Serotonin Is Still Alive and Well in Psychiatry Land

In the September 2015 issue of JAMA Psychiatry, a team of Swedish researchers (see Frick et al.) published a study evaluating the serotonin system in persons with social anxiety.  They used Positron Emission Tomography an imaging technique wherein radio-active molecules that will bind in particular places in the brain and then allow for quantification of particular molecules in the brain are employed.  The researchers used two different molecules:  [11C]5-HTP, which is a precursor to the production of serotonin, and 5-hydoxytryptophan labeled with Carbon-11 that will bind to the serotonin transporter.  What the researchers found was an increase in both of these substances in brain areas that are known to be active during the experience of anxiety, viz., the amygdala and the dorsal Anterior Cingulate Gyrus.  The researchers concluded, “Collectively, these findings suggest that extracellular serotonin in the amygdala and dorsal ACC is positively related to severity of social anxiety symptoms” p. 789.  Translated into English, the researcher found that more serotonin release occurs during social anxiety.

Of course, the findings here are in direct contradiction to what the pharmaceutical companies would have us believe: anxiety and depression are caused by deficit levels of serotonin. There was an editorial by Stein and Andrews published in the same issue of JAMA Psychiatry in the “Clinical Review and Education” section which attempted to obfuscate the findings by referencing the heterogeneity in persons who exhibit social anxiety.

Unfortunately, neither Frick et al. article or the editorial referenced the work of neuroscientist Steven Maier on learned helplessness. Neuroscientists have been investigating what happens in the brains of animals that are subjected to uncontrollable shock for the last 30 years.  Given uncontrollable shock, the animals appear depressed and essentially “give-up” failing to make response that could turn off the shock when the opportunity is presented.  It turns out that one of the first areas to be activated by uncontrollable shock contains serotonin neurons in the caudal-dorsal raphe that project to the amygdala.  If these serotonergic neurons are destroyed, then no learned helplessness.  The Frick et al. findings are very consistent with the animal work: serotonin creates anxiety/depression.

While the Frick et al. findings are consistent with data on learned helplessness, Chris Lowry, a colleague of Steven Maier at University of Colorado, has identified multiple serotonin circuits in the raphe. While one of these circuits produces learned helplessness, another circuit turns it off.  Thus, serotonin is just another work-horse neurotransmitter capable of creating opposite effects.  It’s the connections among the neurons, not the particular chemical making the connections, that determines the outcome.  This is another “bad news” story for the pharmaceutical houses because ingesting a chemical such an SSRI, which presumably elevates serotonin in all circuits, will yield unpredictable effects.  There is no way given current technology to target the serotonin neurons you want.

What is clear from the two articles in JAMA Psychiatry is that psychiatrists are still focused on serotonin.  Whatever glib statements psychiatry-spokespersons utter for the general public (“we always knew it was more complicated”), in the psychiatric journals, where psychiatrists talk to each other, they acknowledge having bought the assumption that low serotonin creates anxiety.  Indeed, Stein and Andrews reflect “how do we understand the apparent paradox that potentiated serotonin signaling might underlie increased anxiety-related endophenotypes and the possible predisposition for developing anxiety disorders with the fact that some patients respond to SSRIs, which presumably further increases extracellular serotonin levels?”  As they went through tortured possibilities they could not resolve the paradox.  If they had read the animal literature, it’s far less confusing.

Frick, A., Åhs,F., Engman, J., Jonasson, M., Alaie, I., Bjöekstrand, J., Frans, O., Faria, V., Linnman, C., Appel, L., Wahlstedt, K., Lubberink, M., Fredrikson, M., & Furmark, T. (2015).  Serotonin synthesis and reuptake in social anxiety disorder:  A positron emission tomography study. JAMA Psychiatry, 77 (8), 794-802.

Stein, M. B., & Andrews, A. M. (2015).  Serotonin states and social anxiety. JAMA Psychiatry, 77 (8), 845-847.


Will the neurotransmitter of pleasure please stand up

Over the years a number of neurotransmitters have been described as the neurotransmitter of pleasure. The list includes serotonin, dopamine, endocannabinoids, and endogenous opiates such as endorphin.  In Chapter 2 of Neuroscience for psychologists and other mental health professionals, I discuss particular emotions (fear, sadness, anger) identifying those brain regions that are active when people report the subjective experience of various emotions.  Pleasure, because it comes in so many flavors (excitement, contentment, orgasms, eating delicious food, hugging friends, enjoying music), I speculated that various pleasures may be triggered by activity in several different circuits.  However, a recent wonderful review by Berridge and Kringelbach argues that all forms of pleasure are associated with activity in the pleasure centers of the ventral pallidum in the mid-brain, the subcortical forebrain regions of the Nucleus Accumbens and subregions of the Orbitofrontal cortex.  We’ll look at why serotonin and dopamine can be ruled out as neurotransmitters of pleasure.

Serotonin has been dubbed the neurotransmitter of pleasure by some. This notion may stem from the fact that the Selective Serotonin Reuptake Inhibitors, commonly prescribed antidepressants, selectively prevent serotonin’s uptake into the neuron that released the serotonin.  So, at least initially, the makers of antidepressants might have believed that serotonin is implicated in the experience of pleasure.  At present time, data have accumulated that SSRIs are not efficacious in treating depression.  (Lack of efficacy was the bottom line from the meta-analyses conducted by Irving Kirsch and others.)  Meanwhile, neuroscientists, who can actually selectively activate or destroy specific clusters of neurons, have conducted systematic investigations to identify the functions of various clusters of serotonergic neurons. Chris Lowry, a neuroscientist at the University of Colorado, has done definitive work clarifying the function of various neurons in the raphe, the area in the brain stem containing the neurons which produce serotonin.  Turns out there are multiple circuits that employ serotonin.  One circuit actually is the proximal cause of learned helplessness. (Learned helplessness results from subjecting an animal to uncontrollable shock.  Subsequently, the animal appears depressed and will not turn off the shock when the researcher makes it possible to do so.)  When the “learned-helplessness” serotonergic neurons are destroyed, then an animal will no longer give up after being subjected to uncontrollable shock.  So one major serotonin region causes anxiety and depression.  Another serotonin circuit is involved in taming the learned helplessness circuitry.  This latter circuit is activated by heat.  There are other circuits as well.  For example, a particular circuit induces movement of the projections on the cells lining the fluid-filled cavity in the brain, such that cerebrospinal fluid in the cavity is returned to the blood stream more rapidly.  (A good thing if there is an infection.)  The problem with raising serotonin levels with an antidepressant drug is that it is impossible to know where serotonin is being raised.  The effects of the antidepressants are unpredictable.  Indeed, antidepressants carry a black-box warning for suicidal ideation.

Dopamine is a second neurotransmitter that has enjoyed a reputation as the neurotransmitter of pleasure. Neuroscientists who study addiction noticed that dopamine is released when animals work for various drugs (cocaine, amphetamine, alcohol, opioids), as well as when animals lever press for food and opportunities for copulation.  This led to the initial idea that dopamine was the “pleasure” neurotransmitter.  Then the discrepancies began to emerge.  The idea that dopamine was about pleasure was reevaluated because of  the following observations: (1) dopamine is also released when an animal works to avoid shock as well as when the animal works for a pleasurable outcome; (2) if the dopamine neurons are selectively destroyed, the animal will still display signs of pleasure when force fed, but the animal will no longer work for the food, and (3) when the animal is actually copulating or eating, the time when pleasure should reach its highest point, then dopamine is no long being released; it’s when the animal is working for food that dopamine neurons fire.  The new view is that dopamine is the neurotransmitter of motivation (striving for), rather than pleasure.

Berridge has further explored the areas in the brain which are active when an animal experiences pleasure. The ventral pallidum, which is connected and very near the area where dopamine is released, is activated when the animal experiences pleasure.  Moreover, this area activates in response to a wide range of pleasurable experiences.  Thus, Berridge and Kringelbach argue that many types of pleasurable experiences converge here.  Berridge and Kringelbach also make a distinction between areas which enhance pleasure and areas which are necessary for pleasure.  While stimulation of areas in the Orbitofrontal cortex, the ventral pallidum, the parabrachial can enhance pleasurable responses, most of these areas if removed, don’t erase pleasure.  Only the ventral pallidum, when damaged, turns liking into disgust. The neurotransmitters released in the hedonic hot spots (rostral-dorsal medial shell of the Nucleus Accumbens and ventral pallidum) include opiate type neurotransmitters, orexin, and cannabinoid type neurotransmitters.

All of this parsing of activity in the brain does have implications for how behaviors are viewed.   Dopamine has been recognized as the neurotransmitter most relevant for addiction.  (All drugs that lead to compulsive use induce dopamine release.)  Addiction happens when the motivational system gets captured by a drug.  Although a drug might initially be taken for its impact on mood (the drug either relieves pain or produces pleasure), affective consequences of the drug cannot explain addiction.  Addicts use because they are compelled.  The affective consequences are irrelevant.  The story on how the dopamine system gets captured by a drug and how recovery can be achieved is also pretty interesting.  This story is told in Chapter 8 and will wait for another blog.

Major depression involves both a diminution of motivation and a decrease in pleasure. Being able to distinguish these two components of “depression” anatomically allows researchers to ask whether various environmental manipulations or chemical interventions will have differential effects on each dimension.  In fact, making an animal’s environment less formidable and more predictable enhances the activity of all the pleasure structures, although this manipulation does not affect motivated behavior.  Perhaps, in the future, the distinctions, which are obvious to neuroscientists, will penetrate the thinking of the lay public.

Berridge, K. C., & Kringelbach, M. L. (2015).  Pleasure systems in the brain. Neuron, 86, 646-664.