Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction.

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.

• Authors: Yue Li, Linda D Simmler, Ruud Van Zessen, Jérôme Flakowski, Jin-Xia Wan, Fei Deng, Yu-Long Li, Katherine M Nautiyal, Vincent Pascoli, Christian Lüscher
• Journal: Science (New York, N.Y.) (Science) Vol. 373 Issue 6560 Pg. 1252-1256 (Sep 10 2021) ISSN: 1095-9203 [Electronic] United States
• PMID: 34516792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, Serotonin, 5-HT1B
• Serotonin Plasma Membrane Transport Proteins
• Serotonin
• Cocaine
• Dopamine

Topics

• Animals
• Cocaine (administration & dosage)
• Cocaine-Related Disorders (genetics, metabolism)
• Dopamine (metabolism)
• Gene Knock-In Techniques
• Mice
• Mice, Knockout
• Optogenetics
• Receptor, Serotonin, 5-HT1B (deficiency, metabolism)
• Serotonin (metabolism)
• Serotonin Plasma Membrane Transport Proteins (metabolism)
• Synaptic Transmission