The 5-Hydroxytryptamine2A Receptor Antagonist R-(+)-α-( 2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) Attenuates Impulsivity after Both Drug-Induced Disruption (Dizocilpine) and Enhancement (Antidepressant Drugs) of Differential-Reinforcement-of-Low-Rate 72-s Behavior in the Rat
The 5-Hydroxytryptamine2A Receptor Antagonist R-(+)-α-( 2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) Attenuates Impulsivity after Both Drug-Induced Disruption (Dizocilpine) and Enhancement (Antidepressant Drugs) of Differential-Reinforcement-of-Low-Rate 72-s Behavior in the Rat
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DOI：
10.1124/jpet.108.143370
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Marek, Gerard J.
中科院分区：
文献类型：
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作者：
Ardayfio, Paul A.;Benvenga, Mark J.;Marek, Gerard J.
以前的工作表明，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂和5-羟色胺（5-HT）（2A）受体阻断剂可能会增强和减弱，分别由皮质丘脑纹状体回路介导的某些类型的冲动。更具体地说，过去5-HT 2A受体拮抗剂和氟西汀对操作性强化的低速率差异强化（DRL）72-s时间表的协同“抗抑郁样”作用的证明可能说明5-HT 2A受体阻滞剂在反应抑制方面的作用是与运动冲动相关的重要前额叶皮层执行功能。为了检查5-HT 2A受体阻断剂可对冲动性发挥作用的动态范围，单独检查[R-（+）-α-（2，3-二甲氧基苯基）-1-[2-（4-氟苯基）乙基-4-哌啶甲醇]（M100907）和与拟精神病NMDA受体拮抗剂地佐环平[例如，（-）-5-甲基-10，11-二氢-5H-二苯并[a，d]环庚烯-5，10-亚胺马来酸盐; MK-801]和两种不同的抗抑郁药，三环类抗抑郁药去甲基丙咪嗪（DEMETHYIMIMIMAMINE，简称DEMETHYIMIMAMINE）和单胺氧化酶抑制剂反苯环丙胺（TRANICYPROMIN）在DRL 72-S方案下进行的大鼠中。MK-801增加了应答率，减少了获得的应答者数量，并如预期的那样使应答时间间（IRT）分布发生了显著偏移。M100907本身对DRL行为产生最小影响的剂量减弱了MK-801的拟精神病效应。扩展了先前的M100907-氟西汀观察结果，在低剂量阿托伐他汀和反苯环丙胺中添加最低活性剂量的M100907可增强抗抑郁药的抗抑郁样作用。因此，可能是5-HT 2A受体的紧张性兴奋在广泛的动态范围内调节皮质丘脑纹状体回路的冲动性和功能。
Previous work has suggested that N-methyl-D-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT)(2A) receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic "antidepressant-like" effects of a 5-HT2A receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of operant reinforcement may speak to the role of 5-HT2A receptor blockade with respect to response inhibition as an important prefrontal cortical executive function relating to motor impulsivity. To examine the dynamic range over which 5-HT2A receptor blockade may exert effects on impulsivity, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol] (M100907) was examined both alone and in combination with the psychotomimetic NMDA receptor antagonist dizocilpine [e.g., (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; MK-801] and two different antidepressants, the tricyclic antidepressant desmethylimipramine (DMI) and the monoamine oxidase inhibitor tranylcypromine in rats performing under a DRL 72-s schedule. MK-801 increased the response rate, decreased the number of reinforcers obtained, and exerted a leftward shift in the inter-response time (IRT) distribution as expected. A dose of M100907 that exerted minimal effect on DRL behavior by itself attenuated the psychotomimetic effects of MK-801. Extending previous M100907-fluoxetine observations, addition of a minimally active dose of M100907 to low doses of DMI and tranylcypromine enhanced the antidepressant-like effect of the antidepressants. Therefore, it may be that a tonic excitation of 5-HT2A receptors modulates impulsivity and function of corticothalamostriatal circuits over an extensive dynamic range.