Increased serotonin prevents cocaine addiction in mice

Elevated levels of serotonin can prevent the development of compulsive cocaine seeking and addiction in mice, researchers report. The findings help to resolve the biological markers of addiction risk. Like other addictive drugs, cocaine acts by blocking the reuptake of key neurotransmitters such as dopamine and serotonin, resulting in its euphoric effects. However, not all who use the drug become addicted – only about 20% of cocaine users lose control and continue to compulsively use the drug despite adverse consequences. What makes some users susceptible to addiction risk isn’t well known. Although previous studies have suggested that the differential efficacy of the brain serotonin system could play a role in developing a cocaine addiction, the relevant brain circuits and processes that underly the transition from casual to compulsive use remain elusive. In this study, Yue Li and colleagues report the discovery of a mechanism that reveals a modulatory role of serotonin in preventing the development of compulsive cocaine seeking and addiction in mice. In a series of experiments using wild-type and transgenic mice, Li et al. show how cocaine binds with serotonin transporters to block reuptake, which results in elevated levels of extracellular serotonin. This buildup activates the serotonin receptor 5-HT_1B and causes presynaptic depression that inhibits synaptic transmission between the orbitofrontal cortex and the dorsal striatum, preventing wild-type mice from becoming addicted. However, in transgenic mice whose serotonin transporters did not bind with cocaine and thus prevented the accumulation of extracellular serotonin, compulsive cocaine-seeking behavior was elevated. According to the authors, the findings suggest that serotonin plays an essential role in modulating the risk of developing addiction. “Further studies should clarify the neural mechanism underlying serotonin modulation of the transition to compulsion in drug addition, what agents specific to serotonin receptors can be used and when these agents can be administered to potentially treat drug addiction,” write Katsuhiko Miyazaki and Kayoko Miyazaki in a related Perspective.