The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems

Michelle L. Gilmor, Kelly H. Skelton, Charles Nemeroff, Michael J. Owens

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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 CRF1 receptor mRNA expression in the cortex, CRF1 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 CRF2A mRNA expression in both the lateral septum and hypothalamus, although CRF2A receptor binding was unchanged. Lithium administration decreased CRF1 mRNA expression in both the amygdala and frontal cortex, but CRF1 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.

Original languageEnglish
Pages (from-to)434-439
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume305
Issue number2
DOIs
StatePublished - May 1 2003
Externally publishedYes

Fingerprint

Corticotropin-Releasing Hormone
Valproic Acid
Lithium
Messenger RNA
Therapeutics
Bipolar Disorder
Lateral Hypothalamic Area
Paraventricular Hypothalamic Nucleus
Frontal Lobe
Post-Traumatic Stress Disorders
Amygdala
Anticonvulsants
Hypothalamus
Depression

ASJC Scopus subject areas

  • Pharmacology

Cite this

The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems. / Gilmor, Michelle L.; Skelton, Kelly H.; Nemeroff, Charles; Owens, Michael J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 305, No. 2, 01.05.2003, p. 434-439.

Research output: Contribution to journalArticle

@article{09530459309147379551eb3486928e96,
title = "The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems",
abstract = "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 CRF1 receptor mRNA expression in the cortex, CRF1 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 CRF2A mRNA expression in both the lateral septum and hypothalamus, although CRF2A receptor binding was unchanged. Lithium administration decreased CRF1 mRNA expression in both the amygdala and frontal cortex, but CRF1 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.",
author = "Gilmor, {Michelle L.} and Skelton, {Kelly H.} and Charles Nemeroff and Owens, {Michael J.}",
year = "2003",
month = "5",
day = "1",
doi = "10.1124/jpet.102.045419",
language = "English",
volume = "305",
pages = "434--439",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems

AU - Gilmor, Michelle L.

AU - Skelton, Kelly H.

AU - Nemeroff, Charles

AU - Owens, Michael J.

PY - 2003/5/1

Y1 - 2003/5/1

N2 - 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 CRF1 receptor mRNA expression in the cortex, CRF1 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 CRF2A mRNA expression in both the lateral septum and hypothalamus, although CRF2A receptor binding was unchanged. Lithium administration decreased CRF1 mRNA expression in both the amygdala and frontal cortex, but CRF1 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.

AB - 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 CRF1 receptor mRNA expression in the cortex, CRF1 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 CRF2A mRNA expression in both the lateral septum and hypothalamus, although CRF2A receptor binding was unchanged. Lithium administration decreased CRF1 mRNA expression in both the amygdala and frontal cortex, but CRF1 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.

UR - http://www.scopus.com/inward/record.url?scp=0037404388&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037404388&partnerID=8YFLogxK

U2 - 10.1124/jpet.102.045419

DO - 10.1124/jpet.102.045419

M3 - Article

C2 - 12606697

AN - SCOPUS:0037404388

VL - 305

SP - 434

EP - 439

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -