Serotonin is a neurotransmitter which helps brain cells communicate with one another, playing important roles in stabilising mood and regulating stress. Despite its importance, current models to explain serotonin's function in the brain remain incomplete. Now, in a review paper published this month in the Journal of Psychopharmacology, researchers from Imperial College London suggest that serotonin pathways are more nuanced than previously thought. They argue that the existing view should be updated to incorporate a 'two-pronged' model of how serotonin acts. The researchers believe their updated model could have implications for treating recalcitrant mental health conditions, including depression, obsessive compulsive disorder and addiction, and could exploit the therapeutic potential of psychedelic drugs. In the brain, serotonin acts via a number of sites called 'receptors' and serotonin has at least 14 of these. Brain drugs such antidepressants, antipsychotics and psychedelics are known to interact with serotonin receptors and two of these are thought to be particularly important -- the so-called serotonin 1A and 2A receptors. For patients with depression, commonly prescribed drugs called SSRIs (Selective Serotonin Reuptake Inhibitors) can help to relieve symptoms by boosting levels of serotonin in the brain. Evidence suggests an important part of how they work is to increase activity at the serotonin 1A receptor, which reduces brain activity in important stress circuitry, thereby helping a person cope better. In contrast, psychedelic compounds such as LSD and psilocybin (the psychoactive component of magic mushrooms), are thought to act primarily on the serotonin 2A receptor. Accumulating evidence suggests that psychedelics with psychotherapy can be an effective treatment for certain mental illnesses and, with a focus on the 2A receptor, the authors' paper attempts to explain why. Writing in the review paper, the researchers say that while the traditional view of developing psychiatric treatments has been focused on promoting 1A activity and often blocking the 2A, the therapeutic importance of activating the 2A pathway -- the mechanism by which psychedelics have their effect -- has been largely overlooked. "We may have got it wrong in the past," said Dr Robin Carhart-Harris, Head of Psychedelic Research at Imperial and lead author on the paper. "Activating serotonin 2A receptors may be a good thing, as it makes individuals very sensitive to context and to their environment. Crucially, if that is made therapeutic, then the combination can be very effective. This is how psychedelics work -- they make people sensitive to context and 'open' to change via activating the 2A receptor." According to the researchers, the 1A and 2A pathways form part of a two-pronged approach which may have evolved to help us adapt to adversity. By triggering the 1A pathway, serotonin can make situations less stressful, helping us to become more resilient. However, they argue that this approach may not always be enough, and that in extreme crises, the 2A pathway may kick in to rapidly open a window of plasticity in which fundamental changes in outlook and behaviour can occur. Growing evidence shows that in conditions such as treatment-resistant depression, obsessive compulsive disorder and addiction, certain brain circuitry may become 'stamped in' and resistant to change. The researchers suggest that in such cases, activating the 2A pathway -- such as through psychedelics -- could potentially offer a way to break the cycle, helping patients to change negative behaviours and thought patterns which have become entrenched. By enabling the brain to enter into a more adaptive or 'plastic' state and providing patients with a suitably enriched clinical environment when they receive a drug treatment, clinicians could create a window for therapy, effectively making patients more receptive to psychotherapy. According to the authors, their updated model of how serotonin acts in the brain could lead to a shift in psychiatric care, with the potential to move patients from enduring a condition using current pharmacological treatments, to actively addressing their condition by fundamentally modifying behaviours and thinking. Professor David Nutt, Director of Neuropsychopharmacology in Imperial's Division of Brain Sciences, explained: "This is an exciting and novel insight into the role of serotonin and its receptors in recovery from depression that I hope may inspire more research into develop 5-HT2A receptor drugs as new treatments." Dr Carhart-Harris added: "I think our model suggests that you cannot just administer a drug in isolation, at least certainly not psychedelics, and the same may also true for SSRIs. We need to pay more attention to the context in which medications are given. We have to acknowledge the evidence which shows that environment is a critical component of how our biology is expressed." He added: "In psychiatry, as in science, things are rarely black and white, and part of the approach we're promoting is to have a more sophisticated model of mental healthcare that isn't just a drug or psychotherapy, it's both. I believe this is the future." 'Serotonin and brain function: a tale of two receptors' by Robin Carhart-Harris and David Nutt is published in the Journal of Psychopharmacology.
A Finnish research group worked with 11 young men and 16 young women who had a heavy 10-year alcohol use, and compared them with 12 young men and 13 young women who had little or no alcohol use. All were between 23 to 28 years old at the time the measurements were taken. The researchers examined the responses of the brain to being stimulated by magnetic pulses -- known as Transcranial Magnetic Stimulation (TMS), which activates brain neurons. The brain activity was measured using EEG (electroencephalogram).
Previously, the researchers had found that heavy alcohol users showed a greater electrical response in the cortex of the brain than non-alcohol users, which indicates that there had been long-term changes to how the brain responds. This time, they found that young men and young women responded differently, with males showing a greater increase in electrical activity in the brain in response to a TMS pulse. As researcher Dr Outi Kaarre (University of Eastern Finland and Kuopio University Hospital, Finland) said:
"We found more changes in brain electrical activity in male subjects, than in females, which was a surprise, as we expected it would be the other way around. This means that male brain electrical functioning is changed more than female brains by long-term alcohol use"
The EEGs also allowed the researchers to show that male brains have greater electrical activity associated with the GABA (gamma-amino butyric acid) neurotransmission than do female brains.
Dr Kaarre continued, "Generally, our work showed that alcohol causes more pronounced changes in both electrical and chemical neurotransmission in men than women. There are two types of GABA receptors, A and B. Long-term alcohol use affects neurotransmission through both types in males, but only one type, GABA-A, is affected in females.
We're still trying to figure out what this means, but GABA is a pretty fundamental neurotransmitter in the inhibition of many brain and central nervous systems functions. It's involved in many neurological systems, and is important in anxiety and depression. Generally it seems to calm down brain activity.
We know from animal studies that GABA-A receptor activity seems to affect drinking patterns, whereas GABA-B receptors seem to be involved in overall desire for alcohol. It has been suggested that women and men may respond differently to alcohol. Our work offers a possible mechanism to these differences."
We know that long-term alcohol use can be risky for young people. What this work means is that long-term alcohol use affects young men and women very differently, and we need to find out how these differences manifest themselves. It may be that we need to look at tightening regulations on youth drinking, since none of our study participants met the diagnostic criteria for alcohol use disorders and still these significant changes in brain functioning were found. It may also mean that gender differences should be taken into account when planning pharmacological treatment for alcoholism."
Commenting, Professor Wim van den Brink (Professor of Psychiatry and Addiction at the Academic Medical Centre, University of Amsterdam, and ex Chair of the ECNP Scientific Programme Committee):
"These are very interesting findings, especially since young women are catching up with young men when it comes to drinking and heavy drinking in Europe. This may also mean that a different group of women is getting involved in early heavy alcohol use than used to be the case; in other words, when heavy drinking occurs more frequently and tends to become the norm, women do not need to have some aberrant personal characteristic to become an early heavy user of alcohol.
The finding of a different EEG-pattern in male and female early heavy drinkers may indeed have important consequences for the treatment of male and female patients with an alcohol use disorder. One of the most recent new medications for the treatment of alcohol dependence is the GABA-B agonist Baclofen, which has shown mixed results which may be explained by this work.
A limitation of the study is that it says nothing about possible pre-existing neurobiological differences between the groups, an explanation for the observed differences that is equally valid."
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