臺灣博碩士論文加值系統

最近幾年研究指出，若幼鼠在新生階段暴露在血壓胺回收抑制劑（selective serotonin reuptake inhibitors, SSRIs）下，將會使得幼鼠腦中血壓胺神經元系統異常，而這些異常會持續到成鼠（Maciag et al., 2006）。我們將利用此一策略進一步研究延腦血壓胺神經元系統異常，是否會造成自主神經功能改變。在幼鼠出生後第八至二十一天（postnatal day, PN8-21），以皮下注射的方式分別施打生理食鹽水或血壓胺回收抑制劑（Citalopram, 10 mg/kg, twice daily），結果顯示實驗組動物的血壓胺速率決定酵素──色胺酸氫化酶（tryptophan hydroxylase, TPH）在幼鼠（PN22-24）與成鼠（PN64-84）腦中縫合核群之表現量相對於控制組顯著減少。生理方面，以無線遙測記錄的方式（telemetry）分別量測實驗組與控制組成鼠在放鬆與緊張情況下之心率與平均動脈壓，並分析兩組動物的心率變異性（heart rate variability），利用頻譜分析（power spectral analysis）來量化交感神經與副交感神經活性，並比較兩組動物的自發性感壓反射敏感度（spontaneous baroreflex sensitivity）。實驗結果顯示SSRI處理動物的交感與副交感神經活性明顯失衡，具有較高的交感神經活性與較低的副交感神經活性；其調控血壓之能力也明顯變差。顯示新生幼鼠暴露於SSRI下，已造成成鼠延腦血壓胺神經網路異常以及調控心血管的自主神經功能受損。

Recent studies have reported that exposure to highly selective serotonin reuptake inhibitors (SSRIs), citalopram, during neonatal stage in rodents produced profound changes in the serotonergic system. Such neurochemical alterations persisted into adulthood (Maciag et al., 2006). We further utilize such strategy to investigate whether the effects of serotonergic abnormalities in medulla play a role on the autonomic function. Rat pups were injected with either saline or citalopram (10 mg/kg, twice daily, s.c.) from postnatal (PN) day 8 to 21. The animals were then studied either at PN22-24 or at PN64-84. The changes of medullary serotonergic system were examined and compared between the two groups. The chronic neonatal exposure to citalopram results in profound reductions of the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase, TPH) in raphe nuclei. Heart rate (HR) and mean arterial pressure (MAP) were monitored by telemetry in freely moving adult rats. The autonomic function were compared between saline- and SSRI-treated animals in resting and stress conditions by means of spectral analysis of heart rate variabilities and spontaneous baroreflex sensitivity (sBRS). SSRI-treated animals showed an imbalance autonomic function including an increased sympathetic modulation and a decreased parasympathetic tone, that accompanied by reduced sBRS. Our present findings provide a potential link between serotonergic abnormality and cardiovascular dysfunction.

Table of Contents
Abbreviations…………………………………………………………6

Introduction…………………………………………………………7
Serotonergic system………………………………………………………………… ……7
Medulla: the cardiorespiratory and autonomic control center………………………………8
Heart rate variability………………………………………………………………………12
Spectral analysis of heart rate variability…………………………………………………13
Blood pressure variability…………………………………………………………………15
Spontaneous baroreflex sensitivity……………………………………………………16
Neonatal Exposure to SSRIs…………………………………………………………17
Purpose of the present study………………………………………………………19

Materials and Methods……………………………………………………20
Animals……………………………………………………………………………………20
TPH Immunocytochemistry ………………………………………………………………20
Intensity analysis………………………………………………………………………21
Cell quantification ……………………………………………………………………22
Telemetry probe implantation………………………………………………………………23
Physiological Test………………………………………………………………………23
Spectra analysis of HRV and BPV…………………………………………………………24
Spontaneous baroreflex sensitivity…………………………………………………………25
Statistical analysis…………………………………………………………………………25

Results………………………………………………………………………26
Effects of Neonatal SSRI exposure on body weight………………………………………26
Effects of Neonatal SSRI exposure on serotonergic cell numbers…………………………26
Effects of Neonatal SSRI exposure on immunoreactivity of TPH………………………27
Effects of Neonatal SSRI exposure on BP, HR, and body temperature……………………28
Effects of Neonatal SSRI exposure on recovery time……………………………………29
Effects of Neonatal SSRI exposure on autonomic function………………………………29
Effects of Neonatal SSRI exposure on sBRS……………………………………………30

Discussion……………………………………………………………………31
Effects of neonatal exposure to citalopram on serotonergic neurons of RMg and ROb………………………………………………………………………………………31
Effects of neonatal citalopram exposure on autonomic function…………………………32
Conclusion and perspectives………………………………………………………………35
References…………………………………………………………………37

Figures……………………………………………………………………52

Appendix……………………………………………………………………66
TPH immunostaining protocol……………………………………………………………66

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