Impaired Acquisition of Nicotine-Induced Conditioned Place Preference in Fatty Acid-Binding Protein 3 Null Mice
Impaired Acquisition of Nicotine-Induced Conditioned Place Preference in Fatty Acid-Binding Protein 3 Null Mice
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DOI：
10.1007/s12035-020-02228-2
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发表时间：
2021-01-07
影响因子：
5.1
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
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作者：
Jia, Wenbin;Wilar, Gofarana;Fukunaga, Kohji
尼古丁通过与大脑中的烟碱乙酰胆碱受体相互作用引起心理依赖。我们以前证明，脂肪酸结合蛋白3（FABP 3）共定位与多巴胺D2受体（D2 Rs）在背侧纹状体，和FABP 3缺乏导致受损的D2 R功能。此外，D2 R敲除小鼠在长期尼古丁给药后未表现出尼古丁诱导的条件性位置偏爱（CPP）增加。为了研究FABP 3在尼古丁诱导的CPP中的作用，在连续给予尼古丁（0.5mg/kg）14天后，使用CPP装置评价FABP 3敲除（FABP 3（-/-））小鼠。重要的是，尼古丁诱导的CPP在FABP 3（-/-）小鼠的调节、戒断和复发阶段受到抑制。为了解决这些小鼠中尼古丁诱导的CPP受损的潜在机制，我们评估了多巴胺D1受体（D1 R）和D2 R阳性神经元中的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。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D1 R和D2 R。尼古丁诱导的CPP受损与CaMKII和ERK磷酸化反应性的缺乏相关。FABP 3（-/-）小鼠D2 R阳性神经元数目增加，D1 R阳性神经元数目减少，c-Fos表达对尼古丁的反应性降低。FABP 3（-/-）小鼠NAc中c-Fos的异常表达与CaMKII而非ERK磷酸化水平密切相关。综上所述，这些结果表明，由于缺乏FABP 3而导致的D2 R信号传导受损可能会影响D1 R和c-Fos信号传导，并成为尼古丁诱导的CPP行为的基础。
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.