Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction
- 9 September 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 373 (6560), 1252-1256
- https://doi.org/10.1126/science.abi9086
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.Keywords
This publication has 33 references indexed in Scilit:
- Social reward requires coordinated activity of nucleus accumbens oxytocin and serotoninNature, 2013
- Reduced Forebrain Serotonin Transmission is Causally Involved in the Development of Compulsive Cocaine Seeking in RatsNeuropsychopharmacology, 2012
- Contributions of serotonin in addiction vulnerabilityNeuropharmacology, 2011
- Serotonin Induces Long-Term Depression at Corticostriatal SynapsesJournal of Neuroscience, 2011
- Drug-Evoked Synaptic Plasticity in Addiction: From Molecular Changes to Circuit RemodelingNeuron, 2011
- Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporterProceedings of the National Academy of Sciences of the United States of America, 2011
- Opponency Revisited: Competition and Cooperation Between Dopamine and SerotoninNeuropsychopharmacology, 2010
- The Mechanistic Classification of Addictive DrugsPLoS Medicine, 2006
- Differential Effects of the 5-HT2A Receptor Antagonist M100,907 and the 5-HT2C Receptor Antagonist SB242,084 on Cocaine-induced Locomotor Activity, Cocaine Self-administration and Cocaine-induced Reinstatement of RespondingNeuropsychopharmacology, 2002
- Bidirectional Control of Quantal Size by Synaptic Activity in the HippocampusScience, 1996