Research reportPrenatal nicotine exposure affects the development of the central serotonergic system as well as the dopaminergic system in rat offspring: involvement of route of drug administrations
Introduction
Tobacco smoking during pregnancy has been reported to be associated with behavioral abnormalities in children, e.g., attention deficit, hyperactivity and retardation in reading and writing 3, 14, 16. Several animal studies support the idea that nicotine is a “behavioral teratogen” 6, 8, 20, 25, 26, 31, 40. The neurochemical alterations induced by prenatal nicotine exposure have also been well documented by several investigators, indicating that prenatal nicotine affects the development of central noradrenergic 12, 13, 18, 22, 30, 32, 36, 37, dopaminergic 12, 13, 18, 30, 37and cholinergic systems 12, 13, 17, 36, 39, 45in the rat brain. However, regarding the effect of nicotine on the development of the serotonergic system, there are only a few reports 9, 29.
With regard to the prenatal nicotine administration, some different routes of administration have been employed, e.g., injection, infusion and via drinking water. Among these administration routes, subcutaneous injection of nicotine is thought to be a potent stressor because an acute increase in nicotine concentration to the dams causes transient ischemia and hypoxia to both mother and fetus. This explanation is supported by the evidence that there are behavioral and biochemical similarities between the effects of maternally injected nicotine and experimental hypoxia [36]. In addition, the subcutaneous injection itself, whether nicotine is included or not, might be a potent factor affecting the brain functions 4, 10, 21, 23, 24, e.g., central serotonergic functions and responsiveness to stressful stimuli. In contrast to the nicotine injection into the dams, the infusion of nicotine via subcutaneously implanted osmotic minipumps induces neither ischemia nor hypoxia 13, 36and is not accompanied by a stressful situation such as injection.
In the present study, we examined the effect of prenatal nicotine exposure by two different routes of administration (injection and infusion) on the development of the central monoaminergic systems and discussed the effect of “prenatal stress” accompanied by nicotine administrations.
With respect to behavioral changes induced by prenatal treatments, Peters indicated hypersensitivity to novel environment using open field test in the rat given stressful manipulation prenatally and also the involvement of serotonergic dysfunctions in these rats [24]. On the other hand, prenatal nicotine exposure was reported to result in the changes in spontaneous activity related to dopaminergic dysfunctions 6, 25. Clinical study also reported that maternal nicotine or smoking induce some adverse effects to behavioral parameters in children including short attention span or hyperactivity [12]. We performed open field test to clarify interrelationship between stress and nicotine exposure during prenatal period on spontaneous activity and stress responsiveness in the neonatal and juvenile rat in this experiment.
We chose the daily dose (6 mg/kg/day) in this animal study, which total daily dose has been compared to those obtained in humans who smoke 2–3 packages of cigarettes/day 13, 36.
Section snippets
Animal treatments
Male and female Sprague–Dawley rats were mated in our laboratory. The morning on which sperm-positive smears were obtained was determined to be GD0. Pregnant rats were housed individually under standard conditions (12-h light/12-h dark cycle, light on 08:00 h) given food and water ad libitum. The pregnant rats were randomly divided into four groups, the Control-Injection group (C-Inj), Nicotine-Injection group (N-Inj), Control-Infusion group (C-Inf) and Nicotine-Infusion group (N-Inf). These
Results
Significant values of the factors of nicotine and route in the two-way ANOVA showed the effects of the nicotine exposure and the injection compared with the infusion, respectively.
Discussion
Our present data showed various disturbances in the development of the monoaminergic nervous systems in the offspring from dams exposed to nicotine by injection and infusion.
The persistent reduction of DA turnover caused by prenatal nicotine exposure in the forebrain is consistent with results reported previously by Navarro [18]or Lichtensteiger 12, 13. These authors have reported reduced dopaminergic neuronal activity in the forebrain or cortex induced by prenatal nicotine exposure by
Acknowledgements
We thank Miss Hisako Nakamura for kind assistance for our experiments.
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