Richtand Neil M, Welge Jeffrey A, Levant Beth, Logue Aaron D, Hayes Scott, Pritchard Laurel M, Geracioti Thomas D, Coolen Lique M, Berger S Paul
Department of Psychiatry V-116A, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA.
Neuropsychopharmacology. 2003 Aug;28(8):1422-32. doi: 10.1038/sj.npp.1300182. Epub 2003 Apr 16.
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.
行为敏化是指重复使用药物后某些行为的渐进性和持久性增强，部分由多巴胺能通路介导。对药物治疗的运动反应增加是一种可敏化的行为，它受到多巴胺受体亚型相反平衡的调节，D1/D2多巴胺受体刺激会增强，而D3多巴胺受体激活会抑制苯丙胺诱导的运动。我们假设D3受体运动抑制的耐受性有助于行为敏化。为了检验行为敏化的表达部分源于D3受体介导的抑制作用的释放，从而导致对D3受体激动剂的反应降低这一假设，我们研究了重复给予苯丙胺对D3受体偏好性激动剂7-OH-DPAT和PD 128907行为反应的影响。最近已描述了这两种药物在低剂量时的D3选择性作用。在重复治疗方案完成后1周，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7-OH-DPAT和PD 128907的D3选择性剂量的反应降低。此外，除了反应的定量改变外，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的运动抑制反应与对苯丙胺的运动兴奋反应之间存在高度显著的负相关。相比之下，在重复苯丙胺治疗10天后，未检测到对PD 128907和苯丙胺反应之间的关系。观察到的行为改变不能用腹侧纹状体中D3受体结合的变化来解释。这些发现表明，D3受体介导的抑制性影响的持续释放有助于对苯丙胺的行为敏化的表达。
