Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats
Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats
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DOI：
10.1523/jneurosci.1924-04.2004
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发表时间：
2004-07-21
影响因子：
5.3
通讯作者：
See, RE
中科院分区：
文献类型：
--
作者：
Fuchs, RA;Evans, KA;See, RE
眶额皮质（OFC）损害兴奋性冲动和持续性，OFC功能的损害可能是可卡因使用者强迫性药物寻求的基础。为了验证这一假设，我们评估了OFC亚区的纤维保留病变或功能失活对大鼠可卡因寻求的影响。训练大鼠按杠杆静脉注射可卡因（0.20 mg/输注），同时给予光加音调刺激。然后允许响应熄灭。大鼠在自我给药训练之前接受双侧NMDA（0.1M）或外侧OFC（IOFC）或内侧OFC（mOFC）的假损伤（实验1），或在恢复测试之前向IOFC或mOFC中注入蝇蕈醇加巴氯芬（0.1和1.0mM）或载体（实验2）。这些操纵对恢复可卡因寻求的影响（即，在光加音调刺激存在下或在可卡因引发注射（10 mg/kg，i. p.）后评估对先前可卡因配对杠杆的反应）。训练后的IOFC失活损害了条件线索诱导的恢复，而其他操作未能改变这种行为。这表明，在评估可卡因条件刺激的当前动机意义或使用此信息来指导可卡因寻求行为，如果刺激奖励学习发生在IOFC损伤之前，IOFC起着关键作用。OFC失活未能改变可卡因引发的恢复。然而，lOFC病变增加可卡因引发的恢复在一个持续的方式，而mOFC病变衰减可卡因引发的恢复，表明OFC亚区的细胞损失延长可能会调节可卡因寻求在一个亚区的特定方式的倾向。
Orbitofrontal cortex (OFC) damage elicits impulsivity and perseveration, and impairments in OFC function may underlie compulsive drug seeking in cocaine users. To test this hypothesis, we assessed the effects of fiber-sparing lesions or functional inactivation of OFC subregions on cocaine seeking in rats. Rats were trained to lever press for intravenous cocaine (0.20 mg/infusion) paired with the presentations of light plus tone stimuli. Responding was then allowed to extinguish. Rats received bilateralNMDA (0.1 M) or sham lesions of the lateral OFC (lOFC) or medial OFC (mOFC) before self-administration training ( experiment 1) or muscimol plus baclofen (0.1 and 1.0 mM) or vehicle infusions into the lOFC or mOFC before reinstatement testing ( experiment 2). The effects of these manipulations on reinstatement of cocaine seeking (i.e., responding on the previously cocaine-paired lever) were assessed in the presence of the light plus tone stimuli or after a cocaine priming injection (10 mg/kg, i.p.). Post-training lOFC inactivation impaired conditioned cue-induced reinstatement, whereas other manipulations failed to alter this behavior. This suggests that the lOFC plays a critical role in assessing the current motivational significance of cocaine-conditioned stimuli or in using this information to guide cocaine-seeking behavior if stimulus-reward learning takes place before lOFC damage. OFC inactivation failed to alter cocaine-primed reinstatement. However, lOFC lesions augmented cocaine-primed reinstatement in a perseverative manner, whereas mOFC lesions attenuated cocaine-primed reinstatement, suggesting that prolonged cell loss in OFC subregions may modulate the propensity for cocaine seeking in a subregion-specific manner.