In rodents and humans stressful events in early life e.g. maternal deprivation, can increase sensitivity to stress in later life. Humans may become more susceptible to mood disorders, e.g. depression. In livestock species, such as pigs, early weaning is a form of maternal deprivation. We investigated behavioural consequences in 99 female pigs weaned at three different ages (12, 21 and 42 days; d12, d21, d42). Pigs were habituated to an open field arena over 6 days before being given 5-min open-field tests over three subsequent days (days 77–79). Early-weaned pigs (d12) showed behavioural inhibition (reduced vocalisations and lower activity) compared with later-weaned pigs, although in all groups these measures declined over the three tests, so this treatment difference might reflect more rapid habituation to the test in d12 pigs. Long-term effects on mood-related 5-HT receptor subtypes were measured in the brain at 90 days in a random sample of the d12 (n=8) and d42 pigs (n=8), using 3H-ligand-binding and autoradiography and in situ hybridisation histochemistry. There were no differences between weaning ages in binding of 3H-8-OH-DPAT (5-HT1A receptor agonist) or of 3H-ketanserin (5-HT2A receptor antagonist) to any brain region studied. In d12 pigs, 5-HT1A receptor mRNA expression per unit area was 29%, 63%, 52% and 64% lower than in d42 pigs in the parvocellular PVN, amygdala and hippocampal dentate gyrus and pyramidal cell layer, respectively. The ratio of expression per cell to expressing cells per unit area was also lower, by 31%, in the pars horizontalis of the PVN in d12 pigs. Conversely, 5-HT2A receptor mRNA was expressed at a 25% and 28% higher density per unit area in the amygdala and pyramidal cell layer of the hippocampus, respectively, in these d12 pigs. In individual pigs, across brain regions, 5-HT1A receptor mRNA data were 70–79% correlated with binding data but no correlation was found for 5-HT2A data, suggesting different regulatory mechanisms. The behavioural and neurobiological responses to early weaning might represent either dysfunction or adaptation. Further investigation is required.

Adverse early life experiences can permanently "programme" increases in stress reactivity in adulthood. We investigated whether weaning, which involves maternal separation, at different ages, altered subsequent behaviour, physiology and neuroendocrine function in young pigs. The litters of twelve primiparous sows were randomly allocated to weaning at 12 days (W12), 21 days (W21) or at 42 days (W42). Four test daughters from each litter (n = 48, 16 from each treatment) were studied from I I days of age until 90 days of age. At 90 days of age, prior to culling, half of each treatment were challenged with restraint and isolation stress. There was a long-term reduction in salivary cortisol levels following weaning in all groups. W12 and W21 piglets gained weight more slowly after weaning, but by 90 days weights were similar in all groups. Behaviourally, W12 piglets showed more substrate directed and aggressive behaviours, postural changes, and nosing and belly nosing littermates. Surprisingly, W42 piglets exhibited the onset of belly nosing at 28 days while still in the presence of the sow. At 90 days of age there was no evidence that weaning age had persisting effects on the hypothalamic-pituitary-adrenal (HPA) axis. Restraint stress increased plasma ACTH and cortisol levels and CRH mRNA in the hypothalamus demonstrating that the absence of weaning age effects on HPA function was not due to a ceiling effect. This study is the first to investigate long-term effects of weaning age in pigs using a combination of behavioural, physiological and neuroendocrine measures. The results suggest that variation in the age of weaning does not apparently programme the HPA axis but has potentially deleterious effects on behaviour certainly up to 56 days of age. However, our study also raises complications when considering the welfare implications of weaning age. Specifically more information is needed on the causes and long term implications of the sustained elevations of salivary cortisol we observed over the suckling period. The occurrence of belly nosing in later weaned pigs also suggests that care is required when designing environments where sows and piglets are housed together beyond 28 days. (c) 2007 Elsevier B.V. All rights reserved.

Sex steroids exert potent effects on mood and mental state in the human. Our previous experimental findings in female rats suggest that these effects may be mediated, in part, by the action of estrogen on the 5-hydroxytryptamine2A receptor (5-HT(2A)R) and serotonin transporter (SERT) in brain. Here we review our recent findings on the effect of acute (approximately 32 h) testosterone manipulation on central 5-HT(2A)R and SERT in male rats. Castration decreased while testosterone or estrogen, but not 5alpha-dihydrotestosterone (5alpha-DHT), increased significantly the content of 5-HT(2A)R mRNA and SERT mRNA in the dorsal raphe nucleus (DR) and the density of 5-HT(2A)R and SERT binding sites in higher centers of the brain. The lack of effect of 5alpha-DHT, a potent androgen which cannot be converted to estrogen, suggests that the action of testosterone depends upon its conversion to estrogen by aromatase. This may also explain why estrogen, but not testosterone or 5alpha-DHT, increased the density of 5-HT(2A)R binding sites in the caudate-putamen, a brain region where aromatase is scarce. The estrogen induction of SERT mRNA is most prominent in the rostral DR and this together with the correlation between sensitivity of DR serotonin neurons to estrogen and neurotoxic amphetamine derivatives provides a potential topochemical handle with which to investigate testosterone/estrogen regulation of SERT gene expression. These findings are discussed in relation to the possible role of interactions between sex steroids and serotonin mechanisms in mood disorders, schizophrenia and Alzheimer's disease.

1. Estrogen exerts profound effects on mood, mental state and memory by acting on both “classical” monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action.

Estrogen exerts a profound effect on mood and mental function in man. Based on our finding that estradiol selectively stimulates the expression of 5-hydroxytryptamine2A (5-HT2A) receptor mRNA in the dorsal raphe nucleus of the female rat, we investigated the effects of estradiol on the density of 5-HT2A receptors in brain. The distribution and density of 5-HT2A receptors were determined by in vitro binding of [3H]ketanserin in the presence of prazosin to exclude binding to α1-adrenoreceptors. Brains were collected, processed and analysed in pairs from six estradiol- and six vehicle-treated animals. Our results show that a single pulse of estradiol induces a significant increase in the density of 5-HT2A receptors in female rat forebrain, particularly the anterior frontal, anterior cingulate and primary olfactory cortex and the nucleus accumbens. Since these brain regions play a pivotal role in cognition and emotion, as well as neuroendocrine and motor control, our findings provide the first experimental evidence for the fact that estrogen could alter mood and mental state by increasing the density of 5-HT2A receptors in cerebral cortex and nucleus accumbens.