Scientists at Johns Hopkins have identified a previously unknown mechanism of cocaine’s activity in the brain, which could open new types of treatment for addiction to the drug. Intriguingly, it seems to work differently in male and female mice.
Cocaine is known to interact with synapses in the brain, preventing neurons from taking up dopamine, a neurotransmitter chemical associated with feelings of reward and pleasure. That causes the dopamine to build up in synapses, making those positive feelings last longer. That’s the mechanism behind why people take cocaine – and why some people can become addicted to it.
Finding ways to block this mechanism has long been proposed as a potential treatment for cocaine use disorder, but it’s been hard to identify the specific receptors that the drug is binding to. A protein known as dopamine transporter (DAT) was the most obvious candidate, but it turns out that cocaine binds to it relatively weakly. This implied that there was still a receptor with a high affinity for cocaine that hadn’t yet been identified.
To find this elusive receptor, the Johns Hopkins researchers experimented with mouse brain cells grown in a lab dish and exposed to cocaine. The cells were ground down to examine them for specific molecules that bound to even small amounts of the drug – and a receptor called BASP1 emerged.
To test it out, the team then engineered mice that had just half of the usual amount of BASP1 receptors in a region of their brains called the striatum, which plays a role in reward systems. When these mice were given low doses of cocaine, the uptake of the drug was about half that of normal mice. The behavior of the edited mice also seemed to be about half the level of stimulation provided by the drug, compared to normal mice.
“These findings indicate that BASP1 is the receptor responsible for cocaine’s pharmacological actions,” said Solomon Snyder, corresponding author of the study. “Drugs mimicking or blocking BASP1 may regulate responses to cocaine.”
Interestingly, the effect of knocking out BASP1 only seemed to change the cocaine response in male mice, while females showed no differences in behavior based on their levels of the receptor. BASP1 is known to bind to the female hormone estrogen, which could be interfering with the mechanism. The team plans to investigate further.
In the meantime, the researchers hope to search for drugs that can prevent the binding of cocaine to BASP1, which could eventually lead to new treatments for cocaine use disorder.
The research was published in the journal PNAS.
Source: Johns Hopkins
