Journal article
Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice
Neuropsychopharmacology (New York, N.Y.), Vol.44(5), pp.994-1006
04/01/2019
DOI: 10.1038/s41386-018-0301-8
PMCID: PMC6462012
PMID: 30578419
Abstract
Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/ hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT2C receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT2C signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.
Details
- Title: Subtitle
- Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice
- Creators
- Adele Stewart - Florida Atlantic UniversityGwynne L. Davis - Florida Atlantic UniversityPaul J. Gresch - Florida Atlantic UniversityRania M. Katamish - Florida Atlantic UniversityRodeania Peart - Florida Atlantic UniversityMaximilian J. Rabil - Florida Atlantic UniversityRaajaram Gowrishankar - Florida Atlantic UniversityF. Ivy Carroll - RTI InternationalMaureen K. Hahn - Florida Atlantic UniversityRandy D. Blakely - Florida Atlantic University
- Resource Type
- Journal article
- Publication Details
- Neuropsychopharmacology (New York, N.Y.), Vol.44(5), pp.994-1006
- Publisher
- Springer Nature
- DOI
- 10.1038/s41386-018-0301-8
- PMID
- 30578419
- PMCID
- PMC6462012
- ISSN
- 0893-133X
- eISSN
- 1740-634X
- Number of pages
- 13
- Grant note
- Elaine Sanders-Bush Scholar's Award from the Vanderbilt Silvio O. Conte Center for Neuroscience Research T32MH064913 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) MC_UP_1502/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) MH065215 / Postdoctoral Training Program in Functional Neurogenomics Vanderbilt International Scholar Program MH086530; MH107132 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 04/01/2019
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618522102771
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