a4 subunit was up-regulated only by withdrawal of 100 mM EtOH (+31%; p < 0.01). This is the first report showing that low concentrations of EtOH, such as
1 mM, can modify GABAAR gene expression. These effects were subunit specific and more evident after withdrawal, suggesting that even such low EtOH concentrations when removed may disrupt neuronal excitability controlled by GABAAR; nevertheless, the key question of whether specific GABAAR subunits are more selectively sensitive to low EtOH remains still unanswered
M-and T-tropic HIVs Promote Apoptosis in Rat Neurons
No full textNeuronal loss, reactive astrocytes, and other abnormalities are seen in the brain of individuals with acquired immune deficiency syndrome-associated Dementia Complex (ADC). Human immunodeficiency virus-1 (HIV-1) is believed to be the main agent causing ADC. However, little is known about the molecular and cellular mechanisms of HIV-1 neurotoxicity considering that HIV-1 does not infect post-mitotic neurons and that viral load does not necessarily correlate with ADC. Various viral proteins, such as the envelope protein gp120 and the transcription activator Tat, have been shown to induce neuronal apoptosis through direct and indirect mechanisms both in vitro and in vivo. Progeny HIV-1 virions can also cause neuronal death. However, it has not been fully established yet whether HIV-1 promotes neuronal apoptosis by a direct mechanism. To explore the neurotoxic effect of HIV-1, we exposed rat cerebellar granule cells and cortical neurons in culture to two different strains of HIV-1, IIIB and BaL, T- and M-tropic strains that utilize CXCR4 and CCR5 coreceptors, respectively, to infect cells. We observed that both viruses elicit a time-dependent apoptotic cell death in these cultures without inducing a productive infection as determined by the absence of the core protein of HIV-1, p24, in cell lysates. Instead, neurons were gp120 positive, suggesting that the envelope protein is shed by the virus and then subsequently internalized by neurons. The CXCR4 receptor antagonist AMD3100 or the CCR5 receptor inhibitor D-Ala-peptide T-amide blocked HIV IIIB and HIV Bal neurotoxicity, respectively. In contrast, the N-methyl-D-aspartate receptor blocker MK801 failed to protect neurons from HIV-mediated apoptosis, suggesting that HIV-1 neurotoxicity can be initiated by the viral protein gp120 binding to neuronal chemokine receptors
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