Abstract
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-HT 2C receptor (5-HT 2C R) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT 2C R functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT 2C R macromolecular protein complex, and editing of the 5-HT 2C R 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-HT 2C R membrane protein levels concomitant with higher levels of 5-HT 2C R:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT 2C R 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-HT 2C R induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT 2C R tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT 2C R functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 360-372 |
| Number of pages | 13 |
| Journal | Neuropsychopharmacology |
| Volume | 39 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 2014 |
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Keywords
- 5-HT receptor
- cocaine
- cue reactivity
- impulsive action
- prefrontal cortex
- RNA editing
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health
Cite this
Functional status of the serotonin 5-HT 2C receptor (5-HT 2C R) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. / Anastasio, Noelle; Stutz, Sonja J.; Fox, Robert G.; Sears, Robert M.; Emeson, Ronald B.; Dileone, Ralph J.; O'Neil, Richard T.; Fink, Latham H.; Li, Dingge; Green, Thomas; Gerard Moeller, F.; Cunningham, Kathryn.
In: Neuropsychopharmacology, Vol. 39, No. 2, 01.2014, p. 360-372.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functional status of the serotonin 5-HT 2C receptor (5-HT 2C R) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence
AU - Anastasio, Noelle
AU - Stutz, Sonja J.
AU - Fox, Robert G.
AU - Sears, Robert M.
AU - Emeson, Ronald B.
AU - Dileone, Ralph J.
AU - O'Neil, Richard T.
AU - Fink, Latham H.
AU - Li, Dingge
AU - Green, Thomas
AU - Gerard Moeller, F.
AU - Cunningham, Kathryn
PY - 2014/1
Y1 - 2014/1
N2 - 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-HT 2C receptor (5-HT 2C R) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT 2C R functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT 2C R macromolecular protein complex, and editing of the 5-HT 2C R 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-HT 2C R membrane protein levels concomitant with higher levels of 5-HT 2C R:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT 2C R 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-HT 2C R induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT 2C R tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT 2C R functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.
AB - 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-HT 2C receptor (5-HT 2C R) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT 2C R functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT 2C R macromolecular protein complex, and editing of the 5-HT 2C R 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-HT 2C R membrane protein levels concomitant with higher levels of 5-HT 2C R:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT 2C R 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-HT 2C R induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT 2C R tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT 2C R functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.
KW - 5-HT receptor
KW - cocaine
KW - cue reactivity
KW - impulsive action
KW - prefrontal cortex
KW - RNA editing
UR - http://www.scopus.com/inward/record.url?scp=84890551235&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890551235&partnerID=8YFLogxK
U2 - 10.1038/npp.2013.199
DO - 10.1038/npp.2013.199
M3 - Article
VL - 39
SP - 360
EP - 372
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 2
ER -