Hypothalamic–Pituitary–Adrenal Responses to 5‐HT<sub>1A</sub> and 5‐HT<sub>2A/C</sub> Agonists Are Differentially Altered in Female and Male Rats Prenatally Exposed to Ethanol

Hofmann, Candace E.; Ellis, Linda; Yu, Wayne; Weinberg, Joanne

doi:10.1111/j.1530-0277.2006.00316.x

Cited by 25 publications

(22 citation statements)

References 94 publications

(108 reference statements)

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“…Moreover, there is a bidirectional regulatory relationship between 5-HT and the HPA axis (44). We have shown that PAE animals exhibit increased hypothermic and anxiolytic responses and blunted ACTH responses to 8-OH-DPAT, a 5-HT 1a receptor agonist, compared with PF and C animals (26), and that E females show alterations in 5-HT 1A receptor levels in the hippocampus that are estrous cycle stage-dependent (62). Furthermore, it has been reported that the short allele of the SLC6A4 promoter variant, 5HTTLPR, increases the probability of neonatal irritability and stress responsiveness in rhesus monkeys exposed prenatally to alcohol and that this gene-environment interaction may affect psychosocial development (58).…”

Section: Discussionmentioning

confidence: 95%

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

Ngai

Sulistyoningrum

O’Neill

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE.

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Section: Discussionmentioning

confidence: 95%

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

Ngai

Sulistyoningrum

O’Neill

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Moreover, PAE males show elevated hypothalamic CRH mRNA levels following DOI, whereas PAE and PF females show a trend toward lower levels compared to their C counterparts. These findings suggest that an important regulatory relationship between the 5-HT receptor and CRH may be disrupted by prenatal ethanol exposure (Hofmann et al, 2002; Hofmann, Patyk, and Weinberg, 2005; Hofmann et al, 2007). Recently, we have extended these studies and demonstrate, for the first time, that 5-HT 1A mRNA levels may be differentially altered in PAE animals depending on gonadal hormone status.…”

Section: Prenatal Alcohol Exposure and Hpa Dysregulationmentioning

confidence: 87%

“…On a functional level, our data have shown that PAE animals exhibit physiological and behavioral abnormalities consistent with altered 5-HT function, including altered hypothermic responses to 8-hydroxy-2-2(di- n -propylamino)tetralin (8-OH-DPAT), a 5-HT 1A receptor agonist, and an increased rate of ‘wet dog shakes’ (stereotyped body movements that consist of shaking the body and head like a dog that has come out of the water) to 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT 2A/C receptor agonist (Hofmann, Simms, Yu, and Weinberg, 2002). Furthermore, PAE females show blunted ACTH responses to 8-OH-DPAT, but increased ACTH responses to DOI compared to controls, suggesting an altered interaction between the HPA axis and the 5-HT system (Hofmann, Ellis, Yu, and Weinberg, 2007). In addition, 8-OH-DPAT increases, whereas DOI reduces, hippocampal 5-HT 1A receptor mRNA expression in PAE compared with PF and C females, overall.…”

Section: Prenatal Alcohol Exposure and Hpa Dysregulationmentioning

confidence: 99%

Prenatal alcohol exposure: Fetal programming and later life vulnerability to stress, depression and anxiety disorders

Hellemans

Śliwowska

Verma

et al. 2010

Neuroscience & Biobehavioral Reviews

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Children with Fetal Alcohol Spectrum Disorder (FASD) exhibit cognitive, neuropsychological and behavioral problems, and numerous secondary disabilities including depression and anxiety disorders. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is common in depression/anxiety, reflected primarily in increased HPA tone or activity. Prenatal alcohol exposure (PAE) increases HPA tone and results in HPA dysregulation throughout life, paralleling many of the HPA changes in depression/anxiety. We review data demonstrating altered HPA function and increased depression/anxiety in FASD. In the context of the stress-diathesis model, we discuss the hypothesis that fetal programming of the HPA axis by PAE alters neuroadaptive mechanisms that mediate the stress response, thus sensitizing the organism to stressors encountered later in life, and mediating, at least partly, the increased vulnerability to depression/anxiety disorders. Furthermore, we present evidence demonstrating sex-specific alterations in both hormonal and behavioral responsiveness to tasks measuring depressive- and anxiety-like behaviors in PAE offspring. Overall, the research suggests that the stress-diathesis model provides a powerful approach for elucidating mechanisms underlying the increased vulnerability to mental illness among individuals with FASD, and developing appropriate treatments for these individuals. Dr. Seymour Levine’s seminal work on the long-term consequences of early life experiences formed a framework for the development of the research described in this review.

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“…We have shown that in adulthood, females prenatally exposed to ethanol (E) have a greater hypothermic response, a blunted ACTH response and increased hippocampal 5HT 1A receptor expression in response to the 5HT 1A agonist 8-OH-DPAT (Hofmann et al, 2007). Similarly, E females show increased 5HT 1A -dependent anxiety-like behavior compared to controls (Hofmann et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Effects of prenatal ethanol exposure on regulation of basal hypothalamic–pituitary–adrenal activity and hippocampal 5-HT1A receptor mRNA levels in female rats across the estrous cycle

Śliwowska

Yamashita

et al. 2008

Psychoneuroendocrinology

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Summary Prenatal ethanol exposure, like other early adverse experiences, is known to alter hypothalamic-pituitary-adrenal (HPA) activity in adulthood. The present study examined the modulatory effects of the gonadal hormones on basal HPA regulation and serotonin type 1A receptor (5-HT1A) levels in adult female rats prenatally exposed to ethanol (E) compared to that in females from pair-fed (PF) and ad libitum-fed control (C) conditions. We demonstrate, for the first time, long-lasting consequences of prenatal ethanol exposure for basal corticosterone (CORT) regulation and basal levels of hippocampal mineralocorticoid (MR), glucocorticoid (GR) and serotonin type 1A (5-HT1A) receptor mRNA, as a function of estrous cycle stage: 1) basal CORT levels were higher in E compared to C females in proestrus but lower in E and PF compared to C females in estrus; 2) there were no differences among groups in basal levels of adrenocorticotropin (ACTH), estradiol or progesterone; 3) hippocampal MR mRNA levels were decreased in E compared to PF and C females across the estrus cycle, with the greatest effects in proestrus, whereas E (but not PF or C) females had higher hippocampal GR mRNA levels in proestrus than in estrous and diestrus; 4) 5-HT1A mRNA levels were increased in E compared to PF and C females in diestrus. That alterations were revealed as a function of estrous cycle stage suggests a role for the ovarian steroids in mediating the adverse effects of ethanol. Furthermore, it appears that ethanol-induced nutritional effects may play a role in mediating at least some of the effects observed. The resetting of HPA activity by early environmental events could be one mechanism linking early life experiences with long-term health consequences. Thus, changes in basal CORT levels, a shift in the MR/GR balance and alterations in 5-HT1A receptor mRNA could have important clinical implications for understanding the secondary disabilities, such as an increased incidence of depression, in children with FASD.

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Hypothalamic–Pituitary–Adrenal Responses to 5‐HT_1A and 5‐HT_2A/C Agonists Are Differentially Altered in Female and Male Rats Prenatally Exposed to Ethanol

Cited by 25 publications

References 94 publications

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

Prenatal alcohol exposure: Fetal programming and later life vulnerability to stress, depression and anxiety disorders

Effects of prenatal ethanol exposure on regulation of basal hypothalamic–pituitary–adrenal activity and hippocampal 5-HT1A receptor mRNA levels in female rats across the estrous cycle

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Hypothalamic–Pituitary–Adrenal Responses to 5‐HT1A and 5‐HT2A/C Agonists Are Differentially Altered in Female and Male Rats Prenatally Exposed to Ethanol

Cited by 25 publications

References 94 publications

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain

Prenatal alcohol exposure: Fetal programming and later life vulnerability to stress, depression and anxiety disorders

Effects of prenatal ethanol exposure on regulation of basal hypothalamic–pituitary–adrenal activity and hippocampal 5-HT1A receptor mRNA levels in female rats across the estrous cycle

Contact Info

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Hypothalamic–Pituitary–Adrenal Responses to 5‐HT_1A and 5‐HT_2A/C Agonists Are Differentially Altered in Female and Male Rats Prenatally Exposed to Ethanol