The serotonin (5-HT) 2C receptor (5-HT2CR) and its downstream signaling components: Distinct adaptations in cortical circuits associated with cocaine exposure

Simple item page
dc.contributor.advisorDr. Kathryn A. Cunninghamen_US
dc.contributor.committeeMemberDr. Xiaodong Chengen_US
dc.contributor.committeeMemberDr. William P. Clarkeen_US
dc.contributor.committeeMemberDr. Kenneth M. Johnsonen_US
dc.contributor.committeeMemberDr. Cheryl S. Watsonen_US
dc.creatorMaria Fe Lanfrancoen_US
dc.date.accessioned2011-12-20T16:04:24Z
dc.date.available2010-09-28en_US
dc.date.available2011-12-20T16:04:24Z
dc.date.created2009-03-20en_US
dc.date.issued2009-03-17en_US
dc.description.abstractRepeated intermittent cocaine administration results in a progressive augmentation of motor stimulant responses to subsequent drug challenge. Neuronal adaptations underlying this enduring behavioral transformation, known as behavioral sensitization, have been proposed to mediate the incentive motivational effects of cocaine that contribute to increased anxiety, craving and paranoia observed in cocaine addicts. Neuroadaptations in the serotonin (5 HT)2C receptor (5-HT2CR) system, which exerts an inhibitory influence over the limbic-corticostriatal circuitry and has been implicated in modulating cocaine-evoked behaviors, may play a key role in the development and maintenance of behavioral sensitization. However, the sensitivity of 5-HT2CR is diminished after withdrawal from a sensitizing cocaine regimen, suggesting that 5-HT2CR function or its downstream signaling components are significantly altered. Cortical brain areas, including motor cortex and prefrontal cortex (PFC), are important sites of action for 5-HT2CR control of cocaine-induced behaviors and are strongly implicated in cocaine-craving and cocaine-seeking behaviors. We investigated changes in four neuroadaptations that could contribute to functional 5-HT2CR subsensitivity following repeated cocaine administration: 1) 5 HT2CR protein expression and subcellular localization; 2) 5-HT2CR mRNA editing; 3) expression and subcellular localization of postsynaptic-density (PSD) protein-95 (PSD-95); and 4) phosphorylation of p44/p42-mitogen-activated protein kinases (p44/p42-MAPK), which influences activity of molecules involved in 5 HT2CR trafficking. We found decreased 5 HT2CR protein expression in total homogenate and PSD compartment of motor cortex and an apparent shift in edited 5 HT2CR mRNA isoforms in the PFC at day 3 of withdrawal from a repeated cocaine regimen. Acute cocaine administration resulted in redistribution of PSD-95 and p42-MAPK to the PSD in motor cortex, but not in PFC. Cocaine challenge following a sensitizing cocaine regimen increased phospho-p42-MAPK in total homogenate only in motor cortex. Our results suggest distinct regulatory mechanisms for 5 HT2CR function in motor cortex and PFC, with motor cortex being more responsive to the pharmacological effects of cocaine. The combination of these neuroadaptations could strengthen the cortico-striatal circuit and activate the reward pathway, exacerbating the behavioral effects of cocaine and contributing to the expression of sensitization, which could parallel the tendency for cocaine use to escalate to addiction in humans.en_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-03202009-114800en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/57
dc.language.isoengen_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.subjectserotonin 2C receptoren_US
dc.subjectmolecular neuroadaptationsen_US
dc.subjectcortexen_US
dc.subjectcocaineen_US
dc.subjectaddictionen_US
dc.titleThe serotonin (5-HT) 2C receptor (5-HT2CR) and its downstream signaling components: Distinct adaptations in cortical circuits associated with cocaine exposureen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentPharmacology and Toxicologyen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
Lanfranco_dissertation032009.pdf
Size:
3.55 MB
Format:
Adobe Portable Document Format
Download

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
891 B
Format:
Plain Text
Description:
Download

Collections

Published ETD Collection