title: Variation within the serotonin (5-HT) 5-HT₂C receptor system aligns with vulnerability to cocaine cue reactivity.
abstract: Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses ('cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.
authors.affiliation: Center for Addiction Research and 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 Neurobehavioral Research on Addictions, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Neurobehavioral Research on Addictions, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Maili
authors.affiliation: Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Swinford
authors.affiliation: Center for Neurobehavioral Research on Addictions, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Lane
authors.affiliation: Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Fox
authors.affiliation: Statistical & Genetic Consulting, LLC, New York, NY, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Hamon
authors.affiliation: Michael E DeBakey VA Medical Center, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Nielsen
authors.affiliation: Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Cunningham
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: F G
authors.initials: FG
authors.lastname: Moeller
mesh_terms: D000328:Adult; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects / Q000502:physiology; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D001381:Azepines / Q000494:pharmacology; D003042:Cocaine; D019970:Cocaine-Related Disorders / Q000235:genetics*; D003463:Cues; D005260:Female; D006801:Humans; D007206:Individuality; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D057190:Stroop Test
chemical_list: C501656:1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole; D001381:Azepines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D003042:Cocaine