Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence.
Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.
1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Noelle C
NC
Anastasio
1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Sonja J
SJ
Stutz
1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Robert G
RG
Fox
Department of Psychiatry, Yale University, New Haven, CT, USA.
Robert M
RM
Sears
Center for Molecular Neuroscience, Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Ronald B
RB
Emeson
Department of Psychiatry, Yale University, New Haven, CT, USA.
Ralph J
RJ
DiLeone
Center for Molecular Neuroscience, Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Richard T
RT
O'Neil
1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Latham H
LH
Fink
1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Dingge
D
Li
1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Thomas A
TA
Green
Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
F Gerard
FG
Moeller
1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Kathryn A
KA
Cunningham
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D010641:Phenotype; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D012008:Recurrence; D012646:Self Administration
D044405:Receptor, Serotonin, 5-HT2C