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Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice.
Neuropsychopharmacology. 2019 04; 44(5):994-1006.N

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.

Authors+Show Affiliations

Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA.Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA. Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA.Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA. Brain Institute, Florida Atlantic University, Jupiter, FL, USA.Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA.Wilkes Honors College, Florida Atlantic University, Jupiter, FL, USA.Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA.Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA. Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA. International Scholars Program, Vanderbilt University, Nashville, TN, USA.Research Triangle Institute, Research Triangle Park, NC, USA.Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA. Brain Institute, Florida Atlantic University, Jupiter, FL, USA.Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA. rblakely@health.fau.edu. Brain Institute, Florida Atlantic University, Jupiter, FL, USA. rblakely@health.fau.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30578419

Citation

Stewart, Adele, et al. "Serotonin Transporter Inhibition and 5-HT2C Receptor Activation Drive Loss of Cocaine-induced Locomotor Activation in DAT Val559 Mice." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 44, no. 5, 2019, pp. 994-1006.
Stewart A, Davis GL, Gresch PJ, et al. Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice. Neuropsychopharmacology. 2019;44(5):994-1006.
Stewart, A., Davis, G. L., Gresch, P. J., Katamish, R. M., Peart, R., Rabil, M. J., Gowrishankar, R., Carroll, F. I., Hahn, M. K., & Blakely, R. D. (2019). Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 44(5), 994-1006. https://doi.org/10.1038/s41386-018-0301-8
Stewart A, et al. Serotonin Transporter Inhibition and 5-HT2C Receptor Activation Drive Loss of Cocaine-induced Locomotor Activation in DAT Val559 Mice. Neuropsychopharmacology. 2019;44(5):994-1006. PubMed PMID: 30578419.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice. AU - Stewart,Adele, AU - Davis,Gwynne L, AU - Gresch,Paul J, AU - Katamish,Rania M, AU - Peart,Rodeania, AU - Rabil,Maximilian J, AU - Gowrishankar,Raajaram, AU - Carroll,F Ivy, AU - Hahn,Maureen K, AU - Blakely,Randy D, Y1 - 2018/12/21/ PY - 2018/08/19/received PY - 2018/12/15/accepted PY - 2018/11/19/revised PY - 2018/12/24/pubmed PY - 2019/12/19/medline PY - 2018/12/23/entrez SP - 994 EP - 1006 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 44 IS - 5 N2 - 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. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/30578419/Serotonin_transporter_inhibition_and_5_HT2C_receptor_activation_drive_loss_of_cocaine_induced_locomotor_activation_in_DAT_Val559_mice_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30578419/ DB - PRIME DP - Unbound Medicine ER -