Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Jagiellonian University, Krakow, Poland.
Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland.
Addict Biol. 2020 Nov;25(6):e12826. doi: 10.1111/adb.12826. Epub 2019 Sep 2.
Preclinical studies strongly suggest that cocaine seeking depends on the neuronal activity of the ventral tegmental area (VTA) and phasic dopaminergic (DA) signaling. Notably, VTA pharmacological inactivation or dopamine receptor blockade in the forebrain may induce behavioral inhibition in general and acute aversive states in particular, thus reducing cocaine seeking indirectly. Such artifacts hinder successful translation of these findings in clinical studies and practice. Here, we aimed to evaluate if dynamic VTA manipulations effectively reduce cocaine seeking. We used male tyrosine hydroxylase (TH) IRES-Cre rats along with optogenetic tools to inhibit directly and briefly VTA DA neurons during conditioned stimulus (CS)-induced cocaine seeking under extinction conditions. The behavioral effects of optogenetic inhibition were also assessed in the real-time dynamic place aversion, conditioned place aversion, and CS-induced food-seeking tests. We found that brief and nondysphoric/nonsedative pulses of VTA photo-inhibition (1 s every 9 s, ie, for 10% of time) attenuated CS-induced cocaine seeking under extinction conditions in rats expressing archaerhodopsin selectively on the TH neurons. Furthermore, direct inhibition of the VTA DA activity reduced CS-induced cocaine seeking 24 hours after photo-modulation. Importantly, such effect appears to be selective for cocaine seeking as similar inhibition of the VTA DA activity had no effect on CS-induced food seeking. Thus, briefly inhibiting VTA DA activity during CS-induced cocaine seeking drastically and selectively reduces seeking without behavioral artifacts such as sedation or dysphoria. Our results point to the therapeutic possibilities of coupling nonpharmacologic treatments with extinction training in reducing cocaine addiction.
临床前研究强烈表明，可卡因的寻求依赖于腹侧被盖区（VTA）的神经元活动和相位多巴胺能（DA）信号。值得注意的是，VTA 的药理学失活或前脑的多巴胺受体阻断可能会导致一般的行为抑制和特别是急性厌恶状态，从而间接地减少可卡因的寻求。这些人工制品阻碍了这些发现在临床研究和实践中的成功转化。在这里，我们旨在评估动态 VTA 操作是否能有效减少可卡因的寻求。我们使用雄性酪氨酸羟化酶（TH）IRES-Cre 大鼠以及光遗传学工具，在条件刺激（CS）诱导的可卡因寻求过程中，在消退条件下直接短暂抑制 VTA DA 神经元。光遗传学抑制的行为效应也在实时动态位置厌恶、条件位置厌恶和 CS 诱导的食物寻求测试中进行了评估。我们发现，短暂的、非烦躁的/非镇静的 VTA 光抑制（每 9 秒 1 次脉冲，即 10%的时间）减弱了在 TH 神经元上选择性表达archaerhodopsin 的大鼠在消退条件下 CS 诱导的可卡因寻求。此外，VTA DA 活性的直接抑制减少了光调制后 24 小时 CS 诱导的可卡因寻求。重要的是，这种效应似乎是可卡因寻求的选择性，因为类似的 VTA DA 活性抑制对 CS 诱导的食物寻求没有影响。因此，在 CS 诱导的可卡因寻求过程中短暂抑制 VTA DA 活性会极大地选择性地减少寻求，而不会产生镇静或烦躁等行为人工制品。我们的结果表明，将非药物治疗与消退训练相结合，有可能治疗可卡因成瘾。
