Different patterns of dopamine release in the reward pathway mediate motivation and addiction
The dopamine myths
There is much confusion these days about what dopamine does in the brain.
The logic goes like this:
Drugs produce addiction by releasing dopamine in the brain.
Pleasurable activities release dopamine in the same brain region.
Therefore, pleasurable activities must also produce addiction.
Yes, the logic is not entirely sound. The devil, as always, is in the details. After all, dopamine is constantly being released inside the brain. When you block dopamine release in mice, they lack motivation for doing anything and die of thirst and starvation (Wise and Jordan, 2021).
Some people even take it a step further (Lembke, 2021). They reason that too much pleasure must deplete the brain of dopamine, leading to an unhealthy state of lack of motivation. Therefore, we must try to conserve dopamine by avoiding too much pleasure. Especially masturbating or watching porn.
These ideas are everywhere nowadays. They are key to the NoFab anti-masturbation movement. Its ideas have been absorbed by the manosphere, which seeks to make men more manly, powerful and less dependent on sex. But they are also supported by radical feminists, who have been campaigning against porn since the 70s. And, of course, religious conservatives are always happy to find arguments against porn, masturbation, sex and anything pleasurable.
Here are a few examples of these dopamine beliefs:
Porn and masturbation are addictive.
Video games are addictive.
Social media, and smartphones in general, are addictive.
You can become addicted to loving a person.
Too much pleasure depletes the brain of dopamine, leading to a state of pain, lack of motivation and weak willpower.
Dopamine fasting - avoiding the addictive drug or behavior for 30 days - can be used to stop an addiction.
Are behaviors addictive?
These beliefs are defended in the book Dopamine Nation, by Anna Lembke, M.D (see critical reviews here). It makes three main claims:
That behaviors like masturbation, watching porn, reading romance novels, gaming, social media, and using your cell phone, are as addictive as drugs like cocaine and heroin;
That pleasure and pain need to be maintained in balance - if you experience too much pleasure, you will pay with pain;
That drugs and behaviors like those listed above require a 30-day dopamine fast to get out of addiction.
These beliefs about dopamine are also featured in some episodes of the podcast of Andrew Huberman, particularly the one of August 16, 2021, where he interviews Dr. Lembke, and the one of March 27, 2023, “Leverage Dopamine to Overcome Procrastination & Optimize Effort.” I generally like the Huberman Podcast. It provides good information about neuroscience and good life advice. However, sometimes (as in the case of dopamine) it lacks enough scientific rigor and critical thinking.
The book The Compass of Pleasure, by Dr. David Linden, also defends the idea that we can become addicted to sex and love. However, it does so as an afterthought. Its main goal is to explain the involvement of the dopamine reward pathway in pleasure.
It is worrisome that these prestigious neuroscientists defend the idea that behaviors can be addictive. This article focuses on examining this issue by diving into the details of dopamine release in the reward pathway of the brain. To keep it short, I will leave other claims related to dopamine for another occasion.
This is a contentious issue with important social and political ramifications. If left unchallenged, this trend of demonizing sex and pleasure as addictive can start a new era of puritanism and repression. Hence, it is important to treat it with the necessary scientific rigor. Besides having a 40-year research career on the neuroscience of pain and opioids, I have researched this issue extensively to find peer-reviewed articles to support what I say.
The reward pathway
In 1953, James Olds and Peter Milner were postdoctoral fellows at McGill University in Montreal. By being a bit clumsy, they made a discovery of great consequence (Olds and Milner, 1954; Olds, 1958; Linden, 2012).
They worked in the lab of neuropsychologist Donald Hebb, famous for hypothesizing the mechanisms of memory by saying “neurons that fire together, wire together.”
Olds and Milner were investigating the reticular system, an area in the midbrain that control sleeping and waking. But the electrodes they implanted in one particular rat were a bit off and landed in the septum instead of the reticular formation. When the rat recovered from surgery, they placed it in a large rectangular box. Every time that the rat was in a particular corner, Olds stimulated its brain by passing current through the electrode. The rat soon learned to return to that corner. Apparently, it liked its brain being stimulated in the septum. In this, it behaved differently than rats that had electrodes placed in the reticular system.
Olds and Milner soon learned just how much rats enjoyed having their brains stimulated in the septum. They used a set-up called a Skinner box, in which rats could press a lever to deliver the electrical stimulus to their brain. When implanted with electrodes in this brain region, the rats would press the lever several thousand times per hour.
Given the choice between water or food, on the one hand, or pressing the lever, on the other hand, the rats always chose to press the lever. Male rats would rather press the lever than mate with female rats in heat. Female rats abandoned their pups to go and press the lever.
It was tempting to call this neuronal path the pleasure pathway. They called it the reward pathway, instead, or by the more technical name of mesolimbic pathway.
By systematically placing electrodes in different parts of the brain of rats, scientists mapped this reward pathway. It runs in the middle of the bottom of the brain, back to front, from the ventral tegmental area (VTA) to the nucleus accumbens. It also sends dopamine-containing axons to the prefrontal cortex, the anterior cingulate cortex, the thalamus and the hypothalamus.
The VTA, together with the substantia nigra, contains many of the dopamine neurons of the brain. VTA neurons also send dopamine-releasing (dopaminergic) axons to the prefrontal cortex (volition), the anterior cingulate cortex (decision-making and planning), the amygdala (involved in fear and anxiety) and the hypothalamus (control of body functions). This is important, because dopamine maintains the function of these areas of the brain over long periods of time. For example, effects of dopamine on the anterior cingulate cortex and the prefrontal cortex are essential for flow (Kotler et al., 2022), a mental state of effortless effort, focused attention and creativity.
What does it feel like to have your reward pathway stimulated?
Inevitably, electrodes were placed in the reward pathway of humans to see what they felt when it was stimulated. Just like the rats, when humans were given the opportunity to stimulate the own reward pathway by pressing a lever, they did so non-stop. But what did they feel?
In his book The Compass of Pleasure, neuroscientist David Linden says that they experienced euphoria, a state of well-being and excitation, but he doesn’t give any references to support this.
Is the reward pathway really a pleasure pathway?
Let’s start with orgasm. Indeed, the VTA and the nucleus accumbens are activated during orgasm (Wise et al., 2017). However, several other brain regions are also activated during orgasm: the insula, operculum, anterior cingulate cortex, orbitofrontal cortex, right angular gyrus, paracentral lobule, cerebellum, hippocampus, amygdala, hypothalamus and dorsal raphe. In particular, the insula and its nearby operculum mediate the emotions associated with body sensations, so they may be key for the pleasure produced by the orgasm. The anterior cingulate and prefrontal cortex may mediate the desire to continue sexual stimulation. The hypothalamus mediates the release of oxytocin that produces bonding during sex.
What about other kinds of pleasure?
The linking reaction to sweets is mediated by a “hedonic hotspot” in the shell of the nucleus accumbens (Mitchell et al., 2018).
The pleasure produced by music is associated with dopamine release in the striatum, which includes the nucleus accumbens (Salimpoor et al., 2011). This study used positron emission tomography (PET) to get images of the brain as dopamine displaces [11C]raclopride from dopamine receptors. Dopamine release occurred when arousal by music reached its peak, as reported by the subjects and measured by the activation of their autonomic system.
Viewing pictures of a person who you love decreases pain by activating the nucleus accumbens, the amygdala and the frontal cortex (Younger et al., 2010).
Some dopaminergic neurons in the reward pathway respond to aversive stimuli: things that we dislike, like pain and distress. The activation of some neurons in the nucleus accumbens with dopamine receptors was correlated with the emotional quality of pain (Scott et al., 2006). The front (rostral) part of the shell of the nucleus accumbens reacts to things that we like, while its back (caudal) part reacts to aversive stimuli (Hurley et al., 2017).
A review paper (Salamone and Correa, 2012) objected to the name of reward pathway. They said that it is really a motivation pathway because it mediates sustained effort to achieve a goal. Another review (Paredes and Agmo, 2004) argued that dopamine is not important for sexual motivation or sexual reward.
Even though this issue remains controversial, I would say that there is strong evidence that the reward pathway is involved in both pleasure and pain. However, scientists use the more precise terms reward for pleasure and aversion for pain.
Dopamine receptors
There are five receptors for dopamine, D1 through D5 (Seeman and Van Tol, 1994). They are the proteins in the membrane of neurons to which dopamine binds to deliver its signal. The five receptors are divided into two groups: D1-like receptors include D1 and D5 receptors, while D2-like receptors are D2, D3 and D4.
The dopamine receptors most important in the reward pathway are D1 and D2 (Wise and Robble, 2020). About half of the neurons of the nucleus accumbens have D1 receptors, which have low affinity for dopamine. This means that their full activation requires high concentrations of dopamine. The other half of these neurons have D2 receptors, which have high affinity for dopamine. This means that relatively low concentrations of dopamine in the nucleus accumbens are able to activate most of the D2 receptors.
Dopamine release
The key to distinguish the effect of addictive drugs on dopamine from the effect of behaviors like masturbating, watching porn or playing video games resides on somewhat obscure concepts: tonic and phasic release of dopamine.
Dopamine, like other neurotransmitters, is released when action potentials in the axon of the dopamine neuron reach a presynaptic terminal. This is a swelling separated by a small gap from the postsynaptic terminal containing the dopamine receptors. In the presynaptic terminal, dopamine is loaded into synaptic vesicles. When an action potential reaches the presynaptic terminals, some of these vesicles fuse with the membrane, releasing dopamine that then crosses the synapse and binds to the dopamine receptors in the postsynaptic terminals.
Dopamine does not hang around the synapse for long. There are proteins called dopamine transporters (or reuptake systems) that take dopamine out of the synaptic space and put it back into the presynaptic terminal. Then dopamine gets quickly loaded back into the synaptic vesicles.
Tonic dopamine release
Neurons fire action potentials in different patterns.
Tonic firing is the simplest pattern. It consists of single action potentials separated by time intervals of 150 to 500 milliseconds (ms). A ms is a thousandth of a second, so 500 ms is half a second. Tonic firing releases small amounts of dopamine that binds to D2 receptors, which present not only in the synapse, but all over the postsynaptic neuron.
Tonic release of dopamine is not triggered by sensory stimuli from the environment, but controlled by stress and hormones related to feeding, like leptin, insulin and ghrelin (Wise and Robble, 2020).
Tonic dopamine release controls the motivational state of the individual, its willingness to exert an effort to achieve a goal. A sustained rate of tonic release keeps basal dopamine levels high, so that D2 receptors are activated. This leads to a state of contentment and satisfaction.
When tonic firing is low, dopamine falls below the levels at which it activates the D2 receptors. This creates a state of uneasy that drives the individual to seek something to relieve it. Based on previous learning, the person gets motivated to find a reward (food, sex, a work goal) that would increase tonic dopamine release again. For example, feeding hormones may cause a drop in tonic dopamine release, motivating the individual to seek food.
Phasic dopamine release
Burst firing of action potentials is more complex. It consists of several groups (bursts) of action potentials at high frequency - up to 100 Hz, which means one action potential every 10 ms.
Burst firing changes synapses by the process of synaptic plasticity, which is how the brain stores memories. Synaptic plasticity is composed of two opposing mechanisms: long-term potentiation (LTP), which increases the efficacy of neurotransmission, and long-term depression (LTD), which decreases it.
Burst firing of dopaminergic neurons induces phasic dopamine release. Phasic means intermittent: a lot of dopamine is released very quickly during each burst of action potentials. This increases dopamine concentrations at the synapse so much that the D1 receptors get fully activated. Together with the burst of action potentials, they induce LTP in these synapses, recording the memory of the rewarding stimulus. Some of these synapses are in the prefrontal cortex or the anterior cingulate cortex, where they drive future decisions.
Some of this dopamine spills out of the synapse and activates D2 receptors. If the D2 receptors are in the bodies of the neurons, this dampens craving. But when the D2 receptors are in nearby synapses, the lower concentrations of spillover dopamine induce LTD in them. These synapses are less efficacious in the future. This sets a signal/noise contrast between the synapses activated by a rewarding stimulus and those unrelated to it, increasing learning.
Phasic dopamine release is driven by sensory stimuli related to rewards (pleasure) or aversion (pain). They are delivered to the VTA-accumbens pathway from brain regions that assign a positive or negative emotional value to sensory signals. For example, the amygdala may assign fear to a perception, or the insula may assign pleasure to another one.
How dopamine mediates addiction to cocaine and amphetamines
This may seem very technical, but the difference between tonic and phasic dopamine is essential to explain why drugs are addictive and behaviors like watching porn or masturbating are not.
Let’s start with cocaine. It acts by blocking the reuptake of dopamine: the proteins that transport dopamine back into the synaptic terminals to end its effect. When neurons cannot capture back dopamine, its spillover to D2 receptors outside the synapse during phasic dopamine release increases considerably. Even tonic dopamine release causes higher levels of dopamine around the neurons. Cocaine increases 3 to 5 folds basal level of dopamine in the nucleus accumbens (Wise and Robble, 2020). But equally important is that these high levels of dopamine are present for long periods of time, for as long as we feel the effect of cocaine.
Exposed to too much dopamine for long periods of time, the D2 receptors are downregulated: taken out of the membrane and degraded. So now there are less D2 receptors to signal satisfaction, leading to a state of craving.
At the same time, the pleasure produced by cocaine sends a signal through D1 receptors that creates an association of cocaine with reward. This, together with the state of craving induced by the downregulation of the D2 receptors, is what drives the compulsive seeking of the drug that constitutes addiction.
Amphetamine and methamphetamine acts in a similar way as cocaine, except that they not just inhibit the dopamine transporter, they reverse it! They also release dopamine from the synaptic vesicles. This results in increases in extrasynaptic dopamine even larger than those produced by cocaine.
Notice that the increases in dopamine produced by cocaine and amphetamines are not mediated by changes in either tonic or phasic dopamine release. They are not related to behavioral rewards or aversions. It is an unnatural interference that completely messes up the reward pathway.
How dopamine mediates addiction to opioids
Opioids like heroin, morphine, fentanyl and oxycodone (the infamous OxyContin that caused the opioid epidemic in the USA) act by a different mechanism.
Neurons that release the neurotransmitter GABA are the main brake system in the brain. GABA is an inhibitory neurotransmitter that reduces action potential firing in other neurons. There are GABA-releasing (GABAergic) neurons that make synapses with the dopamine neurons of the reward pathway, providing a negative feedback. When there is too much release of dopamine in the nucleus accumbens, GABAergic neurons that go to the VTA get activated, decreasing their firing and thus dopamine release.
These GABAergic neurons contain mu-opioid receptors, which are the site of action for the opioid drugs that I listed above. When these opioid receptors are activated, GABA release is decreased. This relieves dopamine release from its inhibition, increasing it - a phenomenon called disinhibition. That is how opioids increase dopamine release in the reward pathway (Johnson and North, 1992; Saigusa et al., 2017, 2021).
As in the case of cocaine and amphetamines, the resulting increases in dopamine are sustained and lead to the downregulation of D2 receptors, setting a state of craving.
In addition, the abnormal activation of the mu-opioid receptors by the opioid drugs seems to induce long-term changes in the GABAergic neurons that reduce their ability to keep dopamine release in check. This may explain why opioids are even more addictive than cocaine.
Curiously, endorphins - the peptides that naturally activate opioid receptors - do not produce addiction (Stoeber et al., 2018). The reason for this is complicated. Endorphins are quickly degraded by enzymes called peptidases (Song and Marvizon, 2003), and this limits the amount of time that they have to activate the opioid receptors. Another reason is that opioid receptors send different signals to the inside of the cell depending on whether they are activated by endorphins or by drugs. The intracellular signals sent by endorphins end the action of the mu-opioid receptors by internalizing them to the inside of the cell, while morphine and other drugs do not produce mu-opioid receptor internalization (Keith et al., 1996; Stoeber et al., 2018).
This is important because it means that natural stimuli that release endorphins - like sex and exercise - do not produce addiction, even though endorphins activate mu-opioid receptors just like morphine and heroin.
Cannabis
Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are two amongst over a hundred psychoactive compounds found in marihuana. They act on CB1, CB2 and GPR55 receptors (Lauckner et al., 2008; Pertwee, 2008).
The natural ligands of CB1 and CB2 receptors are the endocannabinoids anandamide and 2-arachinodylglycerol (2-AG). They are called retrograde neurotransmitters because they signal the opposite way than regular neurotransmitters: they are synthesized in the postsynaptic terminals and diffuse to the presynaptic terminal, where they inhibit neurotransmitter release. Like opioids, cannabinoids inhibit GABA release onto dopamine neurons in the reward pathway, increasing dopamine release by disinhibition (Szabo et al., 2002).
However, cannabis is much less addictive than opioids and does not produce withdrawal (Wise and Robble, 2020). Several things may explain this. CB1 receptors also inhibit glutamate release onto the dopamine neurons, which increases dopamine release. So, in this case, cannabinoids inhibit dopamine release, moderating their effect on the GABAergic neurons.
Cannabinoids increase phasic dopamine release (Wise and Robble, 2020), rather than its tonic release. They also interact with endorphins to increase “liking” instead of “wanting” (Mitchell et al., 2018).
CBD, acting on CB2 receptors, decreases addiction to cocaine (Galaj et al., 2020).
Other addictive drugs
Other addictive drugs have their own mechanisms (Wise and Robble, 2020).
Alcohol is addictive when taken regularly in large amounts. Unlike other drugs, its effects on the brain are not mediated by a particular neurotransmitter receptor, but by its interaction with many receptors. These include glycine receptors, serotonin 5-HT3 receptors and nicotinic acetylcholine receptors. Alcohol produces only small increases in basal dopamine levels, but seems to increase phasic dopamine release. Still, alcoholics show a downregulation of D2 dopamine receptors similar to that produced by cocaine, amphetamines and opioids.
Nicotine - the psychoactive substance of tobacco - is an agonist of nicotinic acetylcholine receptors, some of which are in dopaminergic neurons of the VTA. Nicotine increases dopamine release from these neurons. In the long term, it downregulates D2 dopamine receptors.
Benzodiazepines (Valium) and barbiturates (pentobarbital) act by modulating GABA-A receptors, increasing the inhibitory effects of GABA. They seem to disinhibit dopamine release, like the opioids.
Why natural stimuli induce dopamine release, but not addiction
Let’s now examine how some behaviors considered addictive impact the VTA-nucleus accumbens dopamine pathway.
These things include (Potenza, 2006, 2014):
food: eating sweets and other tasty foods (Lindgren et al., 2018);
sex: masturbating, watching porn, reading romance and erotica, fetishism, kink;
playing: video games, gambling;
social interactions: social media, anxious attachment, obsessive love (Burkett and Young, 2012);
shopping and shop-lifting;
self-harm, like cutting;
exercise: any sport done in excess;
work: workaholics.
These are all natural activities. Although video games and social media depend on the invention of the computer and the internet, playing, gossip and social interactions have always been human activities. The same can be said about sex. People have masturbated, had sex, and watch others have sex since the dawn of humanity.
Living today is much less dangerous and scary that in ancient times. It’s only that sensory stimulation has been increased by tastier foods, more appealing sexual images, more exciting games, etc.
Strong sensory stimuli engage the reward pathway. However, they still do that by inducing phasic dopamine release.
This is completely different from the prolonged elevations of basal dopamine levels produced by psychostimulants like cocaine and amphetamines. Neither does it mess with GABAergic inhibition of dopamine release, like opioids do.
Natural stimuli also fine-tune tonic dopamine release to drive our motivations as we cycle through desire and satisfaction.
Therefore, the stimuli provided by modern technology are not qualitatively different, in terms of dopamine release, from the old rewards with which we evolved. There is no reason to think that these activities would produce the enormous craving and withdrawal syndromes that addictive drugs produce.
Still, it is true that some people develop strong compulsions to gamble, eat in excess or watch porn. However, this is better explained as an excessive tuning of the dopamine system towards one specific reward - gambling, tasty foods, exciting sex, etc. - and not an abnormal hijacking of the reward pathway, as drugs of addiction do.
Is sex addictive?
Unfortunately, science was often used in the past to justify puritanism and sexual repression. Even today, excessive sexual desire is considered a disease, termed Don Juanism and satyriasis in men and nymphomania in women. And let’s not forget that, for the longest time, homosexuality was considered a mental disorder.
Some contemporary papers (Blum et al., 2015) continue this tradition by assuming that departures from culturally approved sexual norms are “maladaptive” and need to be cured. Thus, Bloom et al. define sexual addiction as “any compulsive sexual behavior that interferes with normal living and causes severe stress on the family, friends, loved ones, and one's work environment.”
However, the severe stress may be due to family, friends and co-workers refusing to accept unconventional forms of sexuality, as it still happens with homosexuality. The problem, then, is not with the sexual behavior in itself, but with the bigoted attitudes of society.
Indeed, in their review of the literature, Bloom et al. found no evidence that hypersexuality produces any withdrawal symptoms when the sexual activity is stopped.
They state that “the prevalence rates of sexual addiction-related disorders range from 3% to 6%”, but these include “excessive masturbation, cybersex, pornography use, aberrant sexual behavior with consenting adults, telephone sex, strip club visitation, and other addictive behaviors.” However, these are behaviors accepted as normal by most people in Western societies. Calling these behaviors addictive is based more on their puritanical assumptions than on scientific evidence.
Other scientists align better with modern sex-positive views by showing that hypersexual behavior is just one extreme of the normal range of sexual desire (Steele et al., 2013; Prause et al., 2017).
Indeed, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DMS-5) rejected the concept of sexual addiction (Potenza, 2014).
Addiction or compulsions?
Whether some behaviors are addictive continues to be hotly debated in the scientific community (Potenza, 2006, 2014).
An emerging view is that compulsive behaviors like excessive eating, gambling, gaming and watching porn are not addictions but reflect an underlying deficit in the reward pathway that causes these individuals to be always craving something. This underlying disorder in the reward pathway may be genetic, produced by a disease, or derived from trauma. Only by addressing its true cause can these persons be freed of their basic craving.
Then, curing them of one “addiction” only serves to switch their compulsion to another behavior. For example, when “sex addicts” do not have access to sex, they start smoking or eating in excess. Trying to cure these people of one compulsive behavior has the danger of switching them to consuming addictive drugs, a situation much worse than the original problem.
Closing thoughts
There is much more to the brain than the VTA-nucleus accumbens reward pathway. Like any other system in the brain, it doesn’t work in isolation. Its function is deeply connected to sensory systems that weigh the importance of incoming information, and to cortical systems that plan actions.
Trying to view human behavior through the narrow window of addiction is incredibly short-sighted. Yes, there are many things in the modern world that strive to capture our attention, but they don’t have the hold on our will that drugs have over addicts.
Of course, obsessively seeking pleasure can be a problem. But so is shackling ourselves to the repression of sex and other pleasures of life. Too much self-discipline, guilt and shame can cause much suffering by propelling us on an ego-driven chase of success, money and fame.
Puritanism has been in the collective minds of Americans since the start of this nation. It gave birth to the Prohibition and to the War on Drugs, misguided attempts to address alcoholism and drug addiction through criminalization. One reason why books like Dopamine Nation are so successful is because the narrative of sin and redemption — which underlies the cycles of abuse and sobriety of many addicts — is so deeply imbedded in the American psyche.
In fact, calling porn and video games addictive undermines the importance that we should give to the tragic problem of drug addiction. The current opioid epidemic in the United States was started in 1996 by Purdue Pharma, ran the Sackler family, with its aggressive marketing of OxyContin to American doctors. It was not caused by people chasing pleasure. Its toll is over 300,000 deaths.
Nobody has died from watching too much porn or playing video-games.
Saying that porn, masturbation, gaming and cell phones are problems similar to drug addiction is simply ridiculous. It is a slap in the face of the millions of people who have lost loved ones to real addictions.
I hope that in this article I have shown that the neuronal mechanisms that underlie drug addiction are quite different from those that motive us to do anything else in our lives. Including enjoying pleasures like games, porn, sex and love.
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