ABSTRACT
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 pill 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 pill arterial diameter were dose-dependently decreased by systemic administration of trazodone(0.3-10 mg/kg, i.v.), but not by topical application of trazodone(10-300 micrometer). Pretreatment with 5-HT(2A/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 micrometer 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 micrometer caused a vasoconstriction in association with increases in [Ca2+]i, in a concentration-dependent manner. Pretreatment with 1 micrometerketanserin 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.
Subject(s)
Animals , Humans , Male , Rats , Basilar Artery , Cytochrome P-450 Enzyme System , Hemodynamics , Ketanserin , Laser-Doppler Flowmetry , Microscopy, Video , Rats, Sprague-Dawley , Ritanserin , Trazodone , VasoconstrictionABSTRACT
OBJECTIVES: This study was designed to investigate the effect of antipsychotic drugs (chlorpromazine, haloperidol and clozapine) on the cerebral hemodynamics including the changes in regional cerebral blood flow(rCBF) and the pill arteriolar diameter of male Sprague-Dawley rats. METHODS: The changes in rCBF were determined by laser-Doppler flowmetry, and the changes in diameter of pill arteriole were measured through a closed cranial window. RESULTS: Clozapine(0.1~10 microgram/kg, i.v. or 0.03~3 micrometer caused an increase in rCBF in association with a vasodilation of pill arteriole in a dose-dependent miner, whereas chlorpromazine and haloperidol(5~500 microgram/kg, i.v., or respectively) were without effect on rCBF. Clozapine-induced increases in rCBF were significantly blocked by topical pretrfatment with NMDA receptor blockers(MgCl(2), MK-801, ketamine and D(-)-2-amino-5-phosphonopentanoic acid). Constitutive nitric oxide synthase inhibitors (N(G)-nitro-L-arginine, 7-nitroindazole and diphenyleneiodonium) markedly inhibited the clozapine-induced increases in rCBF. However, aminoguanidine, an inducible nitric oxide synthase inhibitor did not affect the clozapine-induced increases in rCBF. Inhibitors of soluble guanylyl cyclase(methylene blue and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly attenuated the clozapine-induced increases in rCBF. CONCLUSION: These results suggest that typical antipsychotic drugs are without effect on rCBF, but atypical antipsychotir drug clozapine exerts an increase in rCBF with pial arteriolar dilation via mediation of NMDA receptor stimulation, and thereby, leading to activation of neuronal and endothelial nitric oxide synthases and increase in cyclic GMP formation.
Subject(s)
Animals , Humans , Male , Rats , Antipsychotic Agents , Arterioles , Chlorpromazine , Clozapine , Cyclic GMP , Dizocilpine Maleate , Haloperidol , Hemodynamics , Ketamine , Laser-Doppler Flowmetry , N-Methylaspartate , Negotiating , Neurons , Nitric Oxide , Nitric Oxide Synthase , Nitric Oxide Synthase Type II , Rats, Sprague-Dawley , VasodilationABSTRACT
The cognive evoked potential has been used as an objective test of the human cognitive function. The most prominent component of cognitive evoked potential is P3 (also known as the P300) which has been linked in many studies with cognitive function. According to many studies. The latency of P3 corresponds to time involved in stimulus evaluation and categorization. 15 chronic alcoholics and 15 normal controls were studied on the cognitive evoked potential to evaluatt impairment of cognitive function using the auditory stimulus of odd-ball procedure. We measured latencies and arnplitudes of P3 on 20 sites according to the international 10-20 systern for electrode placement, and results were as follows: .1. All latencies of P3 were significantly longer for chronic alcoholics than in norrnal controls on 20 sites. 2. All amplitudes ot P3 were not significantly different between chronic alcoholics and normal controls on 20 sites. 3. P3 arnplitude of chronic alcoholics was highest on Pz, and P4. Fz, C4. F4, and Cz in order. But in normal controls. P3 amplitudes were highest on Fz. And Cz. Pz P4, F4, and C4 in order. With these results, it is suggested that the prolongation of P3 latencies of chronic alcoholics is related to their cognitive impairment.