Tag: serotonin

under the sea on ecstasy – octopuses on MDMA

 

octopus on ecstasy

An octopus explores its surroundings. After receiving ecstasy, octopuses become more social.

Have you ever wondered what would happen to an octopus on ecstasy? If you have, then you aren’t alone. Gul Dolen, a neuroscientist a Johns Hopkins University School of Medicine, had wondered the same thing.

She and Eric Edsinger, conducted a study on the effects of the drug ecstasy, also known as (+/−)-3,4-methylendioxymethamphetamine or MDMA, on the brains and behaviors of octopuses. They placed octopuses  a chamber and allowed them to explore on their own. The chamber was connected to two others, one containing a hidden octopus and another containing a strange object. They then compared the time the octopus spent with either the object or the second octopus. The octopus tended to gravitate toward the other animal but only if it was a female. If the second octopus was a male, it avoided the second creature. This was true for bothe male and female octopuses placed into the chamber.

Then they gave the octopus a hit of MDMA, by dunking it into a solution containing the drug to allow it to soak in through its gills. While on the drug they spent way more time with male octopus. Describing their behavior, Dolen says”

“They mashed themselves against one wall, very slowly extended one arm, touched the [other animal], and went back to the other side. But when they had MDMA, they had this very relaxed posture. They floated around, they wrapped their arms around the chamber, and they interacted with the other octopus in a much more fluid and generous way. They even exposed their [underside], where their mouth is, which is not something octopuses usually do.”

This was very unusual behavior for octopuses, which are known to live in solitude. MDMA appeared to make the animals more social in a way that mimics its effects in humans. After studying serotonin transporter proteins in humans and octopuses, the researchers found that the sequences had a 50% match. It is especially similar in the part of the protein where MDMA binds, and that is why they believe they see similar effects in behavior.

But, some scientists remain unconvinced. The researchers always administered the drug after the control, so their more exploratory behavior could just be due to them being more comfortable in their surroundings. Other scientists suggest that ecstasy may just be interfering with the animal’s ability to detect chemical information from potential mates.

 

a death receptor crystal structure

Illustrations of the binding pockets of 5-HT1B and 5-HT2b Serotonin receptors. Image from Science via C&EN.

Receptors for the neurotransmitter serotonin are popular drug targets. Drugs that target these receptors are used to treat problems like depression and migraine headaches. Serotonin receptors are also the targets of some psychedelic drugs like LSD and mescaline.

There are at least 14 subtypes of serotonin receptors known. Most of the drugs that target one subtype of serotonin receptor will also target the others. This is usually not a problem except in the case of one type called 5-HT2B. This receptor is called the death receptor because activating it can cause heart problems that will lead to death. This receptor is to be avoided.

Chemical & Engineering News brings word of two crystal structures that might help drug developers better avoid activating the 5-HT2B subtype of receptors:

Help will come from new crystal structures of 5-HT1B and of 5-HT2B, each bound to the migraine drugs ergotamine and dihydroergotamine (Science,DOI: 10.1126/science.1232807 and DOI: 10.1126/science.1232808). The findings provide a blueprint for designing more selective 5-HT inhibitors.

The team behind the structures includes Raymond C. Stevens, a chemistry and molecular biology professor at Scripps Research Institute, La Jolla, Calif.; Bryan L. Roth, a pharmacology professor at the University of North Carolina; H. Eric Xu, director of the Center for Structural Biology & Drug Discovery at Van Andel Research Institute in Grand Rapids, Mich., and Hualiang Jiang, a professor at the Shanghai Institute of Materia Medica.

This is major news for our field,” adds Kathryn A. Cunningham, a professor in the pharmacology and toxicology department at the University of Texas Medical Branch. “The structures were solved for the receptor-ligand cocrystals, which provides important insights into how the receptors work.”

The importance of selectivity was most infamously illustrated in the 1990s by the obesity treatment Fen-Phen (fenfluramine-phentermine). Both molecules targeted 5-HT receptors, but they weren’t selective enough. Unbeknown to scientists, they also bound to the death receptor, 5-HT2B, triggering sometimes-fatal cardiovascular side-effects. Fen-Phen’s withdrawal from the market was the largest in history and cost its manufacturer, Wyeth, billions of dollars in damages.

Check out the original research here and here.

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