Serotonin signaling in hippocampus during initial cocaine abstinence drives persistent drug seeking

The initiation of abstinence after chronic drug self-administration is a stressful event. Cocaine-seeking behavior on the first day of the absence of expected drug (extinction day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampus CA1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior, and that dorsal raphe serotonin (DR 5-HT) input to CA1 may be involved. We inhibited 5-HT1A/1B receptors (WAY100,635 plus GR127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2wk later. We also inhibited 5-HT1A or 5-HT1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT1A/1B signaling, in CA1 decreased drug-seeking on ED1 and decreased cocaine-seeking 2wk later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug-seeking during abstinence. In addition, 5-HT1B antagonism alone transiently decreased drug-associated memory performance when given prior to a conditioned place preference (CPP) test, whereas similar antagonism of 5-HT1A alone had no such effect but blocked CPP retrieval on a test 24h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augments recall of the drug-associated context and drug-seeking via 5-HT1B receptors and prevents consolidation of the updated non-drug context via 5-HT1A receptors. Thus, treatments that modulate 5-HT dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence. Significance Statement One of the most complex issues associated with substance use disorder (SUD) treatment is the development of strategies that assist in the initiation and maintenance of abstinence from drug taking. Herein, we show that the persistent propensity for cocaine-seeking during abstinence can be attenuated by 5-HT1A/5-HT1B receptor antagonists, or by inhibition of dorsal raphe signaling to dorsal hippocampus. Our results provide insight towards potential clinical applications for treatment of addiction in human populations.