Glutamatergic compounds for treating drug addiction: Pre

用于治疗药物成瘾的谷氨酸化合物：Pre

• 批准号: 7321124
• 负责人: ELIOT L GARDNER
• 金额: --
• 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/7321124
• 关键词: Glutamatergic; compounds; treating; drug; addiction

Due to diversion of laboratory personnel and resources to the dopamine D3 receptor research project during the reporting period (01 Oct 05 to 30 Sept 06), only limited progress was made on this research project. Recent studies have shown that chronic or repeated cocaine administration produces long-term alterations in glutamate neurotransmission in the brain. NAALADase (N-acetylated-alpha-linked-acidic dipeptidase; glutamate carboxypeptidase II) is a brain enzyme which hydrolyzes the endogenous brain neuropeptide NAAG (N-acetyl-aspartyl-glutamate) to glutamate and NAA (N-acetyl-aspartate). NAAG is an endogenous mGluR3 glutamate receptor agonist, which inhibits presynaptic glutamate release. Therefore, studies of NAALADase inhibitors in preclinical animal models relating to addiction are of interest in the search for clinically useful pharmacotherapeutic agents for the treatment of addiction, craving, and relapse. Consequently, we studied the effects of 3 NAALADase inhibitors - 2-PMPA, GPI-16476, and GPI-16477 - in animal models relating to addiction. We found that all 3 NAALADase inhibitors had no effect on intravenous cocaine self-administration under fixed-ratio reinforcement conditions, but significantly inhibited cocaine-triggered relapse to cocaine-seeking behavior in laboratory rats who has been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. We further found that the NAALADase inhibitor 2-PMPA significantly inhibits cocaine self-administration under progressive-ratio reinforcement conditions (i.e., significantly reduces the amount of work that laboratory rats are willing to expend to receive intravenous cocaine infusions). We further found that blockade of the mGluR5 glutamate brain receptor by the selective, potent, and systemically-active mGluR5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine) inhibits cocaine self-administration under fixed-ratio reinforcement conditions and inhibits cocaine self-administration under progressive-ratio reinforcement conditions in labortaory rats (i.e., significantly reduces the amount of work that laboratory rats are willing to expend to receive intravenous cocaine infusions). We further found that blockade of the mGluR5 glutamate receptor by MPEP significantly inhibits relapse to drug-seeking behavior triggered by cocaine, but not relapse to drug-seeking behavior triggered by either stress or environmental cues previously paired with drug-taking behavior. We further found that, using in vivo brain microdialysis methods, MPEP has no effect on extracellular levels of the neurotransmitter dopamine in the nucleus accumbens of the limbic forebrain in either drug-naive or cocaine-extinguished rats, suggesting a dopamine-independent mechanism underlying MPEP?s actions. In contrast, MPEP (administered either systemically or locally into the nucleus accumbens) elevates extracellular glutamate. Furthermore, MPEP dose-dependently inhibited cocaine-induced increases in nucleus accumbens extracellular glutamate in both drug-naive and cocaine-extinguished rats. These data suggest that alterations in nucleus accumbens glutamate may underlie MPEP?s actions on cocaine-induced reward and cocaine-triggered relapse to drug-seeking behavior. In all, these findings suggest that the glutamate neurotransmitter system in the brain may be an appropriate target-of-action for the development of potential anti-addiction, anti-craving, and anti-relapse medications.

由于报告期内（2005年10月1日至2006年9月30日）实验室人员和资源被转移到多巴胺D3受体研究项目，该研究项目仅取得有限进展。最近的研究表明，长期或重复服用可卡因会导致大脑中谷氨酸神经传递的长期改变。 NAALADase（N-乙酰化-α-连接酸性二肽酶；谷氨酸羧肽酶 II）是一种脑酶，可将内源性脑神经肽 NAAG（N-乙酰-天冬氨酰-谷氨酸）水解为谷氨酸和 NAA（N-乙酰-天冬氨酸）。 NAAG 是一种内源性 mGluR3 谷氨酸受体激动剂，可抑制突触前谷氨酸释放。因此，在与成瘾相关的临床前动物模型中对 NAALADase 抑制剂的研究对于寻找临床上有用的药物治疗剂来治疗成瘾、渴望和复发很有意义。因此，我们研究了 3 种 NAALADase 抑制剂 - 2-PMPA、GPI-16476 和 GPI-16477 - 在与成瘾相关的动物模型中的作用。我们发现，在固定比例强化条件下，所有 3 种 NAALADase 抑制剂对静脉注射可卡因自我给药没有影响，但显着抑制了实验室大鼠因可卡因引发的可卡因寻求行为的复发，这些实验鼠已通过药物解毒并在行为上消除了先前静脉注射可卡因的习惯。我们进一步发现，NAALADase 抑制剂 2-PMPA 在渐进比例强化条件下显着抑制可卡因自我给药（即显着减少实验大鼠愿意接受静脉注射可卡因输注的工作量）。我们进一步发现，通过选择性、强效和系统活性的 mGluR5 受体拮抗剂 MPEP（2-甲基-6-（苯乙炔基）-吡啶）阻断 mGluR5 谷氨酸脑受体，可在固定比例强化条件下抑制可卡因自我给药，并在渐进比例强化条件下抑制可卡因自我给药。 实验大鼠（即显着减少实验大鼠愿意接受静脉注射可卡因输注的工作量）。我们进一步发现，MPEP 阻断 mGluR5 谷氨酸受体可显着抑制由可卡因引发的寻求药物行为的复发，但不会抑制由先前与吸毒行为配对的压力或环境线索引发的寻求药物行为的复发。我们进一步发现，使用体内脑微透析方法，MPEP 对未接受药物或可卡因熄灭的大鼠前脑边缘伏核中神经递质多巴胺的细胞外水平没有影响，表明 MPEP 的作用背后存在不依赖于多巴胺的机制。相比之下，MPEP（全身或局部注射到伏隔核）会升高细胞外谷氨酸。此外，在未接受药物的大鼠和可卡因熄灭的大鼠中，MPEP 剂量依赖性地抑制可卡因诱导的伏核细胞外谷氨酸的增加。这些数据表明，伏隔核谷氨酸的改变可能是 MPEP 对可卡因诱导的奖赏和可卡因触发的药物寻求行为复发的作用的基础。总而言之，这些发现表明，大脑中的谷氨酸神经递质系统可能是开发潜在的抗成瘾、抗渴望和抗复发药物的适当作用目标。