New Drug Class Shows Promise for Treating Brain Disorders Without Addiction

June 2, 2025 – A recent neuropsychiatric advance shows that targeting the kappa opioid receptor (KOR) may restore dopamine function in the absence of the risk of addiction associated with stimulant therapies. 

Dopamine (DA) is a critical neurotransmitter that mediates rewards, motivation, attention, and motor control, making it essential for brain health. Proper DA signaling is essential to normal behavior, and its dysregulation is associated with various psychiatric and neurological conditions, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), schizophrenia, and Parkinson’s disease. The dopamine transporter (DAT) acts to promote dopaminergic signaling by regulating extracellular DA levels through synaptic reuptake. In numerous neuropsychiatric and neurodegenerative disorders, DAT is disrupted.

Rare mutations of the DAT gene (SLC6A3) are linked with a variety of psychiatric disorders. The DAT Val559 variant transports DA effectively but releases DA inappropriately, which can cause chronic DA disruptions. Through animal models possessing this mutation, it is possible to express different behaviors, including impulsivity, memory problems, and anomalous reactions to stimulants; therefore, the study of dopamine pathologies could allow investigators to study new therapeutic approaches.

Recent evidence has emphasized that kappa opioid receptors (KOR) play a key role in regulating dopamine transporter (DAT) activity. Activation of KOR enhances dopaminergic activity by boosting DAT surface expression and transport activity. Phosphorylation of the DAT at the Thr53 site critically regulates KOR activation and DAT activity. Without this phosphorylation site, stimulation of KOR does not result in increased DAT activity, verifying that Thr53 is a key regulatory site of the DAT.

Moreover, investigation of DAT variants that caused an increase in dopamine release (eg, Val559) shows elevated DAT phosphorylation at Thr53. Indeed, when KOR antagonists were administered to these models, most notably norbinaltorphimine (norBNI), the excess was effectively prevented from sequenced dopamine release. In vivo administration of norBNI decreased DAT surface expression to normative levels, normalized dopamine release, and associated functional impairment in Val559 mice.

The above findings have important clinical implications. First, the primary current treatment for ADHD, amphetamines and methylphenidate, which act directly on DAT and have a high potential for abuse. KOR antagonists have the potential to restore normal dopamine homeostasis without reversing DAT function and are not addictive, since the mechanism of KOR antagonism is mediated through changes in the manipulation of transporter trafficking of the DAT and not through blocking its activity.

Importantly, norBNI also enhanced outcomes in both male and female mice, suggesting therapeutic benefits regardless of sex. In vivo KOR antagonism targeting studies suggested a change in DAT trafficking when antagonists were administered and could impact even larger signal transduction that regulates multiple channels, including D2 autoreceptors and dynorphin systems.

Not only did this approach improve behavior, but it also improved clinical and biological measures of dopamine regulation, including clearance rates in the NAcc and extracellular DA levels in the altered brain regions.  KOR antagonists had a favorable safety profile in individuals in clinical trials. If KOR antagonists can produce behavior improvement and biological normalizations without the risks associated with stimulant abuse and abuse potential, then they continue to be potential treatment candidates for ADHD, ASD, and potentially more serious DA dysfunctions associated with other evolving neuropsychological disorders, for example, substance use disorder.

As research develops, the precedent for direct targeting of KOR-DAT interactions may mark a new era in dopamine therapy in clinical and pre-clinical models that could be specific, effective, and devoid of addiction liabilities we have historically associated with most dopamine therapies as they exist today.

References: Mayer FP, Stewart A, Varman DR, et al. Kappa opioid receptor antagonism restores phosphorylation, trafficking, and behavior induced by a disease-associated dopamine transporter variant. Mol Psychiatry. Published online 2025. doi:10.1038/s41380-025-03055-4