Cocaine-Like Motivation Drug Unveiled at Neuroscience Conference

“We didn’t have anyone say ‘This is crazy! This will never work!’”

Motivation is such an intangible aspect of the human spirit that we often forget it has very real, neurochemical origins. We admire it in others and strive for it in ourselves (see: every Nike ad ever made), and now we are getting closer to potentially inducing that motivational feeling with drugs.

John Salamone, Ph.D., a professor at the University of Connecticut with a background in neural and behavioral pharmacology, has been working with the drug company Chronos Therapeutics to develop a drug that can restore motivation in people who have lost it — whether that’s due to the symptoms of depression, struggle with disease, or otherwise. He unveiled his early results on rats this week in a presentation at the Society For Neuroscience’s conference in San Diego, where he tells Inverse his board was bustling with activity:

“Basically we stood there for four hours and were busy the entire time,” says Salamone. The reception was overwhelmingly positive, he adds. “We didn’t have anyone say ‘This is crazy! This will never work!’”

So, How Could This Work?

Put simply, Salamone and his team seem to have created a drug that allows dopamine to collect in the brain’s synapses — little gaps between brain cells where dopamine travels from one neuron to another. Dopamine has a reputation as a warm, fuzzy neurotransmitter that acts as the brain’s main reward system — though importantly, it’s only one of a myriad of transmitters involved in this process.

Salamone’s previous work, published in Cell in 2012, indicates that dopamine may not only reward behavior, but it may also stimulate it too. Certain levels of dopamine in the brain may cause us to act — to begin the work to achieve desirable outcomes or avoid disastrous ones. His experiments on rats support the hypothesis that dopamine increases animals’ effort to obtain a reward: Mice exposed to dopamine-laced food are more likely to press a lever, i.e. exert effort, to obtain a treat, as opposed to settling for normal chow.

Rewards gained from effort aren’t the only way to get a dopamine fix, though. Cocaine, for instance, a drug that’s famous for blasting the brain with an unholy amount of dopamine, blocks a crucial transporter in the brain that clears dopamine away from receptors in brain cells. Ritalin, used to treat ADHD, does this too, but not as dramatically.

“Cocaine rapidly acts on that transporter, so people get a rush when they use cocaine. The dopamine shoots up and then it shoots down,” Salamone says. “So you get this very rapid neurochemical change, and it turns out that rapid neurochemical change is something that people who abuse drugs go for.”

This is the danger of working in this realm of drug discovery. Whenever you mess with dopamine, you run the risk of creating a drug that can make people dependent on that high.

The red shows how dopamine accumulates in mouse brains dosed with d-amphetamine. The blue and green show how it accumulates in mice dosed with the drug under development.


“But the drugs we’re looking at, the effect is slower and smaller,” he adds. “They bind to and inhibit the dopamine transporter, but you don’t get this dramatic rush followed by a crash, you get this slow, ramping increase that lasts for hours.”

Salamone’s early work on a drug called CT-005404 reportedly causes a slow, controlled buildup of dopamine in the brain that can last for hours, and crucially, itreversed the effects of drug-mediated lethargy in rat models.

Salamone’s experiments on rats demonstrated this effect both behaviorally and chemically. His 18 mice who were given tetrabenazine (a drug that artificially reduces their natural levels of dopamine) tended to spring back into action when given this newer drug. He noticed a statistically significant increase in lever-pressing, indicating that the mice were once again willing to work for a reward — in this case a high carbohydrate mouse treat.

Samples of their brains also revealed a slow release of dopamine over the course of hours, as opposed to the spikes he saw in a population of mice who were given an amphetamine. This difference suggests that the drug may not produce the same high as amphetamine, which can be addictive in a similar way as cocaine.

The Next Steps

This drug is in the earliest stages of research. It’s only been given to animals, and there are no plans for human clinical trials in the immediate future. But we can still at least entertain the idea of how a motivational drug might send ripple effects throughout society.

Because a lack of motivation is often associated with depression, Salamone certainly sees a clinical application there, but as with any drug, people will find new ways to use it that doctors may not have intended or anticipated.

"“That’s a complex question for society. Do we want everyone to be drugged on something to enhance their performance?"

Just look at the nootropic modafinil for an example of this happening, Salamone says. In 2013, New York Magazine reported that modafinil had become Wall Street’s “smart drug.” Bankers reported using the prescription medication — which they obtained without a prescription — to make the mundane tasks of investment banking fly by in a frenzy of productiveness. Initially, that drug was intended to treat narcolepsy and other sleep-related conditions.

Salamone agrees that a motivation drug could have a similar allure. That’s not his current intention, though, and he is still a long way from testing this concept on humans. Right now, Salamone is searching for more grants to help solidify his concept. He hopes that its potential for abuse might be mitigated by the slower, more gradual effects.

“I don’t know where this will end up,” he continues. “It could be that these drugs are discovered that are better than caffeine for these kinds of uses, and if that’s true then people will use them to benefit themselves in that particular way.”

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