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KMID : 0361519990100010071
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Korean Journal of Psychopharmacology
1999 Volume.10 No. 1 p.71 ~ p.79
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Effect of Trazodone on the Rat Cerebral Hemodynamics
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Hong Jae-Yong
Byun Won-Tan
Shin Hwa-Kyung
Ko Su-Yeon
Lee Won-Suk
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Abstract
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Objectives：The present study assessed the effect of trazodone on the cerebral hemodynamics of male Sprague-Dawley rats.
Method：The changes of regional cerebral blood flow (rCBF) and pial arterial diameter were measured by laser-Doppler flowmetry and by a videomicroscopy, respectively. The changes in vascular tone and intracellular free Ca2＋ concentration ([Ca2＋] i) of isolated basilar artery were simultaneously measured using a small vessel myograph and a cation measurement system, respectively.
Result：Both the rCBF and the pial arterial diameter were dose-dependently decreased by systemic administration of trazodone (0.3-110 mg/kg,i.v.), but not by topical application of trazodone (10-300 μM). Pretreatment with 5-HT2A/2C receptor antagonist (ketanserin or ritanserin, 1 mg/kg, i.v., respectively) significantly blocked the changes in rCBF induced by trazodone. m-Chlorophenylpiperazine (mCPP；0.1-3 mg/kg, i.v. or 5-500 μM, topical), a major active metabolite of trazodone, also dose-dependently decreased the rCBF as well as the pial arterial diameter. The mCPP-induced decreases in rCBF were significantly blocked by ketanserin. Pretreatment with itraconazole (1 mg/kg, p.o.), a selective inhibitor of CYP3A4, a subfamily of cytochrome P450, markedly attenuated the trazodone-induced changes in rCBF. In an isolated rat basilar arterial strip loaded with fura-2/AM, mCPP (5-500 μM) caused a vasoconstriction in association with increases in [Ca2＋] i in a concentration-dependent manner. Pretreatment with 1 μM ketanserin strongly blocked the effects of mCPP on the vascular tone as well as on the [Ca2＋] i of rat basilar artery.
Conclusion：These results suggest that trazodone decreases rCBF through stimulation of 5-HT 2A/2C receptors by its active metabolite, mCPP.
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KEYWORD
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Trazodone, Cerebral hemodynamics, m-Chlorophenylpiperazine, 5-HT2A/2C receptors
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