Dopamine is a neurotransmitter involved in the brain’s reward circuit and helps to regulate various functions involved in mood, cognitive functioning, movement, and motivation. Its role in pleasure and reward can reinforce positive actions, but it also contributes to the development of addiction.
New research proposes a novel approach to dopamine regulation that might help to treat various emotional, behavioral, and cognitive conditions, with less risk of adverse effects and addiction than current treatment options.
Dopamine and health
When we experience pleasurable things, like eating good food, buying a new outfit, or winning a game of soccer, a burst of dopamine is released. This creates and strengthens neural connections in the brain, reinforcing the association between pleasure and the specific activity, thus making it more likely that the behavior is repeated. [1]
This action also occurs with the use of certain drugs, often to a much larger extent. Substances such as opioids, alcohol, and amphetamines impact dopamine levels in the brain, creating euphoria and reinforcing drug use, potentially leading to addiction. [1]
Additionally, conditions such as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, and autism spectrum disorder (ASD) are associated with disruptions in dopamine activity. These conditions, along with substance use disorders, are often treated with medications that impact dopamine signaling, which may lead to side effects or addiction. [2]
The role of opioid receptors in dopamine regulation
Opioid neurotransmitters are produced naturally in the body, although in small quantities. Naturally produced opioids help to regulate many functions, including pain, digestion, and pleasure. Opioid receptors in the brain include mu, delta, and kappa opioid receptors, which help to regulate opioid transportation and activity. [3]
Naturally produced opioids impact dopamine levels in the brain and are involved in the pleasure and reward response related to drugs and natural stimuli. Drugs, particularly potent opioids such as heroin, have a much greater impact on opioid receptors and dopamine levels, causing euphoric feelings and reinforcing use. [4]
New research: Blocking KOR to restore dopamine balance
Each opioid receptor works differently in the brain. The kappa opioid receptor (KOR) impacts dopamine levels when it is activated, by decreasing dopamine release and increasing synaptic dopamine transporter availability. This means that the synapses are cleared of dopamine, thus reducing dopamine levels in the brain. [5]
New research published in Molecular Psychiatry (Mayer et al, 2025) investigates an approach to modulating disrupted dopamine signaling by targeting KORs. The study suggests that by blocking KORs, disrupted dopamine levels can be normalized. [2]
Mayer and colleagues specifically examined the impact of a rare genetic mutation, DAT Val559, which causes dopamine transportation to work in the opposite direction. Normal KOR activity causes dopamine to be cleared from synapses, whereas DAT Val559 causes dopamine to leak into the synapse, which impacts normal dopamine responses. [2][5]
This variant is found to be associated with various dopamine-related conditions, including ADHD, ASD, and bipolar disorder. The study shows that blocking KOR can improve the issues caused by the DAT Val559 mutation, thereby restoring normal dopamine activity. [2]
Therapeutic implications for addiction recovery
This research can also help to better understand and treat substance use disorders and addiction, which are also related to disrupted dopamine signaling.
Dopamine activity becomes disrupted following chronic drug use and dependence, causing changes in mood such as anxiety and depression symptoms, anhedonia, and cravings. This contributes to repeated drug-seeking and using behaviors, once the drug becomes needed in order to feel ‘normal’. [6]
KOR blockers reduce KOR activity, increasing and stabilizing dopamine levels, which can alleviate these mood and behavior changes, thereby helping to prevent relapse and drug-seeking behavior. The development of this type of treatment might have significant impacts on the outcomes of addiction recovery treatments. [2][6]
Broader psychiatric potential
This research can help with the development of treatment options for conditions associated with the genetic variant DAT Val559, such as ADHD, bipolar disorder, and ASD. Current treatments for these conditions, although effective at managing symptoms, can lead to issues with side effects or addiction potential. For example, some ADHD medications, such as Adderall, are potent stimulants and can have many adverse effects and long-lasting impacts.
Developing KOR blockers to treat these conditions could help alleviate dopamine-related symptoms, such as inattention, cognitive impairments, and mood dysregulation, without the same potential for addiction or side effects. [2][5]
Future directions and research needs
Further research is required to better understand the mechanism of KOR blockers. This study investigated the impact of KOR blockers on animals, meaning that these findings need to be replicated on humans. From there, to adequately develop medications for these conditions, rigorous testing and trials will be required to fully determine their safety, effectiveness, and side effect profiles.
This study can also influence further research regarding the impact of opioid receptors on dopamine signaling and the mechanisms involved in disease and disorder development and treatment. These findings regarding the rare DAT Val559 mutation may not apply to all dopamine-related conditions, but they can offer insights into dopamine-related conditions. [5][7]
