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In the previous study, we reported that exposure to bisphenol-A induced the potentiation of dopamine receptor functions in the mouse limbic area, resulting in supersensitivity to methamphetamine-induced pharmacological actions. The present study was undertaken to investigate whether prenatal exposure to bisphenol-A could produce morphological change in dopaminergic neuron and the pattern of expression of genes regulating the dopaminergic neuron development. Here we found that prenatal and neonatal exposures to bisphenol-A increased the tyrosine hydroxylase- and dopamine transporter-like immunoreactivities in the adult mouse limbic area. The present molecular biological study shows that chronic bisphenol-A treatment produced a significant decrease in the dopaminergic neuron development factors, sonic hedgehog and glial cell line-derived neurotrophic factor, which were also decreased by prenatal exposure to bisphenol-A. These results suggest that chronic exposure to bisphenol-A could disrupt the dopaminergic neurotransmission in the process of dopaminergic neuron development.

Bisphenol-A has been extensively evaluated for toxicity in a variety of tests as the most common environmental endocrine disruptor. In the present study, we found that prenatal and neonatal exposure to bisphenol-A affects the development of the central dopaminergic system in the mouse limbic area. Additionally, this treatment with bisphenol-A produced a down-regulation of dopamine D3 receptor and an up-regulation of dopamine D1 receptor function to activate G-protein in the mouse limbic forebrain, which is thought to play a critical role for rewarding effects by drugs of abuse. We next investigated the relationship between the neurobehavioral toxicity and its exposure period. The exposure to bisphenol-A during either organogenesis or lactation, but not implantation and parturition, significantly enhanced the morphine-induced hyperlocomotion and rewarding effect. Furthermore, the exposure to bisphenol-A during either organogenesis or lactation also produced an up-regulation of dopamine D1 receptor function to activate G-protein in the mouse limbic forebrain. These results indicate that either organogenesis or lactation is more sensitive to the bisphenol-A-induced neuronal toxicity than any other periods. In conclusion, we found here that prenatal and neonatal exposure to bisphenol-A can potentiate the central dopaminergic systems, resulting in the supersensitivity of the drugs of abuse-induced rewarding effects and hyperlocomotion in the mouse. Furthermore, the organogenesis and lactation are the most important period to cause the alteration of dopaminergic system by bisphenol-A exposure in the mouse.

Mice exposed to various stresses, especially restrained-stress, revealed the anxiogenic effect detected by the light-dark test. Under this condition, a remarkable decrease in [35S]GTPgammaS binding to membranes from the prefrontal cortex, amygdala and hypothalamus of restrained-stress mice stimulated by the selective 5-HT1A receptor agonist 5-carboxamidotriptamine (5-CT) was clearly observed, whereas a significant increase in [35S]GTPgammaS binding stimulated by the 5-HT1A receptor agonist was clearly observed in the dorsal raphe nuclei (DRN) of restrained-stress mice. The immunohistochemical study showed a drastic reduction in phosphorylated-CREB-like immunoreactivity in the DRN of restrained-stress mice. Furthermore, we found a drastic reduction in myelin-associated glycoprotein (MAG)-like immunoreactivity (MAG-IR) in the DRN, amygdala and hypothalamus, indicating the direct suppression of synaptic transmission in these regions. It has been accepted that GSK3beta in the Wnt signal pathway plays an important role in various neuronal functions including apoptosis, clustering of synapsin I and early growth and axonal remodeling. In the present study, the increase in protein levels of GSK3beta and phosphorylated-GSK3beta to cytosol fractions of the amygdala was noted in restrained-stress mice. Taken together, these results suggest that restrained stress may directly affect the 5-HT1A receptor-regulated synaptic transmission in the brain, leading to the expression of the anxiogenic effect in mice. It is well known that various stresses induce intracellular oxidative stress. The present study was then undertaken to investigate the effect of the stimulation of 5-HT1A receptors on oxidative stress. Treatment with H2O2 caused the activation of caspase-3-positive cells and the reduction in levels of MAG-IR in the limbic neuron/glia cocultures as compared to medium alone. The stimulation of 5-HT1A receptor by 5-CT produced a dramatic protection against H2O2-triggered activation of caspase-3 and reduction in levels of MAG-IR. These results suggest that 5-HT1A receptors were involved in the modulation of anxiety and the understanding of molecular mechanisms of 5-HT1A receptor-related cascades may pave the way for new therapeutic strategies for affective disorders.