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Serotonin vs. cocaine addiction

Paper Title:

Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction

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Abstract

Compulsive drug use despite adverse consequences defines addiction. While mesolimbic dopamine signaling is sufficient to drive compulsion, psychostimulants such as cocaine also boost extracellular serotonin (5-HT) by inhibiting reuptake. We used SERT Met172 knockin (SertKI) mice carrying a transporter that no longer binds cocaine to abolish 5-HT transients during drug self-administration. SertKI mice showed an enhanced transition to compulsion. Conversely, pharmacologically elevating 5-HT reversed the inherently high rate of compulsion transition with optogenetic dopamine self-stimulation. The bidirectional effect on behavior is explained by presynaptic depression of orbitofrontal cortex–to–dorsal striatum synapses induced by 5-HT via 5-HT1B receptors. Consequently, in projection-specific 5-HT1B receptor knockout mice, the fraction of individuals compulsively self-administering cocaine was elevated. Prevention of compulsive cocaine taking Over time, about 20% of chronic cocaine users lose control and become addicted. There are indications that the differential efficacy of the brain serotonin (5-HT) system may be involved in the vulnerability to drug addiction. However, the relevant circuits and underlying cellular processes remain elusive. Li et al. discovered a synaptic mechanism in mice that underlies the modulatory role of 5-HT in reducing the likelihood of transition to compulsion and eventually addiction (see the Perspective by Miyazaki and Miyazaki). Cocaine binds to 5-HT transporters to block 5-HT reuptake. The elevated extracellular 5-HT activates 5-HT1B receptors and causes presynaptic depression of a projection from the orbitofrontal cortex to the dorsal striatum. These changes reduce the likelihood of inducing postsynaptic potentiation at these synapses, which ultimately drives compulsion. —PRS

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