Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
Pharmacol Biochem Behav. 2019 Apr;179:98-108. doi: 10.1016/j.pbb.2019.02.009. Epub 2019 Feb 21.
Methamphetamine addiction is characterized by compulsive binges of drug intake despite adverse life consequences. A model of methamphetamine self-administration that includes contingent footshocks to constitute adverse consequences has helped to segregate rats that reduce or stop lever pressing for methamphetamine (sensitive) from those that continue to lever press for the drug (resistant) in the presence of negative outcomes. We have observed differential DNA hydroxymethylation and increased expression of potassium channel mRNAs in the nucleus accumbens of sensitive compared to resistant rats, suggesting a role of these channels in suppressing methamphetamine intake. There were also significant increases in nerve growth factor (NGF) expression and activation of its downstream signaling pathway (NGF-TrkA and p75NTR/MAPK signaling) in only the dorsal striatum of sensitive rats after a month of abstinence. In contrast, oxytocin mRNA expression was increased in only the nucleus accumbens of resistant rats compared to sensitive rats euthanized after that time. These results indicate that footshocks can differentiate two behavioral phenotypes with differential biochemical and epigenetic consequences in the ventral and dorsal striatum.
冰毒成瘾的特征是尽管生活状况不佳，但仍会强迫性地大量吸食毒品。一种包括因不良后果而给予足部电击的自我给药模型，有助于将减少或停止按压杠杆以获取冰毒的大鼠（敏感组）与在出现负面结果时仍继续按压杠杆以获取冰毒的大鼠（抵抗组）区分开来。我们观察到，与抵抗组大鼠相比，敏感组大鼠伏隔核中的 DNA 羟甲基化和钾通道 mRNA 的表达增加，这表明这些通道在抑制冰毒摄入方面发挥作用。在仅一个月的戒断后，敏感大鼠的背侧纹状体中还观察到神经生长因子（NGF）表达和其下游信号通路（NGF-TrkA 和 p75NTR/MAPK 信号通路）的显著激活，但在抵抗组大鼠中并未观察到这种情况。相比之下，与敏感组大鼠相比，只有抵抗组大鼠的伏隔核中的催产素 mRNA 表达增加。这些结果表明，足部电击可以区分具有不同生化和表观遗传后果的两种行为表型，分别在腹侧纹状体和背侧纹状体中起作用。
