Bossert Jennifer M, Gray Sarah M, Lu Lin, Shaham Yavin
Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD 21224, USA.
Neuropsychopharmacology. 2006 Oct;31(10):2197-209. doi: 10.1038/sj.npp.1300977. Epub 2005 Dec 7.
Using a rat relapse model, we previously reported that re-exposing rats to a drug-associated context, following extinction of operant responding in a different context, reinstates heroin seeking. In an initial pharmacological characterization, we found that the mGluR2/3 agonist LY379268, which acts centrally to reduce evoked glutamate release, attenuates context-induced reinstatement of heroin seeking when injected systemically or into the ventral tegmental area, the cell body region of the mesolimbic dopamine system. Here, we tested whether injections of LY379268 into the nucleus accumbens (NAc), a terminal region of the mesolimbic dopamine system, would also attenuate context-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of responding, LY379268 was injected to different groups of rats into the NAc core or shell or into the caudate-putamen, a terminal region of the nigrastriatal dopamine system. Injections of LY379268 into the NAc shell (0.3 or 1.0 microg) dose-dependently attenuated context-induced reinstatement of heroin seeking. Injections of 1.0 microg of LY379268 into the NAc core had no effect, while a higher dose (3.0 microg) decreased this reinstatement. Injections of LY379268 (3.0 microg) 1.5 mm dorsal from the NAc core into the caudate-putamen were ineffective. Results suggest an important role of glutamate transmission in the NAc shell in context-induced reinstatement of heroin seeking.
我们之前利用大鼠复发模型报道，在不同环境中操作性反应消退后，让大鼠重新暴露于与药物相关的环境中，会恢复海洛因觅求行为。在最初的药理学特征研究中，我们发现代谢型谷氨酸受体2/3（mGluR2/3）激动剂LY379268可通过中枢作用减少诱发的谷氨酸释放，当全身注射或注射到腹侧被盖区（中脑边缘多巴胺系统的细胞体区域）时，可减弱环境诱导的海洛因觅求行为恢复。在此，我们测试了将LY379268注射到中脑边缘多巴胺系统的终末区域伏隔核（NAc）是否也会减弱环境诱导的海洛因觅求行为恢复。大鼠经训练可自行注射海洛因；药物输注与离散的声光线索配对。随后，在与药物自行注射环境在视觉、听觉、触觉和昼夜节律线索方面不同的环境中，在离散线索存在的情况下，按压杠杆行为被消退。反应消退后，将LY379268注射到不同组的大鼠的NAc核心或壳区或黑质纹状体多巴胺系统的终末区域尾状核-壳核。向NAc壳区注射LY379268（0.3或1.0微克）可剂量依赖性地减弱环境诱导的海洛因觅求行为恢复。向NAc核心注射1.0微克LY379268无效，而更高剂量（3.0微克）可减少这种行为恢复。在距NAc核心背侧1.5毫米处向尾状核-壳核注射LY379268（3.0微克）无效。结果表明谷氨酸传递在NAc壳区环境诱导的海洛因觅求行为恢复中起重要作用。
