Rethinking Healthcare

Why club drug makes you happy, nicotine makes you skinny

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An anesthetic could be an anti-depressant that works within just hours. And a nicotine-based drug could help you stop eating, without triggering the need for tobacco.

Scientists have puzzled out why two noted molecules do the things they do.

1. Ketamine.

It's sometimes taken as a hallucinogen – as a club drug called ‘Special K’ – and at high doses, it’s a widely-used anesthetic. Researchers are now figuring out why ketamine also has fast-acting, antidepressant-like effects as well.

This could be a direct target for quick-acting treatments of major depression.

Traditional antidepressants, like Zoloft or Paxil, often take weeks or months to have an effect – a major drawback for treating high-risk individuals. A single low dose of intravenous ketamine, on the other hand, can alleviate major symptoms within hours, with effects lasting up to 2 weeks.

When put in a tub of water, mice considered depressed quickly give up escape attempts and float motionless. Half an hour after receiving a dose of ketamine, mice swim for a longer period of time.

But what goes on in their brains was unclear. Scientists knew that ketamine binds to, and blocks, a receptor in the brain called NMDAR, which triggers its anesthetic effects.

Now, a team led by Lisa Monteggia from University of Texas Southwestern Medical Center found that by blocking NMDARs in mice, the depression lessened.

  • Blocking NMDARs with ketamine causes neurons to make more of a protein called brain-derived neurotrophic factor (BDNF) – a nerve growth factor that supports the health of brain cells, helping them grow and promoting the development of new neurons. And it’s linked to antidepressant effects.
  • Ketamine causes the rapid synthesis of BDNF by deactivating a chemical called eEF2 kinase, which normally suppresses BDNF.

"We've identified a novel pathway never before linked to any behavior, let alone an antidepressant response," says Monteggia, "that could be a novel drug target."

Drugs that inhibit eEF2 kinase could become antidepressants that work faster than any current medication.

The study was published in Nature this week.

2. Nicotine.

Smokers are, on average, thinner than non-smokers; they also tend to put on weight after they quit. That’s because nicotine decreases appetite. And researchers now show that that’s because nicotine activates a certain group of neurons in the brain.

A team led by Marina Picciotto of Yale focused on one particular nicotine receptor, dubbed α3β4. Mice who received drugs engineered to stimulate only α3β4 receptors were eating less.

In fact, mice who received the drug binding to α3β4 receptors ate half the amount of food as untreated mice in 2 hours after administering the drug. Their body fat dropped 15% to 20% over 30 days.

  • Nicotine activates certain receptors to influence a collection of central nervous system circuits in the hypothalamus, a brain region involved in eating behavior (the one that sends “I’m full” messages after meals).
  • Those receptors increase the activity of POMC neurons, which affect obesity in humans.

These nicotine receptors are involved in the fight-or-flight response that occurs when animals encounter a threat: these responded to nicotine in a way that reduced hunger.

Evolutionarily, "the fight-or-flight response is one where you actually want to preserve your energy to do something very important," Picciotto says. "So maybe you don't want to be out there eating while you're supposed to be running away from a tiger."

So smoking remains a leading cause of preventable death, and this study suggests that nicotine-based treatments could help people quit smoking and control their obesity or metabolic disorders.

"Imagine a nicotine-based medicine which could only target those cells which stop eating and not trigger the need for tobacco," Picciotto says.

The study was published in Science last week.

Images: ketamine by Dr. Saudade, nicotine by lydiashiningbrightly via Flickr

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Janet Fang

Contributing Editor

Janet Fang has written for Nature, Discover and the Point Reyes Light. She is currently a lab technician at Lamont-Doherty Earth Observatory. She holds degrees from the University of California, Berkeley and Columbia University. She is based in New York. Follow her on Twitter. Disclosure