Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Brain Res. 2023 May 1;1806:148310. doi: 10.1016/j.brainres.2023.148310. Epub 2023 Mar 4.
Psychostimulant exposure and withdrawal cause neuroimmune dysregulation and anxiety that contributes to dependence and relapse. Here, we tested the hypothesis that withdrawal from the synthetic cathinone MDPV (methylenedioxypyrovalerone) produces anxiety-like effects and enhanced levels of mesocorticolimbic cytokines that are inhibited by cyanidin, an anti-inflammatory flavonoid and nonselective blocker of IL-17A signaling. For comparison, we tested effects on glutamate transporter systems that are also dysregulated during psychostimulant free period. Rats injected for 9 d with MDPV (1 mg/kg, IP) or saline were pretreated daily with cyanidin (0.5 mg/kg, IP) or saline, followed by behavioral testing on the elevated zero maze (EZM) 72 h after the last MDPV injection. MDPV withdrawal caused a reduction in time spent on the open arm of the EZM that was prevented by cyanidin. Cyanidin itself did not affect locomotor activity or time spent on the open arm, or cause aversive or rewarding effects in place preference experiments. MDPV withdrawal caused enhancement of cytokine levels (IL-17A, IL-1β, IL-6, TNF=α, IL-10, and CCL2) in the ventral tegmental area, but not amygdala, nucleus accumbens, or prefrontal cortex, that was prevented by cyanidin. During MDPV withdrawal, mRNA levels of glutamate aspartate transporter (GLAST) and glutamate transporter subtype 1 (GLT-1) in the amygdala were also elevated but normalized by cyanidin treatment. These results show that MDPV withdrawal induced anxiety, and brain-region specific dysregulation of cytokine and glutamate systems, that are both prevented by cyanidin, thus identifying cyanidin for further investigation in the context of psychostimulant dependence and relapse.
精神兴奋剂暴露和戒断会导致神经免疫失调和焦虑，从而导致依赖和复发。在这里，我们测试了一个假设，即从合成卡西酮 MDPV（甲基enedioxypyrovalerone）戒断会产生类似焦虑的效果，并增强中皮质边缘细胞因子的水平，这些细胞因子被花青素抑制，花青素是一种抗炎类黄酮和 IL-17A 信号的非选择性阻断剂。为了进行比较，我们还测试了对谷氨酸转运体系统的影响，这些系统在精神兴奋剂戒断期间也会失调。连续 9 天注射 MDPV（1mg/kg，IP）或生理盐水的大鼠，每天用花青素（0.5mg/kg，IP）或生理盐水预处理，最后一次 MDPV 注射后 72 小时进行高架十字迷宫（EZM）行为测试。MDPV 戒断导致 EZM 开臂时间减少，花青素可预防这种情况。花青素本身不影响运动活动或开臂时间，也不会在位置偏好实验中引起厌恶或奖励作用。MDPV 戒断导致腹侧被盖区细胞因子水平（IL-17A、IL-1β、IL-6、TNF-α、IL-10 和 CCL2）升高，但杏仁核、伏隔核或前额叶皮质没有升高，花青素可预防这种情况。在 MDPV 戒断期间，杏仁核中的谷氨酸天冬氨酸转运体（GLAST）和谷氨酸转运体亚型 1（GLT-1）的 mRNA 水平也升高，但被花青素处理后恢复正常。这些结果表明，MDPV 戒断诱导焦虑以及大脑区域特定的细胞因子和谷氨酸系统失调，花青素可预防这两种情况，从而确定花青素可进一步研究精神兴奋剂依赖和复发的情况。
