Innate cocaine-seeking vulnerability arising from loss of serotonin-mediated aversive effects of cocaine in rats

• Published in: Cell reports (Cambridge) Vol. 42; no. 5; p. 112404
• Main Authors: Chao, Ying S., Parrilla-Carrero, Jeffrey, Eid, Maya, Culver, Oliver P., Jackson, Tyler B., Lipat, Rachel, Taniguchi, Makoto, Jhou, Thomas C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.05.2023; Elsevier
• Subjects: 5-HT; addiction; Animals; aversion; cocaine; Cocaine - pharmacology; CP: Neuroscience; dopamine; Dopaminergic Neurons - physiology; Rats; Rats, Sprague-Dawley; RMTg; serotonin; Serotonin - pharmacology; Serotonin Agents - pharmacology; serotonin receptor 2c; Tegmentum Mesencephali; Ventral Tegmental Area - physiology; VTA; aversion; serotonin; VTA; cocaine; CP: Neuroscience; addiction; RMTg; serotonin receptor 2c; 5-HT; dopamine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112404

Cocaine blocks dopamine reuptake, thereby producing rewarding effects that are widely studied. However, cocaine also blocks serotonin uptake, which we show drives, in rats, individually variable aversive effects that depend on serotonin 2C receptors (5-HT2CRs) in the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons. 5-HT2CRs produce depolarizing effects in RMTg neurons that are particularly strong in some rats, leading to aversive effects that reduce acquisition of and relapse to cocaine seeking. In contrast, 5-HT2CR signaling is largely lost after cocaine exposure in other rats, leading to reduced aversive effects and increased cocaine seeking. These results suggest a serotonergic biological marker of cocaine-seeking vulnerability that can be targeted to modulate drug seeking. [Display omitted] •Cocaine produces aversive effects that require serotonin 2C receptors at the RMTg•Cocaine aversion varies between individuals due to varying RMTg 5-HT2CR function•Blocking RMTg 5-HT2CR function increases cocaine seeking•Augmenting RMTg 5-HT2CR function blocks cocaine seeking Chao et al. find that cocaine produces a delayed aversive effect that varies widely between individuals, inhibits cocaine seeking, and is mediated by a novel mechanism in which cocaine depolarizes rostromedial tegmental (RMTg) neurons via serotonin 2C receptors. These receptors hence constitute a target for regulating cocaine seeking.