Clark D, Overton P G
Neuropsychophar macology Laboratory, Department of Psychology, University of Wales Swansea UK.
Addict Biol. 1998 Apr;3(2):109-35. doi: 10.1080/13556219872191.
Repeated, intermittent administration of the psychostimulants d-amphetamine and cocaine, as well as other drugs of abuse, leads to an enduring augmentation of certain behavioural responses (e.g. locomotor activity) produced by these drugs. This behavioural sensitization has been the subject of considerable interest due to its potential relevance to drug addiction. Repeated administration of d-amphetamine also leads to an enhancement in the ability of electrical stimulation of the prefrontal cortex to induce burst firing in midbrain dopaminergic (DA) neurones. This hyper-responsiveness probably reflects a potentiation of transmission at excitatory amino acid (EAA)ergic synapses on DA neurones. In addition, we have previously reported that selective activation of mineralocorticoid receptors (MRs) by corticosterone leads to a potentiation of EAA-induced burst firing in midbrain DA neurones, an effect antagonized by glucocorticoid receptor (GR) activation. In this review article, we propose a model describing how drugs of abuse and stress alter EAA function at the level of DA cells in the ventral tegmental area (VTA), which can result in a long-lasting impact on behaviour. D-amphetamine produces a transitory increase in EAA-mediated transmission at the level of DA cells in the VTA, which triggers a more long-lasting change in EAAergic function resembling hippocampal long-term potentiation. Dopaminergic burst events are likely to be a critical link between enhanced EAAergic activity in afferents synapsing on DA neurones and plasticity at these synapses, by increasing calcium transport into the cell, which is known to be an important factor in synaptic plasticity. Selective MR occupation by corticosterone in the VTA facilitates the development of this plasticity. However, we hypothesize that during stress, GR-occupation also activates EAAergic afferents to DA neurones in a manner similar to that following psychostimulants. Under these circumstances, GR-occupation acts via circuitry external to the VTA, which may include the hippocampus. Thus, potentiation of EAAergic synapses on DA neurones in the VTA may represent a final common pathway by which two divserse means (psychostimulants and stress) achieve the same end (sensitization). Alterations in EAA-mediated transmission at the level of DA cells not only plays a critical role in the induction of behavioural sensitization, but probably continues to produce abnormal DA cell responses in the drug-free situation.
反复、间歇性给予精神兴奋剂右旋苯丙胺和可卡因以及其他滥用药物，会导致这些药物所产生的某些行为反应（如运动活性）持久增强。由于其与药物成瘾的潜在相关性，这种行为敏化一直备受关注。反复给予右旋苯丙胺还会增强前额叶皮质电刺激诱导中脑多巴胺能（DA）神经元爆发式放电的能力。这种高反应性可能反映了DA神经元上兴奋性氨基酸（EAA）能突触传递的增强。此外，我们之前曾报道，皮质酮对盐皮质激素受体（MRs）的选择性激活会导致中脑DA神经元中EAA诱导的爆发式放电增强，而糖皮质激素受体（GR）激活则会拮抗这一效应。在这篇综述文章中，我们提出了一个模型，描述滥用药物和应激如何在腹侧被盖区（VTA）的DA细胞水平上改变EAA功能，这可能会对行为产生持久影响。右旋苯丙胺会使VTA中DA细胞水平的EAA介导的传递产生短暂增加，这会引发EAA能功能更持久的变化，类似于海马体的长时程增强。多巴胺能爆发事件可能是在DA神经元上突触的传入神经中增强的EAA能活性与这些突触可塑性之间的关键联系，通过增加钙向细胞内的转运来实现，而钙转运已知是突触可塑性的一个重要因素。皮质酮在VTA中对MR的选择性占据促进了这种可塑性的发展。然而，我们推测在应激期间，GR的占据也会以类似于精神兴奋剂作用后的方式激活DA神经元的EAA能传入神经。在这种情况下，GR的占据通过VTA外部的神经回路起作用，这可能包括海马体。因此，VTA中DA神经元上EAA能突触的增强可能代表了两种不同方式（精神兴奋剂和应激）达到相同结果（敏化）的最终共同途径。DA细胞水平上EAA介导的传递改变不仅在行为敏化的诱导中起关键作用，而且在无药物状态下可能继续产生异常的DA细胞反应。
