Effects of Sodium Valproate on Corticotropin-Releasing Factor Systems in Rat Brain

Stout, Steven C.; Owens, Michael J.; Lindsey, Kimberly P.; Knight, David L; Nemeroff, Charles B.

doi:10.1016/s0893-133x(00)00243-8

Cited by 32 publications

(17 citation statements)

References 32 publications

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“…Preliminary trials and previous work (Stout et al, 2001) indicated that rather high doses of valproic acid were needed to achieve such levels due to the extremely short half-life of valproate in the rat (ϳ17 min). Both valproate and lithium administration were associated with decreased weight gain compared with control groups over the course of the experiment.…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary experiments from our laboratory suggest that subchronic (7-day) treatment with VPA alters CRF neuronal systems (Stout et al, 2001). In the present study, we sought to more thoroughly test the hypothesis that the mood-altering effects of chronic (Ն2 weeks) VPA may be partially attributed to its effects on CRF neuronal systems, and to compare these effects to those of lithium.…”

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confidence: 99%

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The Effects of Chronic Treatment with the Mood Stabilizers Valproic Acid and Lithium on Corticotropin-Releasing Factor Neuronal Systems

Gilmor¹,

Skelton²,

Nemeroff³

et al. 2003

J Pharmacol Exp Ther

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Corticotropin-releasing factor (CRF) plays a preeminent role in coordinating the endocrine, autonomic, and behavioral responses to stress. Dysregulation of both hypothalamic and extrahypothalamic CRF systems have been reported in patients with major depression and post-traumatic stress disorder. Moreover, effective treatment of these conditions leads to normalization of these CRF systems. Although there is virtually no data concerning alterations of CRF systems in bipolar disorder (manic depressive illness), previous work indicates that valproic acid, an anticonvulsant also effective in the treatment of acute mania, alters central CRF neuronal systems. In the current studies, we chronically administered valproic acid and lithium, two clinically effective mood stabilizers, in nonstressed rats to extend our previous findings. Chronic valproic acid administration decreased CRF mRNA expression in the paraventricular nucleus of the hypothalamus; lithium administration increased CRF mRNA expression in the central nucleus of the amygdala. Although valproic acid increased CRF 1 receptor mRNA expression in the cortex, CRF 1 receptor binding was decreased in both the basolateral amygdala and cortex, suggesting that chronic valproate treatment may in fact dampen the overall tone in this central stress pathway. Valproate treatment decreased CRF 2A mRNA expression in both the lateral septum and hypothalamus, although CRF 2A receptor binding was unchanged. Lithium administration decreased CRF 1 mRNA expression in both the amygdala and frontal cortex, but CRF 1 receptor binding also remained unchanged. These results suggest that the therapeutic actions of these mood stabilizers may, in part, result from their actions on central CRF neuronal systems. The distinct actions of each drug on CRF systems may underlie their synergistic clinical effects.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Effects of Chronic Treatment with the Mood Stabilizers Valproic Acid and Lithium on Corticotropin-Releasing Factor Neuronal Systems

Gilmor¹,

Skelton²,

Nemeroff³

et al. 2003

J Pharmacol Exp Ther

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“…Blood valproic acid levels were 42 Ϯ 6 mg/l. This level may not reflect the average daily level of valproic acid because the half-life of valproic acid is Ͻ0.5 hr in rats (Yoshioka et al, 2000;Stout et al, 2001).…”

Section: Methodsmentioning

confidence: 98%

Mood Stabilizer Valproate Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis

Hao¹,

Creson²,

Zhang³

et al. 2004

J. Neurosci.

377

300

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Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproateinduced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness.

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“…Likewise, GABAergic agents may affect CRH mRNA expression within limbic sites (Skelton et al, 2000;Stout et al, 2001;Gilmor et al, 2003). Thus, we assessed CRH peptide levels, and both CRH 1 and CRH 2 receptor mRNAs, because they may be differentially involved in depression.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation in the Suicide Brain: mRNA Expression of Corticotropin-Releasing Hormone Receptors and GABA_AReceptor Subunits in Frontal Cortical Brain Region

Merali¹,

Du²,

Hrdina³

et al. 2004

J. Neurosci.

359

225

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Corticotropin-releasing hormone (CRH) and GABA have been implicated in depression, and there is reason to believe that GABA may influence CRH functioning. The levels of CRH, and mRNA for CRH-binding protein, CRH 1 , and CRH 2 receptors, as well as various GABA A receptor subunits (␣1, ␣2, ␣3, ␣4, ␣5, ␦, and ␥2), were determined in several frontal cortical brain regions of depressed suicide victims and nondepressed individuals who had not died by suicide. Relative to the comparison group, CRH levels were elevated in frontopolar and dorsomedial prefrontal cortex, but not in the ventrolateral prefrontal cortex of suicide victims. Conversely, using quantitative PCR analyses, it was observed that, in frontopolar cortex, mRNA for CRH 1 , but not CRH 2 , receptors were reduced in suicide brains, possibly secondary to the high levels of CRH activity. In addition, mRNA of the ␣1, ␣3, ␣4, and ␦ receptor subunits was reduced in the frontopolar region of suicide victims. Interestingly, a partial analysis of the GABA A receptor functional genome revealed high cross-correlations between subunit expression in cortical regions of nondepressed individuals, suggesting a high degree of coordinated gene regulation. However, in suicide brains, this regulation was perturbed, independent of overall subunit abundance. These findings raise the possibility that the CRH and GABA A receptor subunit changes, or the disturbed coordination between these GABA A receptor subunits, contribute to depression and/or suicidality or are secondary to the illness/distress associated with it.

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Effects of Sodium Valproate on Corticotropin-Releasing Factor Systems in Rat Brain

Cited by 32 publications

References 32 publications

The Effects of Chronic Treatment with the Mood Stabilizers Valproic Acid and Lithium on Corticotropin-Releasing Factor Neuronal Systems

The Effects of Chronic Treatment with the Mood Stabilizers Valproic Acid and Lithium on Corticotropin-Releasing Factor Neuronal Systems

Mood Stabilizer Valproate Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis

Dysregulation in the Suicide Brain: mRNA Expression of Corticotropin-Releasing Hormone Receptors and GABA_AReceptor Subunits in Frontal Cortical Brain Region

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Effects of Sodium Valproate on Corticotropin-Releasing Factor Systems in Rat Brain

Cited by 32 publications

References 32 publications

The Effects of Chronic Treatment with the Mood Stabilizers Valproic Acid and Lithium on Corticotropin-Releasing Factor Neuronal Systems

The Effects of Chronic Treatment with the Mood Stabilizers Valproic Acid and Lithium on Corticotropin-Releasing Factor Neuronal Systems

Mood Stabilizer Valproate Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis

Dysregulation in the Suicide Brain: mRNA Expression of Corticotropin-Releasing Hormone Receptors and GABAAReceptor Subunits in Frontal Cortical Brain Region

Contact Info

Product

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Dysregulation in the Suicide Brain: mRNA Expression of Corticotropin-Releasing Hormone Receptors and GABA_AReceptor Subunits in Frontal Cortical Brain Region