Aked J, Coizet V, Clark D, Overton P G
Department of Psychology, University of Sheffield, Western Bank, Sheffield S10 2TP, UK.
Neuroscience. 2005;134(2):361-7. doi: 10.1016/j.neuroscience.2005.04.044.
Circumstantial evidence suggests that sensitization to the behavioral effects of d-amphetamine is mediated by increased glutamate levels in the ventral tegmental area. To test this directly, the present study examined whether increasing glutamate levels in the ventral tegmental area with a glutamate uptake inhibitor is sufficient, in the absence of d-amphetamine administration, to elicit sensitization to a subsequent d-amphetamine challenge. Rats were treated bilaterally once a day for 2 days with either intra-ventral tegmental area L-trans-pyrollidine-2,4-dicarboxylic acid (50 nmol), saline, L-trans-pyrollidine-2,4-dicarboxylic acid coadministered with the competitive N-methyl-d-aspartate antagonist (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid; CPP, 0.5 nmol), or CPP alone (0.5 nmol; all 1.0 microl/side). Following a 2 day withdrawal period, all rats were administered systemic d-amphetamine (1 mg/kg, i.p.). Repeated intra-ventral tegmental area injection of L-trans-pyrollidine-2,4-dicarboxylic acid sensitized animals to the behavioral effects of a systemic d-amphetamine challenge, an action which was blocked by co-administration of CPP. The results directly implicate ventral tegmental area glutamate in the process of sensitization to d-amphetamine. Furthermore, they demonstrate that inhibition of glutamate uptake produces the neuroadaptations necessary to induce sensitization, adding support to the contention that d-amphetamine sensitizes by modulating glutamate uptake.
间接证据表明，对右旋苯丙胺行为效应的敏感化是由腹侧被盖区谷氨酸水平升高介导的。为了直接验证这一点，本研究考察了在不给予右旋苯丙胺的情况下，用谷氨酸摄取抑制剂提高腹侧被盖区谷氨酸水平是否足以引发对随后右旋苯丙胺激发的敏感化。大鼠双侧腹侧被盖区每天注射一次，连续注射2天，分别注射L-反式-吡咯烷-2,4-二羧酸（50 nmol）、生理盐水、与竞争性N-甲基-D-天冬氨酸拮抗剂（±）-3-（2-羧基-哌嗪-4-基）-丙基-1-膦酸共同注射的L-反式-吡咯烷-2,4-二羧酸；CPP，0.5 nmol）或单独的CPP（0.5 nmol；均为1.0微升/侧）。在2天的撤药期后，所有大鼠均接受全身性右旋苯丙胺（1毫克/千克，腹腔注射）。反复向腹侧被盖区注射L-反式-吡咯烷-2,4-二羧酸使动物对全身性右旋苯丙胺激发的行为效应产生敏感化，这一作用可被同时给予CPP所阻断。结果直接表明腹侧被盖区谷氨酸在对右旋苯丙胺的敏感化过程中起作用。此外，它们还表明抑制谷氨酸摄取会产生诱导敏感化所需的神经适应性变化，这支持了右旋苯丙胺通过调节谷氨酸摄取而产生敏感化的观点。
