Warburton E.C., Mitchell S.N., Joseph M.H.
MRC Behavioural Neurochemistry Group, Department of Psychology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
Behav Pharmacol. 1996 Mar;7(2):119-129.
Repeated amphetamine treatment results in sensitisation both of its behavioural effects, and of its dopamine (DA)-releasing effects on which the former largely depend. Understanding the nature of the sensitised response may help to explain behaviours which emerge only with repeated treatment, such as particular stereotypies and effects on social behaviour in animals, and links between these effects and the emergence of dependence and psychotic symptoms in humans. We show here that a single pretreatment with amphetamine (1mg/kg) is sufficient to sensitise the locomotor response to amphetamine challenge (1mg/kg) 24h later. We have used in vivo microdialysis in the nucleus accumbens in unrestrained rats to demonstrate a corresponding potentiation in the DA response; the marked increase in accumbens dialysate DA following amphetamine (to 427% of basal) was significantly potentiated (to 675% of basal) by the pretreatment, without any alteration in the basal DA. There was also no change in the expected reduction in DA metabolites. Replacement of perfusate calcium by magnesium left the response to acute amphetamine challenge substantially unaffected, as expected from previous reports; however, the potentiation of the DA response by amphetamine pretreatment was prevented. Similarly the potentiated response was attenuated by administration of ondansetron, a 5HT-3 antagonist, (0.01mg/kg) before each amphetamine treatment. The ability of amphetamine to disrupt latent inhibition (L1), which is also disrupted in acute schizophrenia, has been suggested to provide a model of schizophrenia linking underlying cognitive deficits with the DA theory of the disorder. Since LI is disrupted by two systemic administrations of amphetamine 24h apart, but not by one, the present results are consistent with the concept that it is the calcium, and hence impulse, dependence of increased accumbal DA release, rather than its magnitude, which is critical for the disruption of LI.
反复给予苯丙胺会导致其行为效应以及多巴胺（DA）释放效应出现敏感化，而前者很大程度上依赖于后者。了解敏感化反应的本质可能有助于解释仅在反复治疗后才出现的行为，例如动物的特定刻板行为和对社会行为的影响，以及这些影响与人类依赖和精神病症状出现之间的联系。我们在此表明，单次给予苯丙胺（1mg/kg）预处理足以使24小时后对苯丙胺激发（1mg/kg）的运动反应敏感化。我们在未束缚大鼠的伏隔核中使用体内微透析来证明DA反应的相应增强；苯丙胺给药后伏隔核透析液中DA显著增加（达到基础值的427%），而预处理使其进一步显著增强（达到基础值的675%），基础DA水平未发生改变。DA代谢产物预期的减少也没有变化。正如先前报道所预期的那样，用镁替代灌注液中的钙对急性苯丙胺激发的反应基本没有影响；然而，苯丙胺预处理对DA反应的增强作用被阻止。同样，在每次苯丙胺治疗前给予5HT - 3拮抗剂昂丹司琼（0.01mg/kg）会减弱增强的反应。苯丙胺破坏潜伏抑制（LI）的能力——这在急性精神分裂症中也会被破坏——被认为提供了一个将潜在认知缺陷与该疾病的DA理论联系起来的精神分裂症模型。由于相隔24小时两次全身给予苯丙胺会破坏LI，但单次给予则不会，所以目前的结果与这样的概念一致，即对于LI的破坏而言，关键的是伏隔核DA释放增加对钙的依赖性，进而对冲动的依赖性，而非其释放量。
