Verheij Michel M M, Vendruscolo Leandro F, Caffino Lucia, Giannotti Giuseppe, Cazorla Maxime, Fumagalli Fabio, Riva Marco A, Homberg Judith R, Koob George F, Contet Candice
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands, Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037,
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, Neurobiology of Addiction Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
J Neurosci. 2016 Aug 3;36(31):8149-59. doi: 10.1523/JNEUROSCI.2711-14.2016.
Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on the brain regions involved. In the present study, we determined how brain-wide inhibition of TrkB signaling affects cocaine intake, the motivation for the drug, and reinstatement of drug taking after extinction. To overcome the inability of TrkB ligands to cross the blood-brain barrier, the TrkB antagonist cyclotraxin-B was fused to the nontoxic transduction domain of the tat protein from human immunodeficiency virus type 1 (tat-cyclotraxin-B). Intravenous injection of tat-cyclotraxin-B dose-dependently reduced cocaine intake, motivation for cocaine (as measured under a progressive ratio schedule of reinforcement), and reinstatement of cocaine taking in rats allowed either short or long access to cocaine self-administration. In contrast, the treatment did not affect operant responding for a highly palatable sweet solution, demonstrating that the effects of tat-cyclotraxin-B are specific for cocaine reinforcement. Cocaine self-administration increased TrkB signaling and activated the downstream Akt pathway in the nucleus accumbens, and had opposite effects in the prefrontal cortex. Pretreatment with tat-cyclotraxin-B normalized protein levels in these two dopamine-innervated brain regions. Cocaine self-administration also increased TrkB signaling in the ventral tegmental area, where the dopaminergic projections originate, but pretreatment with tat-cyclotraxin-B did not alter this effect. Altogether, our data show that systemic administration of a brain-penetrant TrkB antagonist leads to brain region-specific effects and may be a potential pharmacological strategy for the treatment of cocaine addiction.
Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors plays a well established role in cocaine reinforcement. However, local manipulation of BDNF signaling yields divergent effects, depending on the brain region, thereby questioning the viability of systemic TrkB targeting for the treatment of cocaine use disorders. Our study provides first-time evidence that systemic administration of a brain-penetrant TrkB antagonist (tat-cyclotraxin-B) reduces several behavioral measures of cocaine dependence, without altering motor performance or reinforcement by a sweet palatable solution. In addition, although cocaine self-administration produced opposite effects on TrkB signaling in the nucleus accumbens and prefrontal cortex, tat-cyclotraxin-B administration normalized these cocaine-induced changes in both brain regions.
可卡因暴露会改变大脑中脑源性神经营养因子（BDNF）的表达。通过TrkB受体的BDNF信号传导对可卡因自我给药有不同的调节作用，这取决于所涉及的脑区。在本研究中，我们确定了全脑抑制TrkB信号传导如何影响可卡因摄入量、对该药物的动机以及消退后药物摄取的恢复。为了克服TrkB配体无法穿过血脑屏障的问题，将TrkB拮抗剂环曲毒素-B与人免疫缺陷病毒1型（tat）的tat蛋白无毒转导结构域融合（tat-环曲毒素-B）。静脉注射tat-环曲毒素-B剂量依赖性地减少了可卡因摄入量、对可卡因的动机（如在渐进比率强化程序下所测量），并减少了短期或长期可进行可卡因自我给药的大鼠中可卡因摄取的恢复。相比之下，该处理不影响对高度可口甜味溶液的操作性反应，表明tat-环曲毒素-B的作用对可卡因强化具有特异性。可卡因自我给药增加了伏隔核中的TrkB信号传导并激活了下游的Akt途径，而在额叶前皮质中则产生相反的作用。用tat-环曲毒素-B预处理使这两个多巴胺支配的脑区中的蛋白水平恢复正常。可卡因自我给药还增加了多巴胺能投射起源的腹侧被盖区中的TrkB信号传导，但用tat-环曲毒素-B预处理并未改变这种作用。总之，我们的数据表明，全身给予可穿透大脑的TrkB拮抗剂会导致脑区特异性效应，可能是治疗可卡因成瘾的一种潜在药理学策略。
通过TrkB受体的脑源性神经营养因子（BDNF）信号传导在可卡因强化中发挥着既定作用。然而，BDNF信号传导的局部操纵会产生不同的效果，这取决于脑区，从而对全身靶向TrkB治疗可卡因使用障碍的可行性提出质疑。我们的研究首次提供证据表明，全身给予可穿透大脑的TrkB拮抗剂（tat-环曲毒素-B）可降低可卡因依赖的几种行为指标，而不会改变运动表现或对可口甜味溶液的强化作用。此外，尽管可卡因自我给药在伏隔核和额叶前皮质中对TrkB信号传导产生了相反的作用，但给予tat-环曲毒素-B使这两个脑区中这些可卡因诱导的变化恢复正常。
