Cocaine, a drug that has long been infamous for multiple overdose deaths, and erratic behaviour — from rock prodigy Tom Petty to Charlie Sheen, once Hollywood’s highest paid sitcom star — has ruined talents and fortunes for long.

Now scientists have uncovered what exactly is in cocaine that makes it such a dreaded narcotic substance.

A team at the Medical University of South Carolina (MUSC) has uncovered how cocaine triggers a specific protein in the brain to hijack normal brain circuitry, promoting further drug-taking behaviour. The discovery, detailed in an article in ‘Nature Communications’, sheds light on the mechanisms behind drug-context associations, which are critical factors in relapse vulnerability.

The study, led by Christopher Cowan, Chairman of the Department of Neuroscience at MUSC, identifies the neuronal PAS domain protein 4 (NPAS4) as a key regulator in forming and maintaining drug-context associations.

“These drug-context associations become future triggers for drug seeking,” explained Cowan, emphasising the importance of understanding how these associations are formed.

The MUSC team focused on a small population of cells within the nucleus accumbens, a brain region known for regulating motivation and reward-associated learning. They discovered that NPAS4-expressing neurons increased in response to cocaine exposure. NPAS4, a transcription factor, regulates how cells respond to neuronal activity induced by various stimuli, including drugs.

Surprisingly, the study found that NPAS4 in D2 dopamine receptor-expressing neurons, rather than D1 neurons, is crucial for context-associated drug seeking.

D2 neurons typically act as a brake on drug-taking behaviour, but NPAS4 appears to weaken this brake, strengthening drug-context associations and increasing the likelihood of relapse.

“Drugs are presumably doing multiple things,” said Cowan, adding, “They’re not only strengthening and forming the context memory, but also suppressing the brain’s ability to oppose this association.”

Understanding how NPAS4 mediates these effects could lead to new therapeutic targets aimed at reducing the risk of relapse, a breakthrough that would be fundamental.