Dunn Scott D, Wiah Sonita, Lami Anwar, Rawls Scott M
Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Cytokine. 2025 Aug;192:156967. doi: 10.1016/j.cyto.2025.156967. Epub 2025 May 29.
Cocaine dysregulates tumor necrosis factor (TNF) signaling in mesolimbic substrates, suggesting a role for TNF in cocaine-induced hyperlocomotion, a signature preclinical effect of cocaine. Inhibition of TNF signaling by genetic deletion or with a brain-penetrable TNF antagonist enhances cocaine-induced hyperlocomotion in male mice, but roles for sex and peripheral TNF are unclear. Also unknown is how peripherally restricted etanercept, the world's most widely prescribed TNF inhibitor, affects cocaine-induced locomotor responses. We determined effects of etanercept on a triad of cocaine-induced locomotor responses (e.g., ambulation, stereotypy, distance traveled) in male and female rats and impacts of etanercept-cocaine exposure on tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA levels in the ventral tegmental area (VTA). Etanercept (20 mg/kg, IP) and a submaximal dose of cocaine (10 mg/kg, IP) were used initially, and etanercept was injected 48 h before cocaine to capture peak plasma concentrations. Etanercept itself did not affect spontaneous locomotor responses in male or female rats. In male rats, etanercept increased cocaine-induced ambulatory and stereotypical activities and enhanced cocaine-induced distance traveled. Etanercept modestly reduced TH mRNA levels in the VTA of cocaine-naïve and cocaine treated male rats. Locomotor responses in male rats that were evoked by a higher dose of cocaine (20 mg/kg, IP) were not affected by etanercept. In female rats, etanercept did not affect any cocaine-induced locomotor responses. These results show that etanercept exerts effects on locomotor behaviors induced by cocaine that depend on both sex and cocaine dose and suggest that peripheral inhibition of TNF influences cocaine-induced behaviors. Key words: etanercept; TNF; cocaine; dopamine; tyrosine hydroxylase; DAT; locomotor.
可卡因会使中脑边缘系统中的肿瘤坏死因子（TNF）信号传导失调，这表明TNF在可卡因诱发的运动亢进中发挥作用，而运动亢进是可卡因典型的临床前效应。通过基因敲除或使用可穿透血脑屏障的TNF拮抗剂抑制TNF信号传导，会增强雄性小鼠中可卡因诱发的运动亢进，但性别和外周TNF的作用尚不清楚。同样未知的是，全球处方最广泛的TNF抑制剂依那西普在局部给药时，如何影响可卡因诱发的运动反应。我们确定了依那西普对雄性和雌性大鼠中由可卡因诱发的一系列运动反应（如行走、刻板动作、行进距离）的影响，以及依那西普与可卡因联合给药对腹侧被盖区（VTA）中酪氨酸羟化酶（TH）和多巴胺转运体（DAT）mRNA水平的影响。最初使用依那西普（20mg/kg，腹腔注射）和亚最大剂量的可卡因（10mg/kg，腹腔注射），并且在注射可卡因前48小时注射依那西普，以达到血浆峰值浓度。依那西普本身不会影响雄性或雌性大鼠的自发运动反应。在雄性大鼠中，依那西普增加了可卡因诱发的行走和刻板动作活动，并延长了可卡因诱发的行进距离。依那西普适度降低了未接触过可卡因和接触过可卡因的雄性大鼠VTA中的TH mRNA水平。更高剂量的可卡因（20mg/kg，腹腔注射）诱发的雄性大鼠运动反应不受依那西普影响。在雌性大鼠中，依那西普不影响任何由可卡因诱发的运动反应。这些结果表明，依那西普对可卡因诱发的运动行为的影响取决于性别和可卡因剂量，并提示外周TNF抑制会影响可卡因诱发的行为。关键词：依那西普；TNF；可卡因；多巴胺；酪氨酸羟化酶；DAT；运动。
