Biology subjects

Jayanthi, L. D.

Publications and source records attributed to Jayanthi, L. D..

3 recordsLinked to original sources

bioRxiv2026

Kappa opioid receptors regulate cocaine effects on nucleus accumbens dopamine through phosphorylation of dopamine transporter at the threonine 53 site

Chronic cocaine exposure leads to tolerance of the dopamine transporter (DAT) to cocaine and heightened kappa opioid receptor (KOR)-induced inhibition of dopamine (DA) release in the nucleus accumbens (NAc). KORs on presynaptic DA terminals inhibit DA release and modulate DAT function, but whether KOR signaling causes DAT tolerance is unknown. We demonstrate that rats self-administering cocaine escalate their intake, and the KOR antagonist norbinaltorphimine (nBNI) blunts this escalation. We employed fast-scan cyclic voltammetry (FSCV) in acute brain slices containing the NAc core from these rats and found that the cocaine exposure paradigm resulted in tolerance of the DAT to cocaine, an effect absent in animals pre-treated with nBNI. In drug-naive mice, either superfusion of the KOR agonist U50,488 or a single in vivo injection of U69,593 inhibited DA release and reduced cocaine-induced inhibition of DA reuptake, reproducing the tolerance phenotype without any drug history. We replicated this finding in the NAc of rats, and with the uptake inhibitor nomifensine in rhesus macaques, indicating conservation across rodents and non-human primates. As KOR activation results in phosphorylation of the threonine-53 site on the DAT, we tested whether this is required for the KOR-mediated DAT tolerance to cocaine. We show that a mouse line with a phosphorylation-insensitive alanine-53 mutation of the DAT has enhanced DA release and uptake. Remarkably, KOR agonism no longer mediated DAT tolerance to cocaine in these mice, demonstrating the dependence of this effect on the threonine-53 site and highlighting a KOR-driven mechanism underlying cocaine tolerance at the DAT.

neuroscience↗

bioRxiv2024

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

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.

animal behavior and cognition↗

bioRxiv2023

Kappa Opioid Receptor Antagonism Rescues Genetic Perturbation of Dopamine Homeostasis: Molecular, Physiological and Behavioral Consequences

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, as exemplified by the therapeutic use of d-amphetamine and methylphenidate for the treatment of ADHD, agents with high abuse liability. In search for an improved and non-addictive therapeutic approach for the treatment of DA-linked disorders, we utilized a preclinical mouse model expressing the human DA transporter (DAT) coding variant DAT Val559, previously identified in individuals with ADHD, ASD, or BPD. DAT Val559, like several other disease-associated variants of DAT, exhibits anomalous DA efflux (ADE) that can be blocked by d-amphetamine and methylphenidate. Kappa opioid receptors (KORs) are expressed by DA neurons and modulate DA release and clearance, suggesting that targeting KORs might also provide an alternative approach to normalizing DA-signaling disrupted by perturbed DAT function. Here we demonstrate that KOR stimulation leads to enhanced surface trafficking and phosphorylation of Thr53 in wildtype DAT, effects achieved constitutively by the Val559 mutant. Moreover, these effects can be rescued by KOR antagonism of DAT Val559 in ex vivo preparations. Importantly, KOR antagonism also corrected in vivo DA release as well as sex-dependent behavioral abnormalities observed in DAT Val559 mice. 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.

neuroscience↗