Jomphe C, Lévesque D, Trudeau L-E
Department of Pharmacology, Faculty of Medicine, Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, Québec H3T 1J4, Canada.
Naunyn Schmiedebergs Arch Pharmacol. 2003 May;367(5):480-9. doi: 10.1007/s00210-003-0742-3. Epub 2003 Apr 15.
Antipsychotic drugs such as haloperidol act as dopamine D2 receptor antagonists to produce a number of cellular effects including the induction of immediate-early genes such as c-fos. It has been hypothesized that blockade of D2 receptors by antipsychotics is responsible for the induction of c-fos, but the mechanism has not been determined. Using cultured ventral tegmental area (VTA) dopaminergic neurons as a model, we report that nanomolar concentrations of haloperidol cause a time-dependent increase in Fos expression in dopaminergic neurons.Surprisingly, this induction was not mimicked by sulpiride, a selective D2 receptor antagonist, and was not blocked by Rp-cAMPS, an antagonist of protein kinase A (PKA), thus suggesting that D2 receptors and the cAMP cascade are not required. The induction of Fos expression was blocked by tetrodotoxin, BAPTA and KN-93, thus showing that it is activity- and calcium-dependent and requires the activation of a calmodulin-dependent kinase (CaMK). Together, these results suggest that haloperidol induces Fos expression in dopaminergic neurons through a D2 receptor-independent increase in intracellular calcium, leading to CaMK activation.
抗精神病药物如氟哌啶醇可作为多巴胺D2受体拮抗剂，产生多种细胞效应，包括诱导c-fos等即早基因。据推测，抗精神病药物对D2受体的阻断作用导致了c-fos的诱导，但具体机制尚未明确。我们以培养的腹侧被盖区（VTA）多巴胺能神经元为模型，发现纳摩尔浓度的氟哌啶醇可使多巴胺能神经元中的Fos表达随时间增加。令人惊讶的是，选择性D2受体拮抗剂舒必利无法模拟这种诱导作用，蛋白激酶A（PKA）拮抗剂Rp-cAMPS也不能阻断该作用，这表明D2受体和cAMP级联反应并非必需。Fos表达的诱导被河豚毒素、BAPTA和KN-93阻断，这表明其依赖于活性和钙，且需要钙调蛋白依赖性激酶（CaMK）的激活。综上所述，这些结果表明氟哌啶醇通过细胞内钙的D2受体非依赖性增加诱导多巴胺能神经元中的Fos表达，进而导致CaMK激活。
