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

Abstract

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.

From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists

“…To the extent that reinstatement procedures model processes involved in relapse [47], these data suggest a broad role for 5-HT 2C agonists in the treatment of drug abuse and addiction. This is supported by the recent demonstration that a 5-HT 2C agonist reduced self-administration in a rat model of compulsive cocaine-seeking where punishment was interspersed with cocaine availability [48]. Of further significance, Ro60-0175 reduced cocaine self-administration and reinstatement in non-human primates, and blunted the ability of cocaine to elevate dopamine efflux in the N.Acc [49].…”

Model-Based Control in Dimensional Psychiatry

“…Decreasing forebrain 5-HT and systemic 5HT2C antagonism enhanced compulsive cocaine seeking in rodents, which was reversed by a 5HT2C agonist (59). Greater compulsive cocaine seeking behaviours were also reversible with citalopram, a selective serotonin reuptake inhibitor.…”

Drug Addiction: Updating Actions to Habits to Compulsions Ten Years On

“…Such studies encourage the notion that compulsivity associated with a neural circuit regulated by the OFC may be a general construct of neuropsychiatric disorders, including addiction. These cortical regions are also implicated in the production of compulsive stimulant drug seeking in rats that results in adverse consequences such as electric footshock (Chen et al 2013;Pelloux et al 2012Pelloux et al , 2013.…”