NIDA Backs UT San Antonio Study of the Brain's Natural Brake on Addiction

Neuroscientists trying to explain why addiction rewires the brain have spent decades focused on neurons. A new research project at the University of Texas at San Antonio is looking instead at the cells long dismissed as mere support staff — and asking whether they quietly work as the brain's own brake on drug-seeking.

Backed by a new two-year, $368,392 grant from the National Institute on Drug Abuse, the UT San Antonio team will map how astrocytes — star-shaped glial cells that regulate the environment around neurons — respond to drugs inside the ventral tegmental area, the midbrain hub that supplies dopamine to the rest of the reward circuit. The project will test both cocaine and fentanyl, hunting for a shared molecular signature that could point to treatments working across stimulant and opioid addiction alike.

"Astrocytes have traditionally been thought of as 'support cells' for neurons," said Matthew J. Wanat, professor of neuroscience, developmental and regenerative biology and co-principal investigator on the award. "However, a growing body of research highlights that astrocytes are not necessarily playing second fiddle to neurons but rather are in a partnership with neurons and can directly impact neuronal activity."

Earlier work mostly examined astrocytes in the striatum. The San Antonio researchers are moving upstream to the VTA, where their preliminary observations suggest that drug exposure produces long-lasting adaptations in astrocytes that naturally suppress future drug intake — a built-in restraint system that addiction may gradually overpower.

Decoding the molecular switches

To pin down how drugs leave durable marks on these cells, the team is turning to epigenetics — the instruction layer that switches genes on and off without altering DNA itself. Alexey A. Soshnev, assistant professor and co-principal investigator, describes the genome's roughly 23,000 genes as instructions, with each cell making sequential choices about which ones to follow. The study will measure both the abundance of gene messages and the physical structure of the genes themselves.

The two-drug design is deliberate. "The drugs and their pharmacological mechanisms of action are pretty well understood at this point — and are indeed different," Soshnev said. "However, there is a fundamental similarity between the two: they both hijack the dopamine-producing brain circuit, which is, ultimately, the mechanism of disease. When two different actors cause similar outcomes, it is logical that there must be some fundamental similarity between the two, and our studies are designed to uncover any such 'overlap.'"

From correlation to causation

Observation alone will not be enough. In the project's second phase, the researchers will use epigenetic editing built on dCas9 — a modified version of the CRISPR enzyme that binds precise genome locations without cutting DNA — to dial the activity of candidate genes up or down and watch whether drug-seeking behavior is rescued or worsened.

If the two-year discovery phase identifies high-confidence gene targets altered by both cocaine and fentanyl, the project becomes eligible for a three-year functional validation phase supported by the NIH. Clinical applications remain distant, but an astrocyte-specific target would open a genuinely new avenue for substance use disorder treatments aimed at glial cells rather than neurons.

"The dream would be to find a silver bullet where there is a drug-induced change in astrocytes within the ventral tegmental area that is controlling cravings," Wanat said.