Intracranial Drug Self-administration

颅内药物自我给药

• 批准号: 7966803
• 负责人: SATOSHI IKEMOTO
• 金额: $ 58.95万
• 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/7966803
• 关键词: AMPA Receptors; Address; Agonist; Anatomy; Anterior; Arousal; Baclofen; Behavior; Behavioral; Brain; Brain Stem; Brain region; Cell Nucleus; Chemicals; Communication; Disease; Dorsal; Dose; Drug Addiction; GABA Agonists; Goals; Immunohistochemistry; Infusion procedures; Injection of therapeutic agent; Investigation; Lateral; Lead; Learning; Length; Microinjections; Midbrain structure; Motor; Muscimol; NMDA receptor antagonist; Neurons; Neurotransmitters; Opioid; Pharmaceutical Preparations; Procedures; Psychological reinforcement; Rattus; Rewards; Self Administration; Self-Administered; Site; Specificity; Substantia nigra structure; System; Techniques; Time; Ventral Tegmental Area; brain cell; chemical release; dopaminergic neuron; dorsal raphe nucleus; drug of abuse; effective therapy; endomorphin 1; mu opioid receptors; preference; receptor; research study

I summarize two studies that produced significant results during the fisical year 2009. Prior studies have found that rats will self-administer mu opioid agonists much more avidly into the posterior ventral tegmental area (VTA) than into the anterior VTA. The mechanisms underlying this phenomenon are unknown, but recently a brain nucleus, the rostromedial tegmental nucleus (RMTg) has been identified that resides immediately caudal to the VTA and which expresses high levels of mu opioid receptor immunohistochemistry. The RMTg consists of GABAergic neurons projecting heavily to dopamine neurons in the VTA and substantia nigra, as well as to other brainstem arousal systems including the dorsal raphe nucleus and pedunculopontine nuclei. These anatomic observations led us to hypothesize that the RMTg might contribute to mu opioid effects on arousal, motor behavior, and reward. Consistent with this hypothesis, we found that rats will self-administer small doses (50pmol per 75nl infusion) of the mu opioid agonist endomorphin-1 (EM1) into the RMTg at a rate 2.60.2 (meanSEM) times higher than ACSF (p < 0.002). The RMTg nucleus is anatomically elongated in the rostro-caudal direction, and agonist self-administration was elevated throughout this length, whereas self-administration into sites dorsal, ventral, or lateral to the RMTg did not differ from ACSF (p > 0.8). Further studies are planned using conditioned place preference (CPP) to discriminate between rewarding and locomotor effects of endomorphin-1 in the RMTg. Recent studies suggest that neuronal inhibition brought by administering GABAergic drugs into the median and dorsal raphe nuclei leads to rewarding effects. Rats learn to self-administer muscimol or baclofen into these regions; in addition, injections of such GABA agonists into these regions induce conditioned place preference. In the present investigation, we examined whether the blockade of excitatory inputs to midbrain raphe neurons is also rewarding, using intracranial self-administration procedures. Rats quickly learn to self-administer the AMPA receptor antagonist ZK200775 into the vicinity of the median or dorsal raphe nucleus (Ns = 8 and 7, respectively). ZK200775 (1 mM in 75 l per infusion) was self-administered into the median raphe region at the rates of 0.7-0.9 per min, while it was self-administered into the dorsal raphe region at slower rates. Effects of NMDA receptor antagonist AP-5 were not as reliable. AP-5 was self-administered into the median raphe region when rats received it for the first time; however, rats did not reliably respond for AP-5 in subsequent sessions. Similarly, AP-5 at various concentrations (0.1, 0.3 and 1 mM) was not readily self-administered into the dorsal raphe nucleus in any session. It may be characterized that AP-5 injections into the midbrain raphe regions quickly lose the capacity to induce rewarding effects. These results are consistent with the notion that median and dorsal raphe nuclei exert tonic inhibition over the brain reward system. Ongoing experiments are addressing additional issues of anatomical, receptor and behavioral specificities.

我总结了2009财年产生重大成果的两项研究。 先前的研究已经发现，大鼠将自我施用μ阿片样物质激动剂更积极地进入后腹侧被盖区（VTA）而不是进入前VTA。 这种现象背后的机制是未知的，但最近已经确定了一个脑核，吻内侧被盖核（RMTg），直接位于尾侧腹侧被盖区，并表达高水平的μ阿片受体免疫组化。 RMTg由GABA能神经元组成，其大量投射到腹侧被盖区和黑质中的多巴胺神经元，以及投射到其他脑干唤醒系统，包括中缝背核和脚桥核。 这些解剖学观察使我们假设RMTg可能有助于μ阿片类药物对唤醒、运动行为和奖励的作用。 与该假设一致，我们发现大鼠将以比ACSF高2.6 ± 0.2（平均SEM）倍（p < 0.002）的速率将小剂量（50 pmol/75 nl输注）μ阿片激动剂内吗啡肽-1（EM 1）自我施用到RMTg中。 RMTg核在解剖学上在喙尾方向上伸长，并且激动剂自身给药在整个长度上升高，而在RMTg的背侧、腹侧或外侧部位的自身给药与ACSF没有差异（p > 0.8）。 进一步的研究计划使用条件性位置偏好（CPP）来区分奖励和运动的影响内吗啡肽-1在RMTg。 最近的研究表明，通过将GABA能药物给予中缝核和中缝背核而引起的神经元抑制导致奖赏效应。 大鼠学习自我管理蝇蕈醇或巴氯芬到这些地区，此外，注射这样的GABA激动剂到这些地区诱导条件性位置偏爱。 在目前的调查中，我们研究是否兴奋性输入的封锁中脑中缝神经元也是有益的，使用颅内自我管理程序。 大鼠很快学会将AMPA受体拮抗剂ZK 200775自我给药到正中核或中缝背核附近（Ns分别为8和7）。 ZK 200775（每次输注75 L中1 mM）以0.7-0.9/min的速率自我给药至中缝中部区域，而以较慢的速率自我给药至中缝背侧区域。 NMDA受体拮抗剂AP-5的作用不可靠。 当大鼠第一次接受AP-5时，AP-5被自我施用到中缝区域中;然而，大鼠在随后的会话中对AP-5没有可靠的响应。 类似地，AP-5在各种浓度（0.1，0.3和1 mM）不容易自我管理到中缝背核在任何会话。 其特征可能在于，AP-5注射到中脑中缝区域迅速失去诱导奖励效应的能力。 这些结果与中缝核和中缝背核对大脑奖赏系统产生紧张性抑制的观点是一致的。 正在进行的实验正在解决解剖学，受体和行为特异性的其他问题。