Novelty-induced hyperactivity and suppressed cocaine induced locomotor activation in mice lacking threonine 53 phosphorylation of dopamine transporter

Varman, Durairaj Ragu; Subler, Mark A.; Windle, Jolene J.; Jayanthi, Lankupalle D.; Ramamoorthy, Sammanda

doi:10.1016/j.bbr.2021.113267

Cited by 6 publications

(17 citation statements)

References 72 publications

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“…45 In this study, EA achieved an antidepressant effect with decreased total and phosphorylated DAT, as well as the reversal of DAT phos- increase locomotor activities, and present antidepressant effects. [59][60][61] At present, the phosphorylation of DAT has been learned thoroughly, but it has been hardly discussed in depression. Our experiment initially observed the consistent changes of spontaneous excitatory synaptic Here, ameliorated depression was along with raised TAAR1 and PKA expression of rats after EA treatment.…”

Section: Discussionmentioning

confidence: 99%

Electroacupuncture alleviated depression‐like behaviors in ventromedial prefrontal cortex of chronic unpredictable mild stress‐induced rats: Increasing synaptic transmission and phosphorylating dopamine transporter

Cai

Zhang

et al. 2023

CNS Neurosci Ther

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Aims Electroacupuncture (EA) shows advantages in both clinical practice and depression animal models. Dopaminergic‐related dysfunction in the prefrontal cortex (PFC) may be a hidden antidepressant mechanism of EA, where dopamine transporter (DAT) plays an essential role. This study aimed to investigate the synaptic transmission and DAT‐related changes of EA in depression. Methods Male Sprague–Dawley rats were subjected to 3‐week chronic unpredictable mild stress (CUMS). The successfully modeled rats were then randomly and equally assigned to CUMS, selective serotonin reuptake inhibitor (SSRI), and EA or SSRI + EA groups, followed by a 2‐week treatment respectively. After monitoring body weight and behavioral tests of all rats, the ventromedial PFC (vmPFC) tissue was collected for electrophysiology and the expression detection of DAT, phosphorylated DAT (p‐DAT), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and trace amine‐associated receptor 1 (TAAR1). Results Depressive‐like behaviors induced by CUMS were alleviated by EA, SSRI, and SSRI + EA treatments through behavioral tests. Compared with CUMS group, EA improved synaptic transmission in vmPFC by upregulating spontaneous excitatory postsynaptic currents amplitude. Molecularly, EA reversed the increased total DAT and p‐DAT expression as well as the decreased ratio of p‐DAT/total DAT along with the activation of TAAR1, cAMP, and PKA in vmPFC. Conclusion We speculated that the antidepressant effect of EA was associated with enhanced synaptic transmission in vmPFC, and the upregulated phosphorylation of DAT relevant to TAAR1, cAMP, and PKA may be the potential mechanism.

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Section: Discussionmentioning

confidence: 99%

Electroacupuncture alleviated depression‐like behaviors in ventromedial prefrontal cortex of chronic unpredictable mild stress‐induced rats: Increasing synaptic transmission and phosphorylating dopamine transporter

Cai

Zhang

et al. 2023

CNS Neurosci Ther

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“…Surface protein biotinylation was carried out as described in our previous study [26]. Dorsal or ventral striatal synaptosomes from respective treatment groups and genotypes (under experimental groups and drugs) were used for surface protein biotinylation.…”

Section: Surface Protein Biotinylation and Determination Of Total And...mentioning

confidence: 99%

“…Locomotor activity was measured in open field activity monitoring chambers (Med Associates, St. Albans, VT; Model ENV 510) in a soundproof box as described earlier [26]. The horizontal activity was recorded for 60 min and data were collected in 4 min bins as cm.…”

Section: Locomotor Activity Measurementmentioning

confidence: 99%

“…We recently used a knock-in mouse model (DAT-Ala53) carrying a non-phosphorylatable Ala at Thr53 phosphorylation site in DAT to examine the impact of in-vivo pT53-DAT on DAT function and animal behavior [26]. In the current study, we directly examined the causal role of in-vivo pT53-DAT in mediating KOR-linked DAT regulation, aversion-like behavior, and locomotor suppression using DAT-Ala53 and WT mice.…”

Section: Introductionmentioning

confidence: 99%

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Dopamine transporter threonine-53 phosphorylation dictates kappa opioid receptor mediated locomotor suppression and conditioned place aversion via transporter upregulation

Varman,

Jayanthi,

Ramamoorthy

2024

Preprint

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Dynorphin (DYN)/kappa opioid receptor (KOR) activation contributes to aversion, dysphoria, sedation, depression, and enhanced psychostimulant-rewarding effects, which have been attributed to the inhibition of dopamine (DA) release. DYN fibers synapse onto DA terminals which express both KOR and dopamine transporter (DAT). DAT activity is critical in the regulation of DA dynamics and dopaminergic neurotransmission. Previously, we demonstrated that KOR agonists upregulate DAT activity via ERK1/2 signaling involving phospho-Thr53 DAT (pT53-DAT). However, whether pT53-DAT is involved in KOR-mediated DAT regulation in-vivo and whether such phenomenon contributes to the behavioral effects of KOR agonism are unknown. Here, we investigated the role of endogenous pT53-DAT in KOR-mediated DAT regulation and the effect of KOR agonists on locomotor suppression and aversive behaviors using DAT-Ala53 knock-in mice expressing DAT carrying non-phosphorylatable Ala at position 53 replacing Thr. Acute systemic administration of KOR agonist, U69593 resulted in KOR antagonist-sensitive increases in DAT activity in parallel to increases in pT53-DAT, and DAT Vmax and surface expression in the ventral and dorsal striatum (containing the nucleus accumbens and caudate putamen respectively) of WT, but not DAT-Ala53 mice. KOR agonists produced conditioned place aversion (CPA) and locomotor suppression in WT but not DAT-Ala53 mice. However, both WT and DAT-Ala53 mice exhibited similar lithium chloride-induced CPA and morphine-induced conditioned place preference (CPP). These findings provide the first evidence that locomotor suppression and aversive responses to KOR agonists manifest due to the modulation of DAT activity via DAT-T53 phosphorylation establishing a causal relationship of pT53-DAT in KOR-mediated DAT regulation and KOR agonist-induced adverse effects.

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“…Abnormal DAT availability in humans with neuropsychiatric disorders has been reported (14,15) and first line treatments for ADHD, i.e., methylphenidate and alphamethylphenethylamine (amphetamine) formulations (16) exhibit high affinity towards DAT (11) and modulate extracellular DA in human subjects (17). Moreover, given abnormal behavior of DATmanipulated animals (12,(18)(19)(20)(21)(22)(23)(24) and that the DAT gene SLC6A3 is implicated in neuropsychiatric diseases (25), ample evidence identifies DAT as a direct contributor to pathological DA dysregulation.…”

Section: Introductionmentioning

confidence: 99%

Kappa Opioid Receptor Antagonism Restores Phosphorylation, Trafficking and Behavior induced by a Disease Associated Dopamine Transporter Variant

Mayer

Stewart

Varman

et al. 2023

Preprint

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Aberrant dopamine (DA) signaling is implicated in schizophrenia, bipolar disorder (BPD), autism spectrum disorder (ASD), substance use disorder, and attention-deficit/hyperactivity disorder (ADHD). Treatment of these disorders remains inadequate. We established that the human DA transporter (DAT) coding variant (DAT Val559), identified in individuals with ADHD, ASD, or BPD, exhibits anomalous DA efflux (ADE) that is blocked by therapeutic amphetamines and methylphenidate. As the latter agents have high abuse liability, we exploited DAT Val559 knock-in mice to identify non-addictive agents that can normalize DAT Val559 functional and behavioral effects ex vivo and in vivo. Kappa opioid receptors (KORs) are expressed by DA neurons and modulate DA release and clearance, suggesting that targeting KORs might offset the effects of DAT Val559. We establish that enhanced DAT Thr53 phosphorylation and increased DAT surface trafficking associated with DAT Val559 expression are mimicked by KOR agonism of wildtype preparations and rescued by KOR antagonism of DAT Val559 ex vivo preparations. Importantly, KOR antagonism also corrected in vivo DA release and sex-dependent behavioral abnormalities. Given their low abuse liability, our studies with a construct valid model of human DA associated disorders reinforce considerations of KOR antagonism as a pharmacological strategy to treat DA associated brain disorders.

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Novelty-induced hyperactivity and suppressed cocaine induced locomotor activation in mice lacking threonine 53 phosphorylation of dopamine transporter

Cited by 6 publications

References 72 publications

Electroacupuncture alleviated depression‐like behaviors in ventromedial prefrontal cortex of chronic unpredictable mild stress‐induced rats: Increasing synaptic transmission and phosphorylating dopamine transporter

Electroacupuncture alleviated depression‐like behaviors in ventromedial prefrontal cortex of chronic unpredictable mild stress‐induced rats: Increasing synaptic transmission and phosphorylating dopamine transporter

Dopamine transporter threonine-53 phosphorylation dictates kappa opioid receptor mediated locomotor suppression and conditioned place aversion via transporter upregulation

Kappa Opioid Receptor Antagonism Restores Phosphorylation, Trafficking and Behavior induced by a Disease Associated Dopamine Transporter Variant

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