The results of rodent studies by a Stanford University School of Medicine-led research team have shown that the abuse potential of the illicit street drug, ecstasy—(±)3,4-methylenedioxymethamphetamine (MDMA)—involves a different neuronal signaling pathway to that which mediates the potentially therapeutic, prosocial effects of the drug. If the findings can be confirmed in humans, they could lead to the development of novel treatments for psychiatric disorders that are associated with social awkwardness and withdrawal.

ecstasy
Source: U.S. Drug Enforcement Administration

“We’ve figured out how MDMA promotes social interaction and showed that’s distinct from how it generates abuse potential among its users,” said research lead Robert Malenka, MD, PhD, the Nancy Friend Pritzker professor in psychiatry and behavioral sciences. Malenka and colleagues reported their findings in Science Translational Medicine, in a paper titled, “Distinct neural mechanisms for the prosocial and rewarding properties of MDMA.”

MDMA is a mind-altering drug that is used by an estimated three million people in the United States every year. It gives users a sense of wellbeing, making them extremely sociable, and can even generate feelings of unguarded empathy for strangers, which makes MDMA a natural fit for raves and dance parties.

These features of MDMA use may also have applications in psychiatry, and the drug is in late-stage, multicenter clinical trials as an adjunct to psychotherapy for post-traumatic stress disorder (PTSD). The goal is to harness MDMA’s prosocial effects to strengthen the bond between patient and therapist. It’s hoped that people who have experienced trauma may be able to feel comfortable reliving it through guided therapy.

About 25 million people in the United States who suffer from PTSD could benefit from a drug that helps to establish, with a single dose in a therapist’s office, a trust level that would otherwise typically take months or years to achieve, said Boris Heifets, MD, PhD, assistant professor of anesthesiology, perioperative and pain medicine, who is the newly reported study’s lead author.

The flip side is that MDMA can be addictive. Taken in the wrong settings or in repeated or oversized doses, it can have life-threatening consequences. MDMA’s abuse potential stems from its capacity to stimulate the brain’s reward circuitry, Malenka said. “The brain’s reward circuitry tells us something is good for our survival and propagation. It evolved to tell us food is good when we’re hungry, water is good when we’re thirsty, and warmth is good when we’re cold. For most of us, hanging out with friends is fun, because over the course of our evolution it’s promoted our survival.”

This reward circuitry involves neural connections projecting from one midbrain structure, the ventral tegmental area, to another, the nucleus accumbens (NAc), which is “ … a conserved brain region that regulates appetitive behavior,” the authors noted. When those neurons release a chemical called dopamine, the nucleus accumbens forwards signals throughout the brain that induce a sense of reward. Malenka further commented, “Drugs of abuse trick our brains by causing an unnatural dopamine surge in the nucleus accumbens. This massive increase is much higher and more rapid than the one you get from eating ice cream or having sex.”

MDMA also releases serotonin, but the role of this neurotransmitter is less clear. “MDMA is a substituted amphetamine with high affinity for the serotonin [5-hydroxytryptamine (5-HT)] and dopamine (DA) transporters (SERT and DAT, respectively), through which it stimulates release of these neurotransmitters,” the team explained. “MDMA’s acute reinforcing effects, which strongly predict addictive liability, have been linked to its DA-releasing properties, whereas the role of SERT in this action is uncertain.”

There have been some pointers, however. Serotonin-releasing neurons in the dorsal raphe nucleus of the brain send projections to the same part of the nucleus accumbens that is connected by the dopamine-releasing neurons. And neuroscientists had previously shown that MDMA triggers the release of far more serotonin than dopamine. “We, therefore, hypothesized that MDMA’s interaction with SERT specifically in the NAc could fully account for MDMA’s prosocial effect but not its rewarding effect,” the authors commented. To investigate this they carried out a suite of behavioral, and complementary genetic and brain region-specific pharmacological manipulations in mice, together with in vivo calcium imaging, to demonstrate that MDMA acts at SERT-containing 5-HT terminals in the NAc.

The researchers tested whether an “explorer” mouse given a relatively low dose of MDMA or, control mice given saline, preferred to spend time in a chamber holding another mouse under an upside-down mesh cup (to keep that mouse from moving about) or in an otherwise identical chamber with a cup but no mouse. They found, consistently, that the saline-treated explorer mice get bored after 10 minutes with another mouse. But an explorer mouse given MDMA sustained its social curiosity for at least 30 minutes.

“You can’t ask mice how they’re feeling about other mice,” Malenka said. “But you can infer it from their behavior.” It’s also likely that the same effects would be seen in humans because the midbrain areas have been remarkably conserved among mammalian species over evolutionary time, Malenka said.

The test results also clearly implicated serotonin as the signaling substance responsible for promoting social behavior in both male, and in female mice. Heifets added, “Giving MDMA to both mice enhanced the effect even further. It makes you wonder if maybe the therapist should also be taking MDMA.”

Like humans, mice will return to places where they’ve had a good time. This can also be linked to the brain’s reward circuitry. To determine MDMA’s addictive potential, the researchers gave mice an MDMA dose equal to the one in the first, “social” experiment, but only when the mice were in a particular room of a two-room structure. The next day, the mice showed no preference for either room. This provided evidence that at the dose used, MDMA hadn’t noticeably triggered the reward circuitry.

However, mice given a higher MDMA dose exhibited both its social and abuse-potential effects. Further tests determined that the secretion of dopamine triggered by MDMA is not necessary for promoting sociability. Serotonin release, triggered by the low MDMA dose, was all it took. And in a subsequent set of experiments, the scientists were able to induce sociability in mice by infusing the drug only into the animals’ nucleus accumbens, providing further evidence that this is where the serotonin, released as a result of MDMA administration, exerts its sociability-inducing effect.

“Where, exactly, in the brain that’s happening hadn’t been proven,” Heifets said. “If you don’t know where something’s happening, you’re going to have a hell of a time figuring out how it’s happening.”

The researchers made this discovery when they showed that blocking a specific subtype of serotonin receptor in the nucleus accumbens fully inhibited MDMA’s prosocial effect. And giving the mice a different serotonin-releasing drug, fenfluramine, (FEN), which does not cause dopamine release, was enough to mimic the prosocial effects of MDMA, without causing any addictive, or rewarding, effects. “Consistent with the enhancement of sociability by FEN in our experiments, early clinical data suggest that higher doses of FEN have subjective effects reminiscent of MDMA,” team pointed out. “FEN has been reported to improve social deficits in children with autism.”

Fenfluramine, is also the “fen” part of the once-popular diet pill called fen/phen, a two-drug combination developed in the 1960s. Fen/phen was pulled off the market in the 1990s after 30% of patients taking it were found to be showing signs of heart disease, including pulmonary hypertension. And as the authors pointed out, “… like MDMA, long-term and/or heavy use of FEN is associated with cardiovascular and neurological toxicity … Furthermore, tolerance to MDMA’s acute effects may develop with frequent use.” They suggested that it would seem “prudent to use these drugs sparingly and infrequently, consistent with recent clinical trial designs for MDMA.”

Although the long-term cardiovascular and neurotoxic effects of MDMA and FEN mean that neither drug would be suitable for any indications requiring daily use, Heifets pointed out that the damaging effects of chronic use would be highly unlikely to occur in the one or two sessions that would be required for patient-therapist bonding in a psychiatric setting. Even so, the authors concluded, “Given MDMA’s long history of abuse and potential toxicity, it would be prudent to develop drugs or other therapies that mimic its prosocial effects with reduced associated morbidities. We propose that future therapeutic strategies, including drug design and brain stimulation approaches, may be more successfully developed by targeting relevant brain circuits rather than by modifying existing drugs based on putative structure/activity relationships.”

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