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.


History of Opiates in the US.  I wrote my last post on buprenorphine and methadone with some ambivalence.  I’m not against methadone maintenance clinics.  Generally, limiting access to any drug has proven to be a bad idea.  We all remember prohibition.  When there is demand for a substance, making it illegal merely empowers the gangsters, although the numbers dependent on the substance remain about the same.  (Before the drug laws in 1914, about 1/400=.25% of Americans were addicted to opiates; in 2006, 1.6% of Americans reported having used heroin, Hart, Ksir, Ray, 2009, p.63 & p. 318).  In my class on substance abuse, we review the history of the drug laws in the US.  In fact, when all drugs were legal before the Harrison Act of 1914, there was not much of a problem with drugs in this country.  (However, in the late 1800s, there were reports of infants dying from paregoric, an opiate-based treatment for diarrhea, in the emerging pharmacy literature.)

Why Was Heroin Made Illegal?  The impetus for the Harrison Act was foreign policy.  After the Spanish American War, the US acquired the Philippines.  Given a US presence in the Pacific, Teddy Roosevelt wanted to trade with the Chinese.  But the Chinese did not trust the westerners who ran opiate concessions/parlors all along the coasts.  (The Chinese emperor did not succeed in his attempt to throw out the “foreign devil” in the Boxer Rebellion.)  Roosevelt believed he could ingratiate the US with the Chinese by regulating the world traffic in opiates.  However, the US itself had no domestic policy.  To avoid a charge of hypocrisy when telling the Europeans to clean up their act, America needed to regulate opiates. In order to promote making drugs illegal in the US, the government realized that opposition would emerge from the South to any attempt to legislate morality.  (What’s next, Jim Crow?)  So, drug policies were sold with racist propaganda.  Given that the federal income tax had recently been established in 1913, the government believed that regulating drugs through taxation would be the path of least resistance.  The Harrison Act of 1914 taxed opiates and cocaine, but omitted marijuana.  Enforcement was through the Treasury Department (IRS).  The war on drugs, at least before the recent change in metaphors, has/d been vigorous.  Michele Alexander’s book, The New Jim Crow, argues that US drug laws have effectively been an excuse to disenfranchise African Americans, who are over-represented in prison largely by dint of commission of drug-related crimes.

Why is heroin so devastating:  the drug or the drug-policy?  In talking about opiate addiction so much propaganda has surrounded the topic that it’s hard to discern the truth.  The stereotype is that of the desperate addict devoting all his/her time in pursuit of a drug which compromises values and demands the sacrifice of what one would otherwise hold dear.  There is support for the stereotype but is this stereotype attributable to the opiate drug or America’s drug policy?  In terms of addictive liability, nicotine is touted as one of the most addictive chemicals in the formulary.  Yet, no one neglects his/her children or steals to obtain a cigarette.  Cigarettes are relatively cheap and available.  Cigarettes have devastating long term effects on health, but they don’t impair ability to work or start bar room fights.  So, maybe the desperate efforts to seek an addictive drug (in this case, opiates) at any cost are a function of the government’s restriction.  If opiates were widely available, would many of the social problems evaporate?

The next question is “to what extent do opiates impair job performance?”  Although there are not many data on this issue, I remember the story of William Halsted.  Halsted was a physician at Johns Hopkins during the 1900s.  He is credited with being the father of modern surgery and the physician who came up with sterile procedures.  Halstead was maintained on morphine by his friends throughout his career.  In the modern era, we also have data on methadone maintenance clients.  The justification for the harm reduction approach of methadone maintenance is that it restores peoples’ ability to work.  The data are pretty consistent with this claim.  People in methadone maintenance clinics do return to productive employment.  Methadone is about equivalent to heroin in terms of potency at a mu receptor.  So extrapolating to other opiates from methadone, opiates probably will not rob anyone’s capacity for productive behavior, although taken in excessive doses people will fall asleep.

Then there’s the issue of long term effects on health.  Perhaps surprisingly, opiates are probably the least harmful drug on the body of just about any drug in the formulary.  They don’t damage any organ system.  They do cause immune system suppression, although Sacerdote, the expert on this topic, claims that with long term exposure to opiates cells compensate becoming tolerant to this effect.  Opiates do suppress testosterone levels and sexual function, which might result in muscle and bone wasting, although again some argue that tolerance develops here too.  Whereas withdrawal from alcohol, benzodiazepines, and barbiturates can be lethal, unless an individual is otherwise in poor health, opiate withdrawal is not life threatening.

The big problem with opiates is that they are very dangerous drugs.  They block the function of the baroreceptors (which detect a lack of oxygen) so that breathing centers don’t operate properly.  Addicts using illicit drugs and pain patients treated with OxyContin regularly die from overdoses.  Additionally, methadone (but not heroin) is associated with cardiac arrhythmias (Qtc prolongation) which can be potentiated when combined with antidepressants and antipsychotics.

What concerns me about the federal government’s response to the current opiate epidemic is that they are advocating for more opiates in the form of methadone and buprenorphine.  Although physician-prescribed buprenorphine and methadone are certainly safer than street heroin, they aren’t safe.  After clients show some trustworthiness in the methadone maintenance clinic, clinics are allowed to provide clients with take-home methadone and buprenorphine.  Once this happens, accidents are more likely to occur.  We’ll probably see more accidental poisonings with little kids.  The future should inform regarding whether OD rates decline or increase once more Americans are in “Medication Assisted Treatment.”

Can another drug cure drug addiction?  Over the years, I’ve gone to many a seminar on finding a drug to treat addiction.  I remember the NIDA researcher who came up with a drug to block a cannabinoid receptor.  There was even a guy who thought amphetamines might be the way to treat cocaine addiction.  (Works in the monkeys.)  The problem here is that for most drugs of abuse, they operate on receptors for natural chemicals in the body.  The brain releases endocannabinoids which then operate on cannabinoid receptors and decrease anxiety signaling in the amygdala.  Endorphins and enkephalins are the body’s neurotransmitters at mu and delta opiate receptors.  They function in circuits for pleasure and for energizing behavior.  Do we really want to find some chemical that blocks opiates or cannabinoid receptors?  Although some magic chemical might make it so that the drug of abuse won’t work, the body’s natural chemicals won’t work either.  The cure is often more devastating than the disease.

What is addiction anyway?  There is a lot of confusion in professional journals and in lay publications on what accounts for the compulsion to find and use drugs of abuse, the now generally accepted definition of addiction.  I’ve been convinced by the work of Peter Kalivas and Kent Berridge, among others, that compulsion to use cocaine, alcohol, and opiates has little to do with seeking pleasure or avoiding the pain of withdrawal.  Rather, it’s a story about capturing the brain’s motivational system, which operates independently from seeking pleasure or avoiding pain.  (I review this story in Chapters 2 and 8 of Neuroscience for Psychologists and Other Mental Health Professionals.)  There are ways to take back the brain’s motivational system that don’t involve more chemicals.  But, it’s tricky and knowing when someone is vulnerable to relapse is important.    This story raises the question of whether anyone has free will and ways in which free will might operate.  It’s a very interesting story.  With clarity on what accounts for compulsion to use, a more targeted picture of when people are vulnerable to relapse emerges.

Barceloux, D. G.  (2012).  Medical Toxicology of Drug Abuse. New York:  John Wiley & Sons.

Courtwright, D. T.  (1982; 2001).  Dark Paradise: A History of Opiate Addiction in America.  Cambridge, MA: Harvard University Press.

Hart, C. L., Ksir, C., & Ray, O.  (2009).  Drugs, Society & Human Behavior.  New York:  McGraw Hill.

Musto, D. F.  (1973).  The American Disease:  Origins of Narcotic Control.  New York:  Oxford University Press.

Sacerdote, P., Franchi, S., Gerra, G., Leccese, V., Panerai, A. E., Somaini, L. (2008).  Buprenorphine and methadone maintenance treatment for heroin addicts preserves immune function.  Brain, Behavior, & Immunity, 22(4), 606-613.