Reduced Forebrain Serotonin Transmission is Causally Involved in the Development of Compulsive Cocaine Seeking in Rats

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2012-10, Vol.37 (11), p.2505-2514
• Main Authors: PELLOUX, Yann, DILLEEN, Ruth, ECONOMIDOU, Daina, THEOBALD, David, EVERITT, Barry J
• Format: Article
• Language: English
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; 5,7-Dihydroxytryptamine - pharmacology; Addictive behaviors; Animals; Behavior, Addictive - etiology; Behavior, Addictive - metabolism; Behavior, Addictive - pathology; Biological and medical sciences; Cocaine; Cocaine - adverse effects; Conditioning, Operant - drug effects; Conditioning, Operant - physiology; Disease Models, Animal; Dopamine - metabolism; Dopamine Uptake Inhibitors - adverse effects; Drug abuse; Drug addiction; Drug self-administration; Drug use; Forebrain; Hydroxyindoleacetic Acid - metabolism; Male; Medical sciences; Neuropharmacology; Neurotransmission; Original; Pharmacology. Drug treatments; Prosencephalon - drug effects; Prosencephalon - metabolism; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Punishment - psychology; Rats; Reinforcement (Psychology); Reinforcement Schedule; Self Administration; Serotonin; Serotonin - metabolism; Serotonin Agents - pharmacology; Serotonin S2 receptors; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Time Factors
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2012.111

Whereas the majority of cocaine users quit as they experience the negative consequences of drug use, some lose control over their drug taking and compulsively seek drugs. We report that 20% of rats compulsively seek cocaine despite intermittent negative outcomes after escalating their cocaine self-administration. This compulsive subgroup showed marked reductions in forebrain serotonin utilization; increasing serotonin transmission reduced their compulsive cocaine seeking. Depleting forebrain serotonin induced compulsive cocaine seeking in rats with a limited cocaine taking history; this was reversed by systemic treatment with a 5-hydroxytryptamine (5-HT2C) receptor agonist and mimicked by systemic treatment with a 5-HT2C receptor antagonist in intact animals. These results indicate the causal involvement of reduced serotoninergic transmission in the emergence of compulsive drug seeking after a long cocaine-taking history.