Effects of fenfluramine on free-operant timing behaviour:: evidence for involvement of 5-HT2A receptors
Effects of fenfluramine on free-operant timing behaviour:: evidence for involvement of 5-HT2A receptors
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DOI：
10.1007/s00213-004-1871-1
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发表时间：
2004-11-01
影响因子：
3.4
通讯作者：
Szabadi, E
中科院分区：
文献类型：
--
作者：
Body, S;Kheramin, S;Szabadi, E
理论基础：自由操作的心理物理过程中的时间分化对5-羟色胺(5-HT)(1A)受体激动剂8-羟基-2-(二正丙氨基)-四氢呋喃(8-OH-DPAT)和5-HT2受体激动剂2，5-二甲氧基-4-碘苯丙胺(DOI)敏感；这两种药物都使心理物理曲线左移，降低了无差别点T-50。我们研究了5-羟色胺释放剂芬氟拉明对颞叶分化的影响。目的：研究5-羟色胺受体拮抗剂N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide(Way-100635)和5-羟色胺受体拮抗剂酮丝林能否拮抗芬氟拉明的时间分化作用，并比较芬氟拉明、DOI和8-OH-DPAT对正常大鼠和5，7-二羟色胺破坏5-羟色胺能通路的大鼠的影响。方法：在50只S实验中，大鼠在自由操作的心理物理程序下训练按压杠杆A和B，试验的前半部分间歇提供增强剂，试验后半部分对A和B进行反应。在连续的5-S时期记录对B的反应百分比(%B)；将Logistic心理物理曲线与时间指数(T-50，对应于%B的时间=50%，以及韦伯分数)进行拟合，以得出计时指数。实验1检测芬氟拉明的急性治疗效果，以及芬氟拉明与5-HT1A和5-HT2A受体拮抗剂Way-100635和酮丝林的相互作用；实验2比较芬氟拉明、8-OH-DPAT和DOI对正常大鼠和5，7-二羟色胺破坏5-H能通路的大鼠的影响。用高效液相色谱法测定脑组织中5-羟色胺和儿茶酚胺的浓度。结果：实验1：芬氟拉明(2 mg/kg)降低T(50)，这种作用可被酮色林(1 mg/kg)减弱，但不能被100635(100 mg/kg)所减弱。实验2：8-OH-DPAT(100µg/kg)和DOI(250µg/kg)降低两组T-50，芬氟拉明仅在假手术组降低T-50。损伤组5-羟色胺水平降低80%，儿茶酚胺水平未受影响。结论：芬氟拉明通过释放主要作用于突触后5-HT2a受体的内源性5-羟色胺来影响颞叶分化。
Rationale: Temporal differentiation in the free-operant psychophysical procedure is sensitive to the 5-hydroxytryptamine (5-HT)(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI); both drugs shift the psychophysical curve leftwards, reducing the indifference point, T-50. We have examined the effect of the 5-HT releasing agent fenfluramine on temporal differentiation. Objective: We examined whether fenfluramine's effect on temporal differentiation can be antagonised by the 5-HT1A receptor antagonist N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY-100635) and the 5-HT2A receptor antagonist ketanserin, and compared the effects of fenfluramine, DOI and 8-OH-DPAT in intact rats and rats whose 5-HTergic pathways had been destroyed by 5,7-dihydroxytryptamine. Methods: Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data for derivation of timing indices (T-50, time corresponding to %B=50%, and Weber fraction). Experiment 1 examined the effects of acute treatment with fenfluramine, and the interaction between fenfluramine and the 5-HT1A and 5-HT2A receptor antagonists WAY-100635 and ketanserin; experiment 2 compared the effects of fenfluramine, 8-OH-DPAT and DOI in intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Concentrations of 5-HT and catecholamines in the brain were measured by high-performance liquid chromatography. Results: Experiment 1: fenfluramine (2 mg/kg) reduced T (50); this effect was attenuated by ketanserin (1.0 mg/kg) but not by WAY-100635 (100 mug/kg). Experiment 2: 8-OH-DPAT (100 mug/kg) and DOI (250 mug/kg) reduced T-50 in both groups; fenfluramine reduced T-50 only in the sham-lesioned group. Levels of 5-HT were reduced by 80% in the lesioned group; catecholamine levels were not affected. Conclusions: The results suggest that fenfluramine affects temporal differentiation via the release of endogenous 5-HT which acts mainly on postsynaptic 5-HT2A receptors.