Intracranial Drug Self-administration

颅内药物自我给药

• 批准号: 8148511
• 负责人: SATOSHI IKEMOTO
• 金额: $ 57.33万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148511
• 关键词: Pharmaceutical Preparations; Self Administration

I summarize astudy that produced significant results during the fisical year 2010. The ability to invigorate responding for salient stimuli has been known as a hallmark of ventral striatal dopamine. For example, injections of amphetamine into the ventral striatum facilitate conditioned reinforcement, in which sensory stimuli previously paired with primary reinforcers like food will powerfully instigate responding. More recently, we show that amphetamine administered into the ventral striatum facilitate responding for unconditioned visual signals in rats. Here we show that noncontingent administration of baclofen into the median (MR) or dorsal (DR) raphe nuclei facilitates rats responding for salient visual signals. Rats received baclofen infusions into either the MR or DR on a fixed-interval schedule. Effects of 3 different concentrations of baclofen were examined on lever-pressing. An active lever response illuminated a cue light just above the lever for one sec, while an inactive lever response had no programmed consequence. In the absence of baclofen administration, rats responded on the active lever more than the inactive lever. Non-contingent administration of baclofen into the MR or DR increased responses on both the active and inactive levers. The MR mediated increased lever-pressing at a lower concentration of baclofen than the DR did. In the absence of visual signal reinforcement, intra-MR baclofen did not significantly increase lever-pressing or locomotor activity, whereas in the presence of visual signal reinforcement, baclofen increased both. Heightened locomotor activity induced by intraperitoneal injections of amphetamine failed to concur with increased lever-pressing for visual signals. These results indicate that the observed enhancement of visual signal seeking is distinct from an enhancement of general locomotor activity. Seeking for visual signal decreased when baclofen was co-administered with the GABAB receptor antagonist, SCH 50911, confirming the involvement of local GABAB receptors. Seeking for visual signal also abated when baclofen administration was preceded by intraperitoneal injections of the dopamine antagonist, SCH 23390 (0.025mg/kg), suggesting enhanced visual signal seeking depends on intact dopamine signals. Because GABAB receptors are selectively expressed on serotonergic neurons in the MR, the enhancement of visual signal seeking may be mediated by tonic inhibition of serotonergic neurons. In any case, our data suggest that baclofen administration into the midbrain raphe, particularly MR, facilitates responding for salient stimuli, an effect that is known as a hallmark of ventral striatal dopamine.

我总结了 2010 财年取得重大成果的一项研究。 激发对显着刺激的反应的能力被认为是腹侧纹状体多巴胺的标志。 例如，将安非他明注射到腹侧纹状体有助于条件强化，其中先前与食物等主要强化物配对的感觉刺激将有力地激发反应。 最近，我们发现将安非他明注射到腹侧纹状体有助于对大鼠的非条件视觉信号做出反应。 在这里，我们表明，将巴氯芬非偶然施用到中缝核（MR）或背侧（DR）中缝核中可促进大鼠对显着视觉信号的反应。 大鼠按固定间隔时间在 MR 或 DR 中接受巴氯芬输注。 研究了 3 种不同浓度的巴氯芬对杠杆按压的影响。 主动控制杆响应会在控制杆上方点亮提示灯一秒钟，而非主动控制杆响应则不会产生任何编程结果。 在没有给予巴氯芬的情况下，大鼠对主动杠杆的反应比不主动杠杆的反应更大。 向 MR 或 DR 中非偶然施用巴氯芬可增加活动杠杆和非活动杠杆的反应。 与 DR 相比，MR 在巴氯芬浓度较低的情况下介导了杠杆按压的增加。 在没有视觉信号增强的情况下，MR内巴氯芬不会显着增加杠杆按压或运动活动，而在存在视觉信号增强的情况下，巴氯芬会增加这两者。腹腔注射安非他明引起的运动活动增强与视觉信号的杠杆按压增加不相符。这些结果表明，观察到的视觉信号寻找的增强与一般运动活动的增强不同。 当巴氯芬与 GABAB 受体拮抗剂 SCH 50911 共同给药时，寻找视觉信号减少，证实了局部 GABAB 受体的参与。 当在给予巴氯芬之前腹腔注射多巴胺拮抗剂 SCH 23390 (0.025mg/kg) 时，对视觉信号的寻找也会减弱，这表明增强的视觉信号寻找取决于完整的多巴胺信号。 由于 GABAB 受体在 MR 中的血清素能神经元上选择性表达，因此视觉信号寻找的增强可能是通过血清素能神经元的强直抑制来介导的。 无论如何，我们的数据表明，将巴氯芬注射到中脑中缝，特别是 MR，有助于对显着刺激做出反应，这种效应被称为腹侧纹状体多巴胺的标志。