Increased Activity of the Hypothalamic-Pituitary-Adrenal Axis of Rats Exposed to Alcohol in Utero: Role of Altered Pituitary and Hypothalamic Function

doi:10.1006/mcne.2000.0890

Molecular and Cellular Neuroscience

Volume 16, Issue 4, October 2000, Pages 515-528

https://doi.org/10.1006/mcne.2000.0890 Get rights and content

Abstract

Prenatal exposure to ethanol (E) enhances the offspring's ACTH and corticosterone responses to stressors. Here, we determined the role of increased pituitary responsiveness and/or PVN neuronal activity in this phenomenon. Pregnant rats were exposed to E vapors during days 7–18 of gestation, and we compared the responses of their 55- to 60-day-old offspring (E rats) to those of control (C) dams. PVN mRNA levels of the immediate early genes (IEGs) c-fos and NGFI-B, which were low under basal conditions in all groups, showed a peak response 15 min after shocks and 45 min after LPS treatment. These responses were significantly enhanced in E, compared to C offspring of both genders. CRF, but not VP hnRNA levels were also significantly higher in the PVN of shocked E offspring. Resting median eminence content of CRF and VP, and pituitary responsiveness to CRF, were unchanged, while responsiveness to VP was marginally increased in females. These results indicate that prenatal alcohol selectively augments the neuronal activity of hypothalamic CRF perikarya.

References (85)

F.A. Antoni
Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age
Front. Neuroendocrinol.
(1993)
H.C. Becker et al.
Teratogenic actions of ethanol in the mouse: A minireview
Pharmacol. Biochem. Behav.
(1996)
F. Berkenbosch et al.
Effect of axonal transport blockade of corticotropin-releasing factor immunoreactivity in the median eminence of intact and adrenalectomized rats: Relationship between depletion rate and secretory activity
Brain Res.
(1988)
B. Bohus et al.
The neurobiology of the central nucleus of the amygdala in relation to neuroendocrine and autonomic outflow
R. Chan et al.
Hemodynamic regulation of tyrosine hydroxylase messenger RNA in medullary catecholamine neurons: A c-fos-guided hybridization histochemical study
Neuroscience
(1995)
M.F. Dallman et al.
Feast and famine: Critical role of glucocorticoids with insulin in daily energy flow
Front. Neuroendocrinol.
(1993)
I. Halasz et al.
Sexually dimorphic effects of alcohol exposure in utero on neuroendocrine and immune functions in chronic alcohol-exposed adult rats
Mol. Cell. Neurosci.
(1993)
W.R. Kelce et al.
Effects of fetal alcohol exposure on brain 5α-reductase/aromatase activity
J. Ster. Biochem.
(1990)
K.D. Kim et al.
Expression of bovine inhibin β subunit in escherichia coli
Int. J. Biochem.
(1991)
S. Lee et al.
Administration of corticosterone to pregnant adrenalectomized dams does not alter the hypothalamic-pituitary-adrenal axis' activity of the offspring
Mol. Cell. Neurosci.
(1992)

S. Lee et al.

Alcohol increases the expression of type 1, but not type 2α corticotropin-releasing factor (CRF) receptor messenger ribonucleic acid in the rat hypothalamus

Mol. Brain Res.

(1997)

S.Y. Lee et al.

Effect of prenatal exposure to ethanol on the activity of the hypothalamic-pituitary-adrenal axis of the offspring: Importance of the time of exposure to ethanol and possible modulating mechanisms

Mol. Cell. Neurosci.

(1990)

J.A. Osborn et al.

Fetal ethanol exposure alters pituitary-adrenal sensitivity to dexamethasone suppression

Psychoneuroendocrinology

(1996)

C. Rivier et al.

Acute alcohol administration stimulates the activity of hypothalamic neurons that express corticotropin-releasing factor and vasopressin

Brain Res.

(1996)

P.E. Sawchenko et al.

The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress

A.N. Taylor et al.

Prenatal ethanol and ontogeny of pituitary-adrenal responses to ethanol and morphine

Alcohol

(1986)

A.G. Watts

The impact of physiological stimuli on the expression of corticotropin-releasing hormone (CRH) and other neuropeptide genes

Front. Neuroendocrinol.

(1996)

J. Weinberg

Prenatal ethanol effects: Sex differences in offspring stress responsiveness

Alcohol

(1992)

J. Weinberg

Prenatal ethanol exposure alters adrenocortical response to predictable and unpredictable stressors

Alcohol

(1992)

M.H. Whitnall

Regulation of the hypothalamic corticotropin-releasing hormone neurosecretory system

Prog. Neurobiol.

(1993)

R.A. Baker et al.

Effect of prenatal ethanol and stress on levels of β-endorphin in different brain regions of the rat

Alcohol. Clin. Exp. Res.

(1995)

H.O. Besedovsky et al.

Immune-neuro-endocrine interactions: Facts and hypotheses

Endocrinol. Rev.

(1996)

B.A. Blanchard et al.

Prenatal ethanol exposure alters ethanol-induced dopamine release in nucleus accumbens and striatum in male and female rats

Alcohol. Clin. Exp. Res.

(1993)

G.P. Chrousos

The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation

New Engl. J. Med.

(1995)

J.D. Cooper et al.

Alterations in regional catecholamine content and turnover in the male rat brain in response to in utero ethanol exposure

Alcohol. Clin. Exp. Res.

(1988)

E.R. De Kloet et al.

Brain corticosteroid receptor balance in health and disease

Endocrinol. Rev.

(1998)

N. Detering et al.

Comparative effects of ethanol and malnutrition on the development of catecholamine neurons: Changes in neurotransmitter levels

J. Neurochem.

(1980)

M.J. Druse

Effects of in utero ethanol exposure on the development of neurotransmitter systems

Dev. Central Nervous Syst.

(1992)

A.J. Garro et al.

Ethanol consumption inhibits fetal DNA methylation in mice: Implications for the fetal alcohol syndrome

Alcohol. Clin. Exp. Res.

(1991)

L.E. Goldstein et al.

Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat

J. Neurosci.

(1996)

Gray, T. S.1991. Limbic pathways and neurotransmitters as mediators of autonomic and neuroendocrine responses to...

C. Guerri

Neuroanatomical and neurophysiological mechanisms involved in central nervous system dysfunctions induced by prenatal alcohol exposure

Alcohol. Clin. Exp. Res.

(1998)

F. Holsboer et al.

Antidepressants and hypothalamic-pituitary-adrenocortical regulation

Endocrinol. Rev.

(1996)

M. Irwin et al.

Central corticotropin-releasing hormone activates the sympathetic nervous system and reduces immune function: Increased responsivity of the aged rat

Endocrinology

(1992)

M. Irwin et al.

Central corticotropin-releasing factor mediates the suppressive effect of stress on natural killer cytotoxicity

Endocrinology

(1990)

K. Itoi et al.

Microinjection of norepinephrine into the paraventricular nucleus of the hypothalamus stimulates corticotropin-releasing factor gene expression in conscious rats

Endocrinology

(1994)

L. Jacobson et al.

The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis

Endocrinol. Rev.

(1991)

M. Joëls et al.

Corticosteroid hormones: Endocrine messengers in the brain

News Psysiol. Sci.

(1995)

C. Kim et al.

Effects of prenatal exposure to alcohol on the release of adrenocorticotropic hormone, corticosterone and proinflammatory cytokines

Alcohol. Clin. Exp. Res.

(1999)

C.K. Kim et al.

Effects of prenatal ethanol exposure on hypothalamic-pituitary-adrenal responses to chronic cold stress in rats

Alcohol. Clin. Exp. Res.

(1999)

J. Koenig et al.

The rat brain

A Stereotactic Atlas of the Forebrain and Lower Parts of the Brainstem

(1963)

G.F. Koob et al.

The role of corticotropin-releasing factor in behavioural responses to stress

Ciba Foundation Symposium No. 172 on Corticotropin-Releasing Factor, London

(1993)

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The dense expression of glucocorticoid receptors (GR) within the amygdala, medial prefrontal cortex (mPFC) and paraventricular nucleus of hypothalamus (PVN) mediates many aspects of emotional and stress regulation. Importantly, both prenatal alcohol exposure (PAE) and adolescent stress are known to induce emotional and stress dysregulation. Little is known, however, about how PAE and/or adolescent stress may alter the expression of GR in the amygdala, mPFC, and PVN. To fill this gap, we exposed PAE and control adolescent male and female rats to chronic mild stress (CMS) and assessed GR mRNA expression in the amygdala, mPFC, and PVN immediately following stress or in adulthood. We found that the effects of PAE on GR expression were more prevalent in the amygdala, while effects of adolescent stress on GR expression were more prevalent in the mPFC. Moreover, PAE effects in the amygdala were more pronounced during adolescence and adolescent stress effects in the mPFC were more pronounced in adulthood. GR expression in the PVN was affected by both PAE and adolescent stress. Finally, PAE and/or adolescent stress effects were distinct between males and females. Together, these results suggest that PAE and adolescent CMS induce dynamic alterations in GR expression in the amygdala, mPFC, and PVN, which manifest differently depending on the brain area, age, and sex of the animal. Additionally, these data indicate that PAE-induced hyperresponsiveness to stress and increased vulnerability to mental health problems may be mediated by different neural mechanisms depending on the sex and age of the animal.
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Prenatal alcohol exposure (PAE) is known to cause dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyperresponsivity to stressors. Dysregulation of the HPA axis plays a role in vulnerability to stress-related disorders, such as anxiety and depression. Thus, the effects of PAE on HPA function may result in increased vulnerability to the effects of stress and, in turn, lead to the development of stress-related disorders. Indeed, individuals prenatally exposed to alcohol have an increased risk of developing anxiety and depression. However, it is unclear whether hypersecretion of corticosterone (CORT) in response to stress per se is involved with mediating differential effects of stress in PAE and control animals. To investigate the role of CORT in mediating effects of stress in both adult females and males following PAE, adrenalectomy with CORT replacement (ADXR) was utilized to produce similar CORT levels among prenatal treatment groups before exposure to chronic unpredictable stress (CUS). Anxiety-like behavior was evaluated using the open field and elevated plus maze, and depressive-like behavior was examined in the forced swim test. Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA expression was assessed in the medial prefrontal cortex (mPFC), amygdala, and hippocampal formation. Under the non-CUS condition, PAE alone differentially altered anxiety-like behavior in sham but not ADXR females and males, with females showing decreased anxiety-like behavior but males exhibiting increased anxiety-like behavior compared to their control counterparts. There were no effects of PAE alone on depressive-like in females or males. PAE also decreased GR mRNA expression in the hippocampal formation in females but had no effects on MR or GR mRNA expression in any brain region in males. CUS had differential effects on anxiety- and depressive-like behavior in PAE and control animals, and these effects were sex dependent. Importantly, ADXR unmasked differences between PAE and control animals, demonstrating that CORT may play a differential role in modulating behavior and HPA activity/regulation in PAE and control animals, and may do so in a sex-dependent manner.
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Emerging evidence suggests that deficits in social functioning and social anxiety are associated with adolescent alcohol use. Our previous research has shown that acute exposure to a high dose of ethanol on gestational day (G) 12 produces social alterations in adolescent Sprague Dawley rats. The present study assessed whether these social alterations can affect sensitivity to acute ethanol challenge during adolescence. Pregnant females were exposed intraperitoneally (i.p.) to ethanol (2.5 g/kg followed by 1.25 g/kg in 2 h) or saline on G12, and their male and female offspring were tested on postnatal day (P) 42. Rats were challenged i.p. with one of four ethanol doses (0, 0.5, 0.75, and 1.0 g/kg), and their social behavior was assessed in a modified social interaction test. Social alterations associated with prenatal ethanol exposure and indexed via decreases of social investigation, social preference, and play fighting were evident in males and females challenged with the 0 g/kg ethanol dose. Acute ethanol increased social investigation, social preference, and play fighting in animals prenatally exposed to ethanol. In contrast, rats prenatally exposed to saline, showing no social facilitation, demonstrated significant ethanol-induced (0.75 and 1.0 g/kg) decreases in social behavior. Given that late adolescents demonstrating social alterations induced by prenatal ethanol exposure become sensitive to the socially anxiolytic as well as socially facilitating effects of acute ethanol, it is possible that the attractiveness of ethanol to these adolescents may be based on its ability to alleviate anxiety under social circumstances and facilitate interactions with peers.
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Citation Excerpt :
To test this, Crf and Avp mRNA levels were assessed in adult male rats at the end of the 2-h alcohol administration (4.5 g/kg, ig). In situ hybridization was performed according to a previously published protocol [see Lee et al., 2000a, 2000b for method]. A Nikon optical system, Eclipse E600 microscope (Nikon Instruments Inc., Melville, NY, USA) equipped with a Micro∗Color filter (Model RGB-MS-C, CRI Inc., Woburn, MA, USA) and CoolSNAP camera (Photometrics, Tucson, AZ, USA), coupled to a PC was used to capture images for IHC and in situ sections.
The hypothalamic–pituitary–adrenal (HPA) axis undergoes critical developments during adolescence. Therefore, stressors experienced during this period potentially have long-term effects on adult HPA axis function. We hypothesized that adolescent intermittent ethanol (AIE) exposure would affect adult HPA axis function, resulting in altered responses to an alcohol challenge in young adults or adults. To test these hypotheses, male rats were exposed to alcohol vapor for 6 h per day from post-natal day (PND) 28–42, then acutely challenged with alcohol intragastrically (3.2–4.5 g/kg) in young adults (PND 70) or adults (PND 90). Overall, we observed blunted HPA axis responses to an alcohol challenge due to AIE exposure. Specifically, AIE tended to inhibit the alcohol challenge-induced increase in plasma corticosterone (CORT) concentrations in young adult and adult rats. As well, AIE significantly blunted the alcohol challenge-induced arginine vasopressin (Avp) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus of adult rats. Results of the present study are similar to what we have previously shown, that these changes in PVN responsiveness may result from AIE-induced alterations in adrenergic neurons in brain stem regions C1–C3 known to project to the PVN. AIE elevated the number of colocalized c-fos/phenylethanolamine N-methyltransferase (PNMT)-positive cell bodies in the C1 region of adult rats. Together, these data suggest that AIE exposure produces alterations in male HPA axis responsiveness to administration of an acute alcohol challenge that may be long-lasting.
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Regular ArticleIncreased Activity of the Hypothalamic-Pituitary-Adrenal Axis of Rats Exposed to Alcohol in Utero: Role of Altered Pituitary and Hypothalamic Function

Abstract

Front. Neuroendocrinol.

Pharmacol. Biochem. Behav.

Brain Res.

Neuroscience

Front. Neuroendocrinol.

Mol. Cell. Neurosci.

J. Ster. Biochem.

Int. J. Biochem.

Mol. Cell. Neurosci.

Mol. Brain Res.

Mol. Cell. Neurosci.

Psychoneuroendocrinology

Brain Res.

Alcohol

Front. Neuroendocrinol.

Alcohol

Alcohol

Prog. Neurobiol.

Effect of prenatal ethanol and stress on levels of β-endorphin in different brain regions of the rat

Alcohol. Clin. Exp. Res.

Immune-neuro-endocrine interactions: Facts and hypotheses

Endocrinol. Rev.

Prenatal ethanol exposure alters ethanol-induced dopamine release in nucleus accumbens and striatum in male and female rats

Alcohol. Clin. Exp. Res.

The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation

New Engl. J. Med.

Alterations in regional catecholamine content and turnover in the male rat brain in response to in utero ethanol exposure

Alcohol. Clin. Exp. Res.

Brain corticosteroid receptor balance in health and disease

Endocrinol. Rev.

Comparative effects of ethanol and malnutrition on the development of catecholamine neurons: Changes in neurotransmitter levels

J. Neurochem.

Effects of in utero ethanol exposure on the development of neurotransmitter systems

Dev. Central Nervous Syst.

Ethanol consumption inhibits fetal DNA methylation in mice: Implications for the fetal alcohol syndrome

Alcohol. Clin. Exp. Res.

Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat

J. Neurosci.

Neuroanatomical and neurophysiological mechanisms involved in central nervous system dysfunctions induced by prenatal alcohol exposure

Alcohol. Clin. Exp. Res.

Antidepressants and hypothalamic-pituitary-adrenocortical regulation

Endocrinol. Rev.

Central corticotropin-releasing hormone activates the sympathetic nervous system and reduces immune function: Increased responsivity of the aged rat

Endocrinology

Central corticotropin-releasing factor mediates the suppressive effect of stress on natural killer cytotoxicity

Endocrinology

Microinjection of norepinephrine into the paraventricular nucleus of the hypothalamus stimulates corticotropin-releasing factor gene expression in conscious rats

Endocrinology

The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis

Endocrinol. Rev.

Corticosteroid hormones: Endocrine messengers in the brain

News Psysiol. Sci.

Effects of prenatal exposure to alcohol on the release of adrenocorticotropic hormone, corticosterone and proinflammatory cytokines

Alcohol. Clin. Exp. Res.

Effects of prenatal ethanol exposure on hypothalamic-pituitary-adrenal responses to chronic cold stress in rats

Alcohol. Clin. Exp. Res.

The rat brain

A Stereotactic Atlas of the Forebrain and Lower Parts of the Brainstem

The role of corticotropin-releasing factor in behavioural responses to stress

Ciba Foundation Symposium No. 172 on Corticotropin-Releasing Factor, London

Regular Article
Increased Activity of the Hypothalamic-Pituitary-Adrenal Axis of Rats Exposed to Alcohol in Utero: Role of Altered Pituitary and Hypothalamic Function