Prenatal Alcohol Exposure Results in Long-Term Serotonin Neuron Deficits in Female Rats: Modulatory Role of Ovarian Steroids

Abstract

Background Previous studies on male rodents found that prenatal alcohol exposure (PAE) decreases the number of serotonin immunoreactive (5-HT-ir) neurons in the brainstem. However, data on the effects of PAE in females are lacking. In light of known sex differences in responsiveness of the 5-HT system and known effects of estrogen (E2) and progesterone (P4) in the brain, we hypothesized that sex steroids will modulate the adverse effects of PAE on 5-HT neurons in adult females. Methods Adult females from 3 prenatal groups (Prenatal alcohol-exposed [PAE], Pair-fed [PF], and ad libitum-fed Controls [C]) were ovariectomized (OVX), with or without hormone replacement, or underwent Sham OVX. 5-HT-ir cells were examined in key brainstem areas. Results Our data support the hypothesis that PAE has long-term effects on the 5-HT system of females and that ovarian steroids have a modulatory role in these effects. Intact (Sham OVX) PAE females had marginally lower numbers of 5-HT-ir neurons in the dorsal raphe nucleus of the brainstem compared with PF and C females. This marginal difference became signiffcant following removal of hormones by OVX. Replacement with E2 restored the number of 5-HT-ir neurons in PAE females to control levels, while P4 reversed the effects of E2. Importantly, despite these differential responses of the 5-HT system to ovarian steroids, there were no differences in E2 and P4 levels among prenatal treatment groups. Conclusions These data demonstrate long-term, adverse effects of PAE on the 5-HT system of females, as well as differential sensitivity of PAE compared with control females to the modulatory effects of ovarian steroids on 5-HT neurons. Our findings have important implications for understanding sex differences in 5-HT dysfunction in depression/anxiety disorders and the higher rates of these mental health problems in individuals with fetal alcohol spectrum disorder.

Docosahexaenoic acid partially ameliorates deficits in social behavior and ultrasonic vocalizations caused by prenatal ethanol exposure

“…Anxiety has been shown to be induced with prenatal ethanol exposure in some animal models [76–79], although not by others [80]. To determine whether anxiety or motivation could underlie the outcome of the gap crossing task, we performed an elevated plus maze test [81–83].…”

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

“…Prenatal alcohol exposure has been reported to alter development and function of the serotonergic system, resulting in reduced density of 5-HT neurons and concentrations of 5-HT and 5-HT reuptake sites, and impaired development of 5-HT 1A receptors in several brain areas (17,63). Moreover, there is a bidirectional regulatory relationship between 5-HT and the HPA axis (44).…”

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

“…While the studies discussed show how genetic disruptions in specific 5-HT genes can influence brain development, a number of studies have shown persistent alterations in the 5-HT system, including lower 5-HT innervation, receptor function, protein and enzyme expression, synaptic density and metabolite levels, following in utero or early postnatal exposure to experimentally induced stress 95,96 and/or substances of abuse, such as nicotine or alcohol (see the studies by Parker and colleagues, 97 Sliwowska and colleagues, 98 Slotkin and colleagues 99 and Williams and colleagues 100 ). Some of these effects appear to be sex-specific.…”

“…Some of these effects appear to be sex-specific. 96,98,99 Studies in mice demonstrate a clear sex effect for the behavioural and physiologic effects of prenatal stress exposure. Male mice exposed to prenatal stress exhibited an increased sensitivity to a low dose of SSRIs.…”