A new study published in the journal Science Signaling has found that an immune system protein plays a central role in the addictive mechanisms of methamphetamine. The findings suggest that tumor necrosis factor-alpha, or TNF-α, works in tandem with dopamine transporters to amplify the drug’s effects on neural activity in the brain’s reward centers.
Methamphetamine use disorder presents a persistent and severe public health challenge. Unlike opioid or alcohol addiction, there are currently no FDA-approved pharmaceutical treatments available to help individuals stop using methamphetamine. This lack of therapeutic options makes the search for biological targets a high priority for medical science.
Scientists have understood for some time that methamphetamine use leads to severe inflammation throughout the body. This is visibly manifested in conditions such as severe dental decay, often called “meth mouth,” and systemic wound-healing issues. However, the specific relationship between this inflammation and the drug’s addictive properties in the brain has remained unclear.
The authors of this study sought to determine if the immune system directly influences the release of dopamine, the chemical messenger associated with pleasure and euphoria. They hypothesized that the inflammation caused by the drug might not just be a side effect, but a driver of the addiction itself.
“Methamphetamine addiction remains a major public health crisis with limited treatment options,” said study author Habibeh Khoshbouei, a professor and vice chair in the Departments of Neuroscience at the University of Florida College of Medicine.
“While we knew that methamphetamine triggers neuroinflammation and increases inflammatory molecules like TNF-α in the brain, the specific role of TNF-α in addiction mechanisms was unclear. We wanted to understand whether TNF-α contributes to methamphetamine’s effects on dopamine signaling, as this could reveal new treatment targets for addiction.”
To investigate, the research team conducted a series of preclinical experiments using brain tissue from mice. They focused specifically on the ventral tegmental area, a region of the brain critical for processing reward and motivation. The researchers utilized sophisticated electrical recording techniques to monitor the activity of individual neurons.
Khoshbouei and her colleagues identified dopamine neurons based on specific physiological criteria. They looked for neurons that showed a decrease in firing frequency when exposed to dopamine and an increase when exposed to a dopamine blocker. They also looked for specific electrical signatures, such as a “sag” in voltage during electrical testing, which is characteristic of these cells.
When the researchers applied methamphetamine to these brain slices, they observed a distinct pattern in the dopamine neurons. The drug caused a rapid acceleration in the firing frequency of these cells. This initial spike in activity was followed by a progressive deceleration over a period of several minutes.
The researchers used phase-plane plots to visualize the shape of the electrical spikes produced by the neurons. They found that methamphetamine altered the waveform of the action potentials, which are the electrical impulses neurons use to communicate. The drug suppressed the upward phase of the spike and broadened its duration.
The researchers then examined whether TNF-α alone could mimic these effects without the presence of methamphetamine. When they applied TNF-α to the brain slices, the dopamine neurons exhibited a similar biphasic increase in firing activity. This suggested that the immune protein itself has the capacity to stimulate the reward circuitry in a manner resembling the drug.
To test the necessity of this immune signal, Khoshbouei and her colleagues used a compound called UCB-9260 to inhibit TNF-α signaling. When they pre-treated the slices with this inhibitor, the methamphetamine-induced changes in neuronal firing were significantly reduced. The inhibitor effectively prevented the drug from altering the electrical properties and firing rates of the neurons.
The researchers also explored the role of the dopamine transporter, a protein responsible for recycling dopamine back into the neuron. They found that blocking this transporter with a drug called nomifensine prevented TNF-α from increasing neuronal activity. This finding indicates a bidirectional connection where the immune system and the dopamine transport system regulate each other.
“The most surprising findings were the bidirectional crosstalk between TNF-α and dopamine transporters, and the effect of TNF-α on increasing dopamine,” Khoshbouei told PsyPost. “We didn’t expect TNF-α might modulate methamphetamine’s effects, and we didn’t anticipate that blocking dopamine transporters would also prevent TNF-α from affecting neurons, and vice versa. This reveals these seemingly separate systems are interconnected.”
To further understand the mechanism, the team investigated the role of calcium, which is essential for neuronal firing. They utilized a technique called calcium imaging with a sensor named GCaMP6f to track calcium levels in living cells. Both methamphetamine and TNF-α triggered a significant rise in intracellular calcium levels.
The data showed that these effects relied on specific channels known as L-type calcium channels. These channels allow calcium to flow into the cell, increasing its excitability. Blocking these channels dampened the effects of both the drug and the immune protein.
Consequently, the study identified a shared pathway involving calcium influx that drives the increased excitability of dopamine neurons. The team confirmed this cross-talk using chemogenetics, a method that allows researchers to stimulate specific neurons using designer drugs. They expressed a receptor called hM3Dq in the dopamine neurons to artificially activate them.
Activating these receptors increased the firing frequency of the neurons, as expected. However, the researchers found that they could block this artificially induced firing by inhibiting either TNF-α signaling or the dopamine transporter. This reinforced the conclusion that these two systems are functionally intertwined.
The researchers also measured the release of dopamine directly using a genetically encoded sensor called GRAB-DA. This sensor becomes fluorescent when it binds to dopamine outside the cell. Imaging of mouse brain tissue showed that applying TNF-α caused a rapid increase in fluorescence, indicating dopamine release.
Methamphetamine caused an even larger increase in dopamine release, as anticipated. However, the application of the TNF-α inhibitor significantly reduced the dopamine release triggered by methamphetamine. Similarly, blocking the dopamine transporter reduced the dopamine release triggered by TNF-α.
“We discovered that inflammation isn’t just a side effect of methamphetamine use, it amplifies the drug’s addictive properties,” Khoshbouei explained. “TNF-α, an inflammatory molecule, works alongside methamphetamine to increase dopamine release and enhance the activity of reward-related brain cells. This means FDA-approved anti-inflammatory drugs that block TNF-α (already used for conditions like rheumatoid arthritis) could potentially be repurposed to help treat methamphetamine addiction.”
“Our findings show robust, consistent effects across multiple experimental approaches, from individual neurons to whole brain tissue. The fact that blocking either TNF-α signaling or dopamine transporters reduced methamphetamine’s effects by similar magnitudes suggests this is a fundamental mechanism, not a minor pathway.”
“The availability of existing TNF-α blockers makes this relevant for potential clinical translation,” Khoshbouei continued. “We plan to submit a grant to NIH to seek funding for clinical trials investigating the efficacy of TNF-α blockers on reducing methamphetamine reward properties that can reduce relapse rate.”
While the study establishes a mechanistic link in animal models, it is important to note that these findings come from experiments conducted on mouse brain tissue and cell cultures, which do not perfectly replicate the complexity of human addiction. The dosage and timing of drug exposure in a controlled dish differ from chronic use patterns in humans.
“While our findings suggest TNF-α blockers could help reduce the rewarding properties of methamphetamine and this methamphetamine addiction, we want to emphasize this was basic neuroscience research,” Khoshbouei said. Clinical trials would be needed to determine the dosage and efficacy in humans with methamphetamine use disorder.”
Although these inhibitors are already approved for conditions like rheumatoid arthritis and Crohn’s disease, their use in addiction treatment is novel. Safety profiles would need to be re-evaluated in this specific context. “Completely blocking TNF-α has risks since it plays important roles in normal immune function,” Khoshbouei noted.
TNF-α plays a vital role in the body’s normal immune defense against infections and tumors. Long-term suppression of this protein could lead to unwanted side effects or vulnerabilities to illness.
Future research aims to investigate whether these inhibitors can reduce drug-seeking behavior in live animals. The current study focused on cellular mechanisms, but behavioral studies are needed to see if this translates to reduced cravings or relapse.
“We’re conducting behavioral studies to test whether TNF-α inhibitors can reduce methamphetamine-seeking behavior in animal models,” Khoshbouei told PsyPost. “We’re also investigating whether this neuroimmune mechanism applies to other stimulants like cocaine. Ultimately, we hope to collaborate with clinical researchers to test whether existing TNF-α blockers could help people struggling with methamphetamine addiction.”
“This work highlights how addiction involves much more than just the brain’s reward system; it could be a neuro-immune dysregulation. Understanding the Brain-Body connections and how immune system affect the reward pathway open new avenues for treating addiction, potentially allowing us to repurpose existing FDA approved medications. We also want to thank NIH supporting our research and giving us the opportunity to do this work.”
The study, “TNF-α signaling mediates the dopaminergic effects of methamphetamine by stimulating dopamine transporters and L-type Ca2+ channels,” was authored by Landon M. Lin, Marcelo Febo, Adriaan W. Bruijnzeel, Leah Phan, Adithya Gopinath, Jordan Seibold, Emily Miller, and Habibeh Khoshbouei.
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