Intracranial Drug Self-administration

颅内药物自我给药

• 批准号: 7593269
• 负责人: SATOSHI IKEMOTO
• 金额: $ 133.89万
• 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/7593269
• 关键词: Affect; Agonist; Amphetamines; Anterior; Area; Arousal; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain Stem; Brain region; Cannulas; Cell Nucleus; Chemicals; Cocaine; Communication; Complement; Condition; Corpus striatum structure; Data; Dextroamphetamine; Discrimination; Disease; Dopamine; Dopamine Antagonists; Dorsal; Dose; Drug Addiction; Electric Stimulation; Environment; Fiber; Goals; Hand; Hour; Implant; Infusion procedures; Injection of therapeutic agent; Intraventricular Injections; Lateral; Lead; Learning; Light; Localized; Medial; Mediating; Microinjections; Midbrain structure; Modeling; Motivation; Motor; Muscimol; Neurons; Neuropeptides; Nicotine; Nucleus Accumbens; Olfactory tubercle; Opiates; Paper; Pharmaceutical Preparations; Picrotoxin; Play; Procedures; Prosencephalon; Psychological reinforcement; Publishing; Rate; Rattus; Regulation; Review Literature; Rewards; Role; Self Administration; Self-Administered; Signal Transduction; Site; System; Techniques; Thinking; Training; Variant; Ventral Striatum; Ventral Tegmental Area; Ventricular; Wistar Rats; Work; brain cell; brain research; chemical release; conditioning; day; dopamine system; dopaminergic neuron; dorsal raphe nucleus; dosage; drug of abuse; drug reward; ecstasy; lateral ventricle; locus ceruleus structure; male; mesolimbic system; neuronal cell body; neurotransmission; preference; raphe nuclei; receptor; research study; response; reward circuitry; reward processing

In the past year, we largely worked on four projects. Because rats learn to lever-press for brief electrical stimulation of the median and dorsal raphe nuclei (MRN and DRN, respectively), these brain sites have long been implicated in reward processes. However, it is not clear whether the MRN and DRN integrate reward-related signals or merely contain fibers of passage involved in reward processes. To shed light on this issue, the present study employed chemicals that selectively modulate neurotransmission, in particular the GABAA receptor agonist muscimol. Rats quickly learned to lever-press for muscimol infusions (50 and 100 M) into the MRN or DRN. Muscimol was not self-administered when cannulae were placed just outside these nuclei. The reinforcing effects of muscimol appeared to be greater when the drug was administered into the MRN than into the DRN, as demonstrated by higher infusion rates and better response discrimination. These observations are consistent with the additional finding that muscimol administration into the MRN, but not the DRN, induced conditioned place preference. The reinforcing effects of muscimol administration into the MRN were blocked by co-administration of the GABAA antagonist picrotoxin (100 M) and by pretreatment with the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.). The present results suggest that median and dorsal raphe neurons via GABAA receptors are involved in integration of primary reinforcement, and that median raphe neurons, presumably inhibited by muscimol administration, may exert tonic inhibition over dopamine-dependent reward circuitry. The midbrain raphe nuclei may be involved in a variety of reward-related phenomena including drug addiction. Our recent data demonstrated that selective regions of the ventral striatum, such as the medial accumbens shell and medial olfactory tubercle, but not accumbens core, lateral accumbens shell, or lateral olfactory tubercle supported self-administration of cocaine and amphetamine delivered via intracranial infusions. These findings suggest that the ventromedial striatum is more important than the ventrolateral striatum in mediating rewarding effects of certain drugs of abuse. The present experiment sought to investigate whether intracranial self-administration of ()-3,4-methylenedioxymethamphetamine (MDMA) into these same forebrain regions would elicit similar rewarding behaviors. Over four consecutive days, rats were trained to lever press for 30mM MDMA or vehicle infusions for a period of 90 min each day. Subsequently, on three separate days, an increasing dosage of MDMA (10, 30, 100mM) or vehicle was presented for self-administration. Rats learned to self-administer MDMA at very moderate rates into medial accumbens shell, medial olfactory tubercle and accumbens core, but did not self-administer it into the lateral shell or lateral tubercle. In a separate experiment, very high dosages of MDMA (500mM, 1M) over several sessions followed by amphetamine were examined. Rats learned to self-administer MDMA into the medial shell at similar rates as they did d-amphetamine into the same site. On the other hand, rats did not learn to self-administer MDMA into the medial tubercle or core, even though medial tubercle rats did learn to self-administer d-amphetamine into the same site. Taken together, these data suggest the rewarding effects of MDMA is most effectively mediated by the medial shell among ventral striatal regions. Neuropeptide S (NPS) is a recently identified neuropeptide. NPS-containing cell bodies are localized in the lower brainstem just adjacent to the locus coeruleus and its receptors are expressed in the brain areas that are implicated in motivation and reward. Indeed, NPS appears to play an important role in arousal. We examined possible rewarding effects of NPS injected into the lateral ventricle, using intracranial self-administration and conditioned place preference procedures. Each male Wistar rat was implanted with a permanent unilateral guide cannula ended just above the lateral ventricle. For intra-ventricular self-administration, rats received NPS at the dose of 3.39 nmol per infusion in sessions 2-4 and vehicle in sessions 1 and 5 followed by three sessions with 0.339, 3.39 and 33.9 nmol doses. Each session lasted for 90 min, and sessions were separated by 24 hours. Rats learned quickly to self-administer the 3.39 nmol dose into the lateral ventricle. It is unclear whether rats self-administer NPS at a lower dose. Effects of two doses of NPS were evaluated for conditioned place preference. Each rat was confined in a compartment for 20 min immediately after intraventricular injections of NPS (100 or 1,000 nmol) and confined in another compartment for 20min after vehicle injections. Injections were separated by 24 hours. Pairings of NPS and vehicle injections with these compartments were alternated over 8 days. Place preference of each rat was examined in the first session, prior to conditioning, and the last session, after conditioning, by allowing them to have free access to both compartments for 15 min without injections. The high dose (1,000 nmol) of NPS induced conditioned place preference, whereas the low dose (100 nmol) induced conditioned place avoidance. These data suggest that NPS injections into the lateral ventricle are rewarding, although NPS injections at some doses may also be aversive. These findings and the previous finding that intra-ventricular injections of NPS elicit motor stimulant effects raise the possibility that the NPS system interacts with the mesolimbic dopamine system. Finally, we reviewed anatomical and functional refinements of the meso-limbic dopamine system of the rat in the paper published in Brain Research Reviews. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that: (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive, and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization.

在过去的一年里，我们主要致力于四个项目。 由于大鼠学会通过杠杆按压对中缝核和中缝背核（分别为 MRN 和 DRN）进行短暂的电刺激，因此这些大脑部位长期以来一直与奖励过程有关。 然而，尚不清楚 MRN 和 DRN 是否整合了奖励相关信号，或者仅包含参与奖励过程的通道纤维。 为了阐明这个问题，本研究采用了选择性调节神经传递的化学物质，特别是 GABAA 受体激动剂蝇蕈醇。 大鼠很快学会了按下杠杆将蝇蕈醇输注（50 和 100 M）到 MRN 或 DRN 中。 当将插管放置在这些细胞核外时，蝇蕈醇不能自行给药。 当将药物注射到 MRN 中时，蝇蕈醇的增强作用似乎比注射到 DRN 中更大，这通过更高的输注率和更好的反应辨别力来证明。 这些观察结果与另外的发现相一致，即向 MRN 而不是 DRN 中施用蝇蕈醇会诱导条件性位置偏好。 通过同时给予 GABAA 拮抗剂印防己毒素 (100 M) 和用多巴胺受体拮抗剂 SCH 23390 (0.025 mg/kg，腹腔注射) 进行预处理，可阻断 MRN 中给予蝇蕈醇的增强作用。 目前的结果表明，中缝神经元和背侧中缝神经元通过 GABAA 受体参与初级强化的整合，并且中缝神经元可能受到蝇蕈醇给药的抑制，可能对多巴胺依赖性奖赏回路产生强直抑制。 中脑中缝核可能涉及多种与奖赏相关的现象，包括毒瘾。 我们最近的数据表明，腹侧纹状体的选择性区域，例如内侧伏隔核壳和内侧嗅结节，但不是伏隔核、外侧伏隔核壳或外侧嗅结节支持通过颅内输注输送的可卡因和安非他明的自我给药。 这些发现表明，腹内侧纹状体在调节某些滥用药物的奖赏效应方面比腹外侧纹状体更重要。 本实验旨在研究颅内自我施用（）-3,4-亚甲二氧基甲基苯丙胺（MDMA）到这些相同的前脑区域是否会引起类似的奖励行为。连续四天，训练大鼠每天 90 分钟压杠杆以输注 30mM MDMA 或载体。 随后，在三天内，增加剂量的 MDMA（10、30、100mM）或载体进行自我给药。 大鼠学会了以非常中等的速率将MDMA自我施用到内侧伏隔壳、内侧嗅结节和伏隔核中，但没有将其自我施用到外侧壳或外侧结节中。 在一项单独的实验中，对多次使用高剂量的 MDMA（500mM、1M）以及随后使用安非他明进行了检查。 老鼠学会了将 MDMA 自我注射到内侧壳中，其速度与将 d-苯丙胺注射到同一部位的速度相似。 另一方面，尽管内侧结节大鼠确实学会了将 d-苯丙胺自我施用到同一部位，但大鼠并未学会将 MDMA 自我施用到内侧结节或核心。 总而言之，这些数据表明 MDMA 的奖励作用最有效地由腹侧纹状体区域的内侧壳介导。 神经肽 S (NPS) 是最近发现的一种神经肽。 含有 NPS 的细胞体位于靠近蓝斑的下脑干，其受体在与动机和奖励有关的大脑区域表达。 事实上，NPS 似乎在唤醒方面发挥着重要作用。 我们使用颅内自我给药和条件性位置偏好程序检查了注射到侧脑室的 NPS 可能的奖励效应。 每只雄性 Wistar 大鼠都植入了一个永久性的单侧引导插管，其末端位于侧脑室上方。 对于心室内自我给药，大鼠在第2-4节中每次输注3.39 nmol的剂量接受NPS，并在第1和5节中接受媒介物，随后三个节次分别接受0.339、3.39和33.9 nmol剂量。 每次会议持续 90 分钟，会议间隔 24 小时。 大鼠很快学会了将 3.39 nmol 剂量自行注射到侧脑室。 目前尚不清楚大鼠是否能够自行施用较低剂量的 NPS。 评估了两种剂量的 NPS 对条件位置偏好的影响。 每只大鼠在脑室内注射 NPS（100 或 1,000 nmol）后立即被限制在一个隔室中 20 分钟，并在注射媒介物后被限制在另一个隔室中 20 分钟。 注射间隔24小时。 NPS 和载体注射与这些隔室的配对在 8 天内交替进行。 在调节之前的第一阶段和调节之后的最后一个阶段，通过允许它们在不注射的情况下自由进入两个隔室15分钟来检查每只大鼠的位置偏好。 高剂量（1,000 nmol）NPS 诱导条件性位置偏好，而低剂量（100 nmol）诱导条件性位置回避。 这些数据表明，侧脑室注射 NPS 是有益的，尽管某些剂量的 NPS 注射也可能令人厌恶。 这些发现和先前发现的脑室内注射 NPS 引起运动兴奋作用的发现提出了 NPS 系统与中脑边缘多巴胺系统相互作用的可能性。 最后，我们在《大脑研究评论》发表的论文中回顾了大鼠中脑边缘多巴胺系统的解剖学和功能改进。 目前的实验表明，位于后内侧腹侧被盖区（VTA）和中央线状中缝核的多巴胺能神经元选择性地投射到腹内侧纹状体（内侧嗅结节和内侧伏隔核壳），而前内侧VTA几乎没有投射到腹侧纹状体，而外侧VTA则主要投射到腹内侧纹状体。 腹外侧纹状体（伏隔核、侧壳和侧结节）。 这些发现补充了最近的行为学发现，即可卡因和安非他明在注入腹内侧纹状体时比注入腹外侧纹状体更有价值。 尼古丁和阿片类药物等药物注射到后 VTA 或中央线性核中比注射到前 VTA 更有效。 文献综述表明：（1）中脑有伏隔核和内侧壳对应的区域； (2) 嗅结节的纹状体部分是伏隔核壳的腹侧延伸； (3)从腹侧中脑到腹侧纹状体的两个多巴胺投射系统的模型对于理解奖励功能很有用。 内侧投射系统在以情感和驱动为特征的唤醒调节中很重要，并且在目标导向学习中与外侧投射系统发挥不同的作用，如纹状体功能组织的变异选择假说中所述。