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

Abstract

BackgroundThe initiation of abstinence (extinction day 1, ED1) represents a stressful event involving abstinence from drug. We showed previously that ED1 cocaine-seeking behavior is reduced by blocking 5-HT signaling in dorsal hippocampus 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) signaling to dorsal hippocampus (DH) may be involved.\n\nMethodsWe used pharmacological inhibition of dorsal hippocampus 5-HT1A/1B receptors (via WAY100,635 plus GR127935), and chemogenetic inhibition of dorsal raphe-dHPC signaling to test the roles of these pathways on cocaine-seeking 2 weeks after ED1. We also tested specific effects of 5-HT1A or 5-HT1B receptor antagonism on conditioned place preference for cocaine.\n\nResultsInhibition of DR-DH signaling via DREADDs or 5-HT1A/1B antagonists decreased ED1 drug-seeking with persistent effects on cocaine-seeking 2 weeks later, confirming the involvement of 5-HT signaling to dorsal hippocampus in driving drug-seeking persistence. Administration of a 5-HT1B antagonist alone on ED1 transiently decreased drug-associated memory performance in CPP, whereas administration of a 5-HT1A antagonist had no effect on memory but blocked CPP on a subsequent test 24h later.\n\nConclusionsWe conclude that blockade of DR inputs or 5HT1 signaling in DH on ED1 prevents recall of the drug-associated context and reduces drug seeking via antagonism of 5-HT1B receptors, and consolidates the memory of the newly non-drug context via antagonism of 5-HT1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms during initial abstinence may facilitate later maintenance of abstinence.