Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective α2A-adrenoceptor antagonism
Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective α2A-adrenoceptor antagonism
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DOI：
10.1017/s1461145709991088
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发表时间：
2010-10-01
影响因子：
4.8
通讯作者：
Beyer, Chad E.
中科院分区：
文献类型：
--
作者：
Dwyer, Jason M.;Platt, Brian J.;Beyer, Chad E.
生物胺如去甲肾上腺素、多巴胺和血清素在治疗情绪障碍和某些类型的疼痛中起着众所周知的作用。由于α（2A）-肾上腺素受体调节这些神经递质的释放，我们检查了BRL 44408的治疗潜力，BRL 44408是一种有效（Ki =8.5 nM）和选择性（>50倍）α（2A）-肾上腺素受体拮抗剂（K-B=7.9 nM）。在大鼠中，BRL 44408渗透中枢神经系统，导致脑和血浆峰浓度分别为586 ng/g和1124 ng/ml。在药效学试验中，对在固定比率30操作性反应范例下反应的大鼠进行BRL 44408预处理，导致可乐定剂量-反应曲线发生显著偏移，这是体内α（2）-肾上腺素受体拮抗作用的一种指示性效应。与突触前自身受体拮抗作用和神经递质释放的紧张性调节一致，BRL 44408的急性给药升高了内侧前额叶皮质中去甲肾上腺素和多巴胺的细胞外浓度，但不升高血清素。此外，BRL 44408可能通过抑制α（2A）异受体，使乙酰胆碱皮质水平显著增加。在强迫游泳试验和时间表诱导的烦渴试验中，BRL 44408分别通过剂量依赖性地减少不动时间和连续饮水量产生抗抑郁样反应，而在内脏痛模型中，BRL 44408通过减少对苯基醌（PPQ）诱导的腹部拉伸表现出镇痛活性。最后，BRL 44408没有产生整体运动协调的缺陷，也没有改变一般运动活动。BRL 44408的神经化学和行为特征的临床前表征表明，α（2A）-肾上腺素受体的选择性拮抗作用可能是情绪障碍和内脏痛的有效治疗策略。
Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha(2A)-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (K-i=8.5 nM) and selective (>50-fold) alpha(2A)-adrenoceptor antagonist (K-B=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha(2)-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha(2A) heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha(2A)-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.