BACKGROUND Reduced expression of the serotonin transporter (SERT) promotes anxiety and cocaine intake in both humans and rats. We tested the hypothesis that median raphe nucleus (MRN) and dorsal raphe nucleus (DRN) serotonergic projections differentially mediate these phenotypes. METHODS We used virally mediated RNA interference to locally downregulate SERT expression and compared the results with those of constitutive SERT knockout. Rats were allowed either short access (ShA) (1 hour) or long access (LgA) (6 hours) to cocaine self-administration to model moderate versus compulsive-like cocaine taking. RESULTS SERT knockdown in the MRN increased cocaine intake selectively under ShA conditions and, like ShA cocaine self-administration, reduced corticotropin-releasing factor (CRF) immunodensity in the paraventricular nucleus of the hypothalamus. In contrast, SERT knockdown in the DRN increased cocaine intake selectively under LgA conditions and, like LgA cocaine self-administration, reduced CRF immunodensity in the central nucleus of the amygdala. SERT knockdown in the MRN or DRN produced anxiety-like behavior, as did withdrawal from ShA or LgA cocaine self-administration. The phenotype of SERT knockout rats was a summation of the phenotypes generated by MRN- and DRN-specific SERT knockdown. CONCLUSIONS Our results highlight a differential role of serotonergic projections arising from the MRN and DRN in the regulation of cocaine intake. We propose that a cocaine-induced shift from MRN-driven serotonergic control of CRF levels in the hypothalamus to DRN-driven serotonergic control of CRF levels in the amygdala may contribute to the transition from moderate to compulsive intake of cocaine.

中文翻译：

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中缝和背侧中缝5-羟色胺能神经元控制中度与强迫性可卡因摄入

背景 血清素转运蛋白 (SERT) 的表达降低会促进人类和大鼠的焦虑和可卡因摄入。我们测试了中缝核 (MRN) 和中缝背核 (DRN) 5-羟色胺能投射差异介导这些表型的假设。方法我们使用病毒介导的 RNA 干扰来局部下调 SERT 表达，并将结果与​​组成型 SERT 敲除的结果进行比较。大鼠被允许短期访问（ShA）（1 小时）或长期访问（LgA）（6 小时）可卡因自我给药，以模拟中度与强迫性可卡因服用。结果 MRN 中的 SERT 敲低在 ShA 条件下选择性地增加了可卡因摄入量，并且与 ShaA 可卡因自我给药一样，降低了下丘脑室旁核中的促肾上腺皮质激素释放因子 (CRF) 免疫密度。相比之下，DRN 中的 SERT 敲低在 LgA 条件下选择性地增加了可卡因的摄入量，并且与 LgA 可卡因自我给药一样，降低了杏仁核中央核中的 CRF 免疫密度。MRN 或 DRN 中的 SERT 敲低产生焦虑样行为，ShA 或 LgA 可卡因自我给药的戒断也是如此。SERT 敲除大鼠的表型是由 MRN 和 DRN 特异性 SERT 敲低产生的表型的总和。结论 我们的结果强调了由 MRN 和 DRN 产生的血清素能预测在可卡因摄入量调节中的不同作用。我们提出，可卡因诱导的从下丘脑 CRF 水平的 MRN 驱动的血清素控制转变为杏仁核中 CRF 水平的 DRN 驱动的血清素控制可能有助于从中度摄入可卡因到强迫性摄入的转变。