Altered behavioral response to dopamine D3 receptor agonists 7-OH-DPAT and PD 128907 following repetitive amphetamine administration
Altered behavioral response to dopamine D3 receptor agonists 7-OH-DPAT and PD 128907 following repetitive amphetamine administration
复制标题
DOI：
10.1038/sj.npp.1300182
复制
发表时间：
2003-08-01
影响因子：
7.6
通讯作者：
Berger, SP
中科院分区：
文献类型：
--
作者：
Richtand, NM;Welge, JA;Berger, SP
行为敏感化，即重复使用药物后某些行为的渐进和持久的增强，部分是由多巴胺能通路介导的。对药物治疗增加的运动反应是一种敏感行为，受多巴胺受体亚型的相反平衡调节，其中D1/D2多巴胺受体刺激增加，D3多巴胺受体激活抑制苯丙胺诱导的运动。我们假设对D3受体运动抑制的耐受性有助于行为敏化。为了验证行为敏化表达的部分原因是释放D3受体介导的抑制，从而导致对D3受体激动剂的反应降低的假设，我们考察了重复给予苯丙胺对D3受体首选激动剂7-OH-DPAT和PD 128907的行为反应的影响。最近，这两种药物在低剂量下都有D3选择性作用的描述。在重复治疗方案完成一周后，与接受生理盐水预处理的动物相比，苯丙胺预处理的大鼠对D3选择性剂量的7-OH-DPAT和PD 128907的反应降低。此外，除了反应的数量变化外，对苯丙胺和D3激动剂的反应之间的相互关系也发生了变化。在苯丙胺治疗前，观察到对PD 128907的运动抑制反应和对苯丙胺的运动兴奋反应之间存在高度显著的负相关。相反，在重复安非他明治疗10天后，没有检测到PD 128907和安非他明的反应之间的关系。观察到的行为改变不能用腹侧纹状体D3受体结合的变化来解释。这些发现表明，D3受体介导的抑制影响的持续释放有助于苯丙胺行为敏化的表达。
Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.