TNF-a Inhibitors Show Promise as Treatment for Meth Addiction

In a study that aimed to provide a deeper understanding of the mechanisms at work in meth addiction, University of Florida neuroscientists identified a previously unknown sequence of reactions in the brain involving meth-induced spikes of dopamine and a key signaling protein, tumor necrosis factor-alpha (TNF), a regulator of both acute and chronic inflammation.

“Unlike alcohol or opioids, there currently is no medicinal therapeutic approach for methamphetamine addiction,” said Habibeh Khoshbouei, senior author of the study published in Science Signaling. “So this is an important societal issue.”

Meth, a highly addictive psychostimulant, boosts dopamine to create pleasure and euphoria. It also triggers inflammation, contributing to issues like “meth mouth,” or severe dental decay.

In mouse brain specimens, the team uncovered a surprising dynamic interplay. Meth not only increased the release of dopamine but also unexpectedly stimulated TNF. The researchers then were able to mitigate these effects using a chemical compound to target either a dopamine transporter or the signaling of TNF.

Using electrophysiological recordings, “we found that TNF increases firing activity of dopaminergic neurons,” Khoshbouei said. “And if you block the target of methamphetamine or the receptor for TNF, you block the effect of either methamphetamine or TNF.”

This is significant because there are FDA-approved medicines already on the market that can inhibit the effects of TNF, Khoshbouei said, such as those for autoimmune disorders like Crohn’s disease.

While TNF is not typically associated with activating dopamine release, “in the case of methamphetamine, it seems like not only does meth increase inflammation, which involves the presence of immune cells and the release of TNF, but TNF itself evokes the release of dopamine, and that’s fascinating,” explained co-author Marcelo Febo.

The hope, added Febo, is that the findings could open the door to new treatment targets to reduce cravings and drug-seeking behavior as well as neuroinflammatory effects associated with meth use.