Serotonin transporter inhibition and 5-HT 2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 44; no. 5; p. 994
• Main Authors: Stewart, Adele, Davis, Gwynne L, Gresch, Paul J, Katamish, Rania M, Peart, Rodeania, Rabil, Maximilian J, Gowrishankar, Raajaram, Carroll, F Ivy, Hahn, Maureen K, Blakely, Randy D
• Format: Journal Article
• Language: English
• Published: England 01.04.2019
• Subjects: Animals; Behavior, Animal - drug effects; Cocaine - analogs & derivatives; Cocaine - pharmacology; Conditioning, Classical - drug effects; Disease Models, Animal; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - drug effects; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Uptake Inhibitors - pharmacology; Fluoxetine - pharmacology; Locomotion - drug effects; Methylphenidate - pharmacology; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Neostriatum - drug effects; Neostriatum - metabolism; Receptor, Serotonin, 5-HT2C - drug effects; Selective Serotonin Reuptake Inhibitors - pharmacology; Serotonin Plasma Membrane Transport Proteins
• ISSN: 1740-634X
• DOI: 10.1038/s41386-018-0301-8

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-HT 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-HT signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.