title: Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system.
abstract: Intensification of craving elicited by drug-associated cues during abstinence occurs over time in human cocaine users while elevation of cue reactivity ("incubation") is observed in rats exposed to extended forced abstinence from cocaine self-administration. Incubation in rodents has been linked to time-dependent neuronal plasticity in the medial prefrontal cortex (mPFC). We tested the hypothesis that incubation of cue reactivity during abstinence from cocaine self-administration is accompanied by lower potency and/or efficacy of the selective serotonin (5-HT) 5-HT2C​ receptor (5-HT2CR) agonist WAY163909 to suppress cue reactivity and a shift in the subcellular localization profile of the mPFC 5-HT2CR protein. We observed incubation of cue reactivity (measured as lever presses reinforced by the discrete cue complex) between Day 1 and Day 30 of forced abstinence from cocaine relative to sucrose self-administration. Pharmacological and biochemical analyses revealed that the potency of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity, the expression of synaptosomal 5-HT2CR protein in the mPFC, and the membrane to cytoplasmic expression of the 5-HT2CR in mPFC were lower on Day 30 vs. Day 1 of forced abstinence from cocaine self-administration. Incubation of cue reactivity assessed during forced abstinence from sucrose self-administration did not associate with 5-HT2CR protein expression in the mPFC. Collectively, these outcomes are the first indication that neuroadaptations in the 5-HT2CR system may contribute to incubation of cocaine cue reactivity.
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Swinford-Jackson
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Anastasio
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Fox
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Stutz
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: kcunning@utmb.edu.
authors.forename: K A
authors.initials: KA
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology; D001381:Azepines / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D015331:Cohort Studies; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D019422:Dietary Sucrose / Q000008:administration & dosage; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012646:Self Administration; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000378:metabolism*; D013997:Time Factors
chemical_list: C501656:1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole; D001381:Azepines; D019422:Dietary Sucrose; D018765:Dopamine Uptake Inhibitors; D007211:Indoles; D012333:RNA, Messenger; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D003042:Cocaine
keywords: 5-HT(2C) receptor; cocaine; cue reactivity; incubation; medial prefrontal cortex; sucrose