Serotonergic mechanisms in addiction-related memories

Drug-associated memories are a hallmark of addiction and a contributing factor in the continued use and relapse to drugs of abuse. Repeated association of drugs of abuse with conditioned stimuli leads to long-lasting behavioral responses that reflect reward-controlled learning and participate in the establishment of addiction. A greater understanding of the mechanisms underlying the formation and retrieval of drug-associated memories may shed light on potential therapeutic approaches to effectively intervene with drug use-associated memory. There is evidence to support the involvement of serotonin (5-HT) neurotransmission in learning and memory formation through the families of the 5-HT₁ receptor (5-HT₁R) and 5-HT₂R which have also been shown to play a modulatory role in the behavioral effects induced by many psychostimulants. While there is a paucity of studies examining the effects of selective 5-HT_1AR ligands, the available dataset suggests that 5-HT_1BR agonists may inhibit retrieval of cocaine-associated memories. The 5-HT_2AR and 5-HT_2CR appear to be integral in the strong conditioned associations made between cocaine and environmental cues with 5-HT_2AR antagonists and 5-HT_2CR agonists possessing potency in blocking retrieval of cocaine-associated memories following cocaine self-administration procedures. The complex anatomical connectivity between 5-HT neurons and other neuronal phenotypes in limbic-corticostriatal brain structures, the heterogeneity of 5-HT receptors (5-HT_XR) and the conflicting results of behavioral experiments which employ non-specific 5-HT_XR ligands contribute to the complexity of interpreting the involvement of 5-HT systems in addictive-related memory processes. This review briefly traces the history of 5-HT involvement in retrieval of drug-cue associations and future targets of serotonergic manipulation that may reduce the impact that drug cues have on addictive behavior and relapse.