Reynolds Lauren M, Gifuni Anthony J, McCrea E Tess, Shizgal Peter, Flores Cecilia
Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada; Department of Psychiatry and Department of Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montréal, QC, Canada.
Department of Psychiatry and Department of Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montréal, QC, Canada.
Behav Brain Res. 2016 Feb 1;298(Pt A):27-31. doi: 10.1016/j.bbr.2015.05.020. Epub 2015 May 22.
Mesocortical dopamine connectivity continues to mature during adolescence. This protracted development confers increased vulnerability for environmental and genetic factors to disrupt mesocortical wiring and subsequently influence responses to drugs of abuse in adulthood. The netrin-1 receptor, DCC, orchestrates medial prefrontal cortex dopamine input during adolescence and dictates the functional organization of local circuitry. Haploinsufficiency of dcc results in increased dopamine innervation to the medial prefrontal cortex, which in turn leads to resilience against the behavioral activating effects of stimulant drugs. However, whether sensitivity to the rewarding effects of drugs of abuse is also altered in dcc haploinsufficiency remains to be resolved. Here, we used the curve-shift method to measure cocaine-induced facilitation of intracranial self-stimulation (ICSS) in adult dcc haploinsufficient mice and wild-type littermates. We found that dcc haploinsufficient mice acquire ICSS behavior at comparable stimulation parameters to wild-type controls. However, cocaine-induced potentiation of ICSS is significantly blunted in dcc haploinsufficient mice. These results are consistent with decreased sensitivity to the rewarding effects of cocaine and/or decreased proclivity to invest effort in the pursuit of reward in dcc haploinsufficient mice. Moreover, these findings suggest that DCC signaling determines adult susceptibility to drug abuse most likely by controlling prefrontal cortex development in adolescence.
中脑皮质多巴胺连接在青春期持续成熟。这种长期的发育使个体更容易受到环境和遗传因素的影响，从而破坏中脑皮质的神经连接，进而影响成年期对滥用药物的反应。神经纤毛蛋白-1受体DCC在青春期协调内侧前额叶皮质的多巴胺输入，并决定局部神经回路的功能组织。DCC单倍剂量不足会导致内侧前额叶皮质的多巴胺神经支配增加，进而增强对兴奋剂药物行为激活作用的抵抗力。然而，DCC单倍剂量不足时对滥用药物奖赏效应的敏感性是否也会改变仍有待解决。在此，我们使用曲线移动法测量成年DCC单倍剂量不足小鼠和野生型同窝小鼠中可卡因诱导的颅内自我刺激（ICSS）增强。我们发现，DCC单倍剂量不足的小鼠在与野生型对照相当的刺激参数下获得ICSS行为。然而，可卡因诱导的ICSS增强在DCC单倍剂量不足的小鼠中明显减弱。这些结果与DCC单倍剂量不足的小鼠对可卡因奖赏效应的敏感性降低和/或在追求奖赏时投入努力的倾向降低一致。此外，这些发现表明，DCC信号传导最有可能通过控制青春期前额叶皮质的发育来决定成年人对药物滥用的易感性。
