5-HT2A and α1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants
5-HT2A and α1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants
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DOI：
10.1111/j.1460-9568.2004.03805.x
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发表时间：
2004-12-01
影响因子：
3.4
通讯作者：
Tassin, JP
中科院分区：
文献类型：
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作者：
Auclair, A;Drouin, C;Tassin, JP
滥用药物的成瘾特性通常被认为是由腹侧纹状体中多巴胺(DA)释放增加所介导的。然而，最近的实验表明，α1b-肾上腺素能受体与精神刺激剂和鸦片类药物的行为反应有关。结果表明，吗啡(20 mg/kg)诱导的腹侧纹状体DA释放可被α1肾上腺素能拮抗剂哌唑嗪(1 mg/kg)完全阻断。然而，在α1b-肾上腺素能受体(Alpha1b-AR KO)缺失的小鼠和野生型(WT)小鼠中，发现吗啡诱导的腹侧纹状体DA释放的增加是相似的，这表明存在代偿机制。5-HT2A拮抗剂SR46349B(1 mg/kg)可完全阻断α1b-AR KO小鼠吗啡诱发的这种急性DA释放。SR46349B还完全阻断了Alpha1b-AR KO小鼠的运动反应和对吗啡(20 mg/kg)和D-苯丙胺(2 mg/kg)的行为敏化发展。因此，同时阻断WT小鼠的5-HT2a和α1b-肾上腺素能受体，不仅完全阻止了急性运动反应，而且还阻止了对吗啡、D-苯丙胺或可卡因(10 mg/kg)的行为敏化发展。然而，我们观察到，在未出生的WT小鼠中，每个拮抗剂对吗啡或D-苯丙胺的运动反应的抑制作用超过相加(160%)，但在对这两种药物敏感的小鼠中没有抑制作用。由于后者的数据和5-HT2a受体对α1b-肾上腺素能受体基因缺失的可能补偿，我们假设这些受体之间存在功能联系，这种联系在行为敏化的发展过程中消失。
Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of alpha1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an alpha1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the alpha1b-adrenergic receptor (alpha1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in alpha1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in alpha1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and alpha1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naive WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of alpha1b-adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.