David A.V. Peters

Prenatal stress: Effects on brain biogenic amine and plasma corticosterone levels

Pregnant rats were subjected to once daily stress treatments consisting of handling and a saline injection. The offspring showed region-specific changes in brain 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in infancy but only the hypothalamus still showed significant changes at 60 days of age. In a reaction-to-stress test 23-day-old offspring in the prenatal stress group showed a greater elevation in plasma corticosterone level but smaller changes in hypothalamic NE and 5-HIAA levels than control offspring suggesting that prenatal stress may have altered the functioning of the hypothalamic-pituitary-adrenal axis. It is suggested that changes in the development of specific monoamine-containing neurons may be associated with the reported behavioral deficits in offspring of female rats stressed during pregnancy.

Maternal stress increases fetal brain and neonatal cerebral cortex 5-hydroxytryptamine synthesis in rats: A possible mechanism by which stress influences brain development

Previous studies have shown that maternal stress modifies 5-hydroxytryptamine (5-HT) receptor binding in several brain regions of the adult offspring and alters the intensity of the behavioral responses to 5-HT receptor agonists. We now report that the same stress, crowding combined with daily saline injections during the final week of pregnancy, elevates maternal plasma free tryptophan level without significantly affecting total tryptophan. The increased maternal plasma tryptophan was associated with significantly increased fetal brain levels of tryptophan, 5-HT and 5-hydroxyindoleacetic acid. These increases were maintained after birth until at least postnatal day 10. Since 5-HT is recognised as having a role in the control of neuron development during the perinatal period, we suggest that the stress-induced increase in fetal brain 5-HT synthesis may play a part in the mechanisms by which prenatal stress alters adult behavior.

Effects of maternal stress during different gestational periods on the serotonergic system in adult rat offspring

Pregnant Sprague-Dawley rats were exposed to mild stress treatments during different gestational periods and the offspring were investigated at 60 days of age. In the first study, stress from embryonic day (ED) 11 to ED 20 produced effects similar to those reported following stress throughout pregnancy; increased numbers of 5-HT2 binding sites in cerebral cortex and a reduced intensity of the behavioral syndrome produced by injections of the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). In the second study, stress from ED 3 to ED 14 had no significant effect on the intensity of the 5-MeODMT-elicited 5-HT syndrome while stress from ED 15 to ED 20 had a similar effect as stress throughout pregnancy. These data provide evidence that the critical period for prenatal stress-induced changes in brain 5-HT neurons is between ED 15 and birth. This suggests that the mechanism involves an interaction with developmental events occurring within this time span such as the growth of nerve axons and the formation of synaptic contacts. Our findings also provide further evidence that stress during the final trimester of pregnancy may have serious adverse effects on fetal brain development.

Prenatal stress: Effect on development of rat brain serotonergic neurons

Maternal low-level stress was found to produce persistent changes in serotonin (5-HT) receptor binding in several brain regions of the offspring. [3H]5-HT binding was increased in cerebral cortex, decreased in hippocampus and unchanged in pons medulla while [3H]spiperone binding was increased in all three regions at 60 days of age. The binding changes appeared to be due to altered numbers of binding sites with no change in dissociation constants. Regional differences were also found when the ability of nerve terminals to synthesize [14C]5-HT from L-[14C]tryptophan was studied. Prenatal stress reduced the rate of [14C]5-HT synthesis in hippocampus but not in cortex or pons medulla. When younger offspring were studied, binding of [3H]5-HT to cerebrocortical membranes was found to be reduced at 16 days of age and increased at 40 days while [3H]spiperone showed only an increased binding at 40 days. In contrast, prenatal stress resulted in increased nighttime locomotor activity whether measured at 23, 40 or 60 days of age. The present study provides additional evidence that prenatal stress affects the development of serotonergic neurons and it is possible that such changes may underlie the reported behavioural deficits in offspring of stressed female rats.

Prenatal stress increases the behavioral response to serotonin agonists and alters open field behavior in the rat

Female rats were exposed to mild stress throughout pregnancy and the offspring tested at 60 days of age. In an open field test the prenatal stress group showed increased locomotion and increased rearing compared to control rats confirming that the prenatal stress treatment was sufficient to produce persistent behavioural changes in the offspring. The prenatal stress offspring also showed an increased behavioural response to injections of 5-hydroxy-L-tryptophan (wet-dog shakes) and an enhanced 5-HT syndrome following treatment with the 5-HT agonist 5-methoxy-N,N- dimethyltryptamine. These results provide further evidence that maternal stress produces long-lasting changes in the functioning of central 5-HT neurons in the offspring.

Monoamines and Aversively Motivated Behaviors

The role of the monoamines, norepinephrine (NE), dopamine (DA), and serotoin (5-HT), has been evaluated across numerous behavioral situations, ranging from apparently simple response patterns, e.g., locomotor activity, to complex ones involving associations between stimulus events and response consequences. Not surprisingly, theorizing concerning the relations between monoamines and behavior has extended beyond models involving infrahuman animals, and has been employed to account for a variety of aberrant human behaviors.

Sex-dependent biological changes following prenatal nicotine exposure in the rat

Nicotine was administered to adult female rats in drinking water starting 6 weeks before mating and continuing throughout pregnancy. The litters were cross-fostered to control dams at birth. Prenatal nicotine treatment reduced both the number of male rats born and the male birth weight. Female offspring were not significantly affected. Rearing activity was reduced in male but not female offspring either when tested over a 24 hour period in a home cage environment or during a 10 minute exposure in an open field. Horizontal locomotor activity was reduced only during the first 5 minutes in the open field and again the effect was found only in the males. Baseline plasma corticosterone levels were reduced in both male and female offspring but there was no effect on stress-elevated corticosterone levels.

Both prenatal and postnatal factors contribute to the effects of maternal stress on offspring behavior and central 5-hydroxytryptamine receptors in the rat

Litters from stressed and control females were cross-fostered at birth to determine whether the effects of maternal stress on the offspring originated prenatally or during the neonatal period. Offspring of stressed females reared by control mothers from birth showed a reduced behavioral response to injections of the 5-hydroxytryptamine (5-HT) agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), increased 5-HT2 receptor binding in cerebral cortex and increased open field activity when tested at 60 days of age. In contrast, control litters reared by previously stressed females showed an increased behavioral response to 5-MeODMT, increased 5-HT2 receptor binding and only minor changes in open-field activity. These results provide further evidence that adult rat behavior can be significantly altered by exposure to the effects of maternal stress in utero. However, the effect of maternal stress on central 5-HT receptors is also strongly influenced by the postnatal rearing conditions.

Some neurochemical alterations during acute DDT poisoning

Administration of a lethal dose (600 mg/kg) of 1,1,1-trichloro-2,2-bis( p -chlorophenyl)ethane ( p,p′ -DDT) to rats produced typical neurotoxic signs (e.g., hyperexcitability, tremors, convulsions and hyperthermia) and resulted in marked changes in brain acetylcholine (ACh), norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA). Significant decreases in the amounts of cortical and striatal ACh as well as of brainstem NE were noted 5 hr after the administration of the insecticide. No significant alterations were found in striatal dopamine (DA) and brainstem 5-hydroxytryptamine (5-HT). However, brainstem 5-HIAA was significantly enhanced after treatment with p,p′ -DDT. In pargyline-pretreated rats, p,p′ -DDT produced increases in 5-HT which were greater than those observed in animals given the monoamine oxidase (MAO) inhibitor alone. Treatment with 6-fluorotryptophan (6-FT) or α -methyl- p -tyrosine ( α -MT), inhibitors of 5-HT or NE synthesis, respectively, prevented the DDT-induced hyperthermia, but not the tremors and convulsions. In contrast, administration of p -chlorophenylalanine ( p CPA) blocked all of the neurotoxic signs of p,p′ -DDT. In addition, cycloheximide, but not actinomycin D, prevented the insecticide-induced changes in striatal ACh and brainstem 5-HIAA, as well as the occurrence of tremors and hyperthermia. These results suggest that changes in the metabolism of brain 5-HT and NE may be responsible for the DDT-induced hyperthermia, while the tremors and convulsions seen after an acute lethal dose of this insecticide may be related to changes in brain ACh.

Role of brain acetylcholine and dopamine in acute neurotoxic effects of DDT

Abstract Neurotoxic effects (hyperexcitability, tremor) and hyperpyrexia seen after the acute administration of p , p ′-DDT (600 mg/kg) were associated with a significant decrease in ACh concentration without any concomitant changes in the levels of dopamine in the striatum of male and female rats. In contrast, the same dose of o , p ′-DDT failed to produce any of these symptoms and did not alter the concentration of the two neurohormones in rats of either sex. The results suggest that cholinergic mechanisms in the striatum may be involved in neurotoxic effects observed after the administration of p , p ′-DDT.