The initiation of abstinence after chronic drug self-administration is stressful. Cocaine-seeking behavior on the first day of the absence of the expected drug (Extinction Day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampal cornu ammonis 1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior and that dorsal raphe (DR) serotonin (5-HT) input to CA1 may be involved. We inhibited 5-HT_1A/1B receptors (WAY-100635 plus GR-127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2 weeks later. We also inhibited 5-HT_1A or 5-HT_1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in the persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT_1A/1B signaling, in CA1 decreased drug seeking on ED1 and decreased cocaine seeking 2 weeks later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug seeking during abstinence. In addition, 5-HT_1B antagonism alone transiently decreased drug-associated memory performance when given prior to a CPP test, whereas similar antagonism of 5-HT_1A alone had no such effect but blocked CPP retrieval on a test 24 h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augment recall of the drug-associated context and drug seeking via 5-HT_1B receptors and prevent consolidation of the updated nondrug context via 5-HT_1A receptors. Thus, treatments that modulate 5-HT–dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence.

长期自我给药后开始戒断是有压力的。通过阻断雄性和雌性大鼠背海马角氨 1 (CA1) 中的 5-HT 信号传导，可以减少缺乏预期药物的第一天（灭绝第 1 天，ED1）的可卡因寻求行为。我们假设 ED1 的经历可以显着影响后来的复发行为，并且可能涉及中缝背侧 (DR) 血清素 (5-HT) 输入到 CA1。我们抑制了 ED1 上 CA1 中的 5-HT _1A/1B受体（WAY-100635 加 GR-127935）或 DR 输入（化学遗传学），以测试该通路对 2 周后可卡因寻求持久性的作用。我们还在可卡因条件性位置偏好 (CPP) 过程中抑制了 CA1 中的 5-HT _1A或 5-HT _1B受体，以检查与 ED1 操作的持久效应有关的机制。抑制 CA1 中的 DR 输入或 5-HT _1A/1B信号传导可减少 ED1 上的药物寻求，并减少 2 周后的可卡因寻求，这表明 ED1 期间 CA1 中的 5-HT 信号传导有助于戒断期间的持续药物寻求。此外，在 CPP 测试之前单独使用5-HT _{1B拮抗剂会暂时降低药物相关的记忆表现，而单独使用 5-HT 1A}的类似拮抗剂则没有这种效果，但会在 24 小时后的测试中阻断 CPP 检索。这些 CPP 发现与先前的研究结果一致，表明 CA1 的 DR 输入通过 5-HT _{1B受体增强了对药物相关背景和药物寻找的回忆，并防止通过 5-HT 1A}受体巩固更新的非药物背景。因此，在最初戒断期间调节 CA1 中 5-HT 依赖性记忆机制的治疗可能有助于以后维持戒断。