Dopamine Nation

People, Places, and Things
The pleasure-pain balance is triggered not only by reexposure to the drug
itself but also by exposure to cues associated with drug use. In Alcoholics
Anonymous, the catchphrase to describe this phenomenon is people, places,
and things. In the world of neuroscience, this is called cue-dependent
learning, also known as classical (Pavlovian) conditioning.
Ivan Pavlov, who won the Nobel Prize in Physiology or Medicine in 1904,
demonstrated that dogs reflexively salivate when presented with a slab of
meat. When the presentation of meat is consistently paired with the sound of
a buzzer, the dogs salivate when they hear the buzzer, even if no meat is
immediately forthcoming. The interpretation is that the dogs have learned to
associate the slab of meat, a natural reward, with the buzzer, a conditioned
cue. What’s happening in the brain?
By inserting a detection probe into a rat’s brain, neuroscientists can
demonstrate that dopamine is released in the brain in response to the
conditioned cue (e.g., a buzzer, metronome, light) well before the reward

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itself is ingested (e.g., cocaine injection). The pre-reward dopamine spike in
response to the conditioned cue explains the anticipatory pleasure we
experience when we know good things are coming.
DOPAMINE LEVELS: ANTICIPATION AND CRAVING
Right after the conditioned cue, brain dopamine firing decreases not just to
baseline levels (the brain has a tonic level of dopamine firing even in the
absence of rewards), but below baseline levels. This transient dopamine
mini-deficit state is what motivates us to seek out our reward. Dopamine
levels below baseline drive craving. Craving translates into purposeful
activity to obtain the drug.
My colleague Rob Malenka, an esteemed neuroscientist, once said to me
that “the measure of how addicted a laboratory animal is comes down to how
hard that animal is willing to work to obtain its drug—by pressing a lever,
navigating a maze, climbing up a chute.” I’ve found the same to be true for
humans. Not to mention that the entire cycle of anticipation and craving can
occur outside the threshold of conscious awareness.
Once we get the anticipated reward, brain dopamine firing increases well
above tonic baseline. But if the reward we anticipated doesn’t materialize,

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dopamine levels fall well below baseline. Which is to say, if we get the
expected reward, we get an even bigger spike. If we don’t get the expected
reward, we experience an even bigger plunge.
DOPAMINE LEVELS: ANTICIPATION AND CRAVING
We’ve all experienced the letdown of unmet expectations. An expected
reward that fails to materialize is worse than a reward that was never
anticipated in the first place.
How does cue-induced craving translate to our pleasure-pain balance? The
balance tips to the side of pleasure (a dopamine mini spike) in anticipation of
future reward, immediately followed by a tip to the side of pain (a dopamine
mini deficit) in the aftermath of the cue. The dopamine deficit is craving and
drives drug-seeking behavior.
Over the past decade, significant advances have been made in
understanding the biological cause of pathological gambling, leading to the
reclassification of gambling disorders in the Diagnostic and Statistical
Manual of Mental Disorders (5th edition) as addictive disorders.
Studies indicate that dopamine release as a result of gambling links to the
unpredictability of the reward delivery, as much as to the final (often

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monetary) reward itself. The motivation to gamble is based largely on the
inability to predict the reward occurrence, rather than on financial gain.
In a 2010 study, Jakob Linnet and his colleagues measured the dopamine
release in people addicted to gambling and in healthy controls while winning
and losing money. There were no distinct differences between the two groups
when they won money; however, when compared to the control group, the
pathological gamblers showed a marked increase in dopamine levels when
they lost money. The amount of dopamine released in the reward pathway
was at its highest when the probability of losing and winning was nearly
identical (50 percent)—representing maximum uncertainty.
Gambling disorder highlights the subtle distinction between reward
anticipation (dopamine release prior to reward) and reward response
(dopamine release after or during reward). My patients with gambling
addiction have told me that while playing, a part of them wants to lose. The
more they lose, the stronger the urge to continue gambling, and the stronger
the rush when they win—a phenomenon described as “loss chasing.”
I suspect something similar is going on with social media apps, where the
response of others is so capricious and unpredictable that the uncertainty of
getting a “like” or some equivalent is as reinforcing as the “like” itself.
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The brain encodes long-term memories of reward and their associated cues
by changing the shape and size of dopamine-producing neurons. For example,
the dendrites, the branches off the neuron, become longer and more numerous
in response to high-dopamine rewards. This process is called experience-