Nicotine causes psychological dependence through its interactions with nicotinic acetylcholine receptors in the brain. We previously demonstrated that fatty acid-binding protein 3 (FABP3) colocalizes with dopamine D2 receptors (D2Rs) in the dorsal striatum, and FABP3 deficiency leads to impaired D2R function. Moreover, D2R null mice do not exhibit increased nicotine-induced conditioned place preference (CPP) following chronic nicotine administration. To investigate the role of FABP3 in nicotine-induced CPP, FABP3 knockout (FABP3^−/−) mice were evaluated using a CPP apparatus following consecutive nicotine administration (0.5 mg/kg) for 14 days. Importantly, nicotine-induced CPP was suppressed in the conditioning, withdrawal, and relapse phases in FABP3^−/− mice. To resolve the mechanisms underlying impaired nicotine-induced CPP in these mice, we assessed c-Fos expression and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) signaling in both dopamine D1 receptor (D1R)- and D2R-positive neurons in the nucleus accumbens (NAc). Notably, 64% of dopamine receptor-positive neurons in the mouse NAc expressed both D1R and D2R. Impaired nicotine-induced CPP was correlated with lack of responsiveness of both CaMKII and ERK phosphorylation. The number of D2R-positive neurons was increased in FABP3^−/− mice, while the number of D1R-positive neurons and the responsiveness of c-Fos expression to nicotine were decreased. The aberrant c-Fos expression was closely correlated with CaMKII but not ERK phosphorylation levels in the NAc of FABP3^−/− mice. Taken together, these results indicate that impaired D2R signaling due to lack of FABP3 may affect D1R and c-Fos signaling and underlie nicotine-induced CPP behaviors.

尼古丁通过与大脑中的烟碱乙酰胆碱受体相互作用而导致心理依赖。我们以前证明脂肪酸结合蛋白 3 (FABP3) 与背侧纹状体中的多巴胺 D2 受体 (D2R) 共定位，并且 FABP3 缺乏导致 D2R 功能受损。此外，在长期服用尼古丁后，D2R 无效小鼠并未表现出尼古丁诱导的条件性位置偏好 (CPP) 增加。为了研究 FABP3 在尼古丁诱导的 CPP 中的作用，在连续给予尼古丁 (0.5 mg/kg) 14 天后使用 CPP 装置评估FABP3 敲除 (FABP3 ^-/- ) 小鼠。重要的是，尼古丁诱导的 CPP 在 FABP3 ^-/-的条件反射、戒断和复发阶段受到抑制老鼠。为了解决这些小鼠中尼古丁诱导 CPP 受损的潜在机制，我们评估了多巴胺 D1 受体中的c-Fos 表达和 Ca ²⁺ /钙调蛋白依赖性蛋白激酶 II (CaMKII) 和细胞外信号调节激酶 (ERK) 信号传导（伏隔核 (NAc) 中的 D1R) 和 D2R 阳性神经元。值得注意的是，小鼠 NAc 中 64% 的多巴胺受体阳性神经元同时表达 D1R 和 D2R。受损的尼古丁诱导的 CPP 与 CaMKII 和 ERK 磷酸化缺乏反应性相关。FABP3 ^-/-中 D2R 阳性神经元的数量增加小鼠，而 D1R 阳性神经元的数量和 c-Fos 表达对尼古丁的反应性降低。异常的 c-Fos 表达与 CaMKII 密切相关，但与 FABP3 ^-/-小鼠NAc 中的 ERK 磷酸化水平无关。综上所述，这些结果表明，由于缺乏 FABP3 导致的 D2R 信号受损可能会影响 D1R 和 c-Fos 信号并成为尼古丁诱导的 CPP 行为的基础。