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How Tolerance Changes the Brain

Dopamine is a neurotransmitter. Neurotransmitters are released from neurons and travel in the
microscopic spaces (called synapses) to inter-connected neurons to send messages from one
brain cell to another. To accomplish this, neurotransmitters dock with receptors on the surface of
message-receiving neurons, stimulating them via an electro-chemical exchange. Dopamine creates
the feeling of pleasure by docking with neurons in the Reward System, stimulating those neurons
and the Reward System as a whole.

Excessive drug use can cause permanent change to Reward System neurons. This results
from increasing drug tolerance, a process of accelerating change that makes the Reward System
less efficient and requires users to take more drugs to obtain the same high they used to get from
less. Tolerance alters brain cells physically, changing their function. Eventually, as tolerance
deepens, it alters the nature of the drug-using experience, from liking drugs for their euphoric
effects to needing them simply to feel normal and hold off withdrawal.

How does this happen?

The brain must be balanced to operate properly and has defensive systems to monitor and correct
imbalances. If the brain encounters drug-induced overstimulation occasionally, the brains defensive
systems respond to each as an individual event. However, if the Reward System is overstimulated
regularly over a long period, the brain learns to anticipate the overstimulation, prompting a much
more powerful and long-lasting even permanent defensive reaction.

The correction to repeated overstimulation is to make the Reward System less excitable restoring a
more normal balance. One way this is accomplished is by reducing the number of receptors
available for docking with dopamine. Its like removing extra seats in a game of musical chairs while
keeping the same number of players fewer players get a seat. Likewise, the fewer receptors there
are for dopamine to dock with, the less stimulation of neurons occurs, blunting the high.

Addiction researchers found, for example, that alcoholics brains contain significantly fewer
dopamine receptors (called D2 receptors) than non-alcoholics. Similarly, monkeys allowed to self-
administer cocaine for a year had 15%-20% fewer dopamine receptors.3 Non-dopamine receptors
can also be involved in tolerance. For example, marijuana impacts both dopamine and the
brains cannabinoid system. (The psychoactive component in pot is THC, a cannabinoid
compound.) Chronic daily marijuana smokers were found to have 20% fewer cannabinoid
receptors than control subjects.1

Tolerance also operates on other critical parts of the Reward System to make it less efficient. One
study found that methamphetamine abusers, for example, had an average of 24% fewer dopamine
transporters than non-users in a key part of the Reward System.2 (Transporters are involved in
shuttling neurotransmitters to and from receptors.)
In other words, in the face of chronic overstimulation by drugs, the brains defensive systems cause
physical and structural changes in Reward System neurons: Ultimately, adaptations that drug
exposure elicits in individual neurons alter the functioning of those neurons, which in turn alters the
functioning of the neural circuits in which those neurons operate. This leads eventually to the
complex behaviorsthat characterize an addicted state.3 Essentially, long-term, predictable drug
abuse causes the brain to reprogram itself in defense. Thats what tolerance does.

However, since tolerance dulls the high that drugs evoke, users retaliate by taking more.
They increase the amount of dopamine by increasing the dose or frequency of drugs, or both,
so they get the same reward they used to feel with less, before tolerance developed.4 The brain, in
turn, responds by making the system even less efficient, deepening tolerance. A vicious downward-
spiraling cycle develops as the brain tries to counteract drug abuse by gumming up the reward
system ever further while the user compensates by taking more and more drugs. This prompts
further brain change, which in turn elicits increasing drug taking, accelerating the downward spiral.
Thats a key reason addiction is a progressively-worsening disease.

The neural changes caused by tolerance establish what scientists refer to as a new normal for the
addict brain a less efficient Reward System. Without the dopamine boost provided by drugs,
abusers suffer a dopamine deficit, resulting in withdrawal and depression: Eventually, the dopamine
circuit becomes blunted; with tolerance, a drug simply pushes the circuit back to normal, boosting
the user out of depression, but no longer propelling him or her toward euphoria.5 The essence of the
addict experience, neuroscientists say, is that addicts have to take drugs not to produce euphoria,
but to maintain an ever-harder-to-achieve new normal in which the brain, having developed
tolerance, now requires a drug-induced dopamine boost to maintain the new normal. It now needs
drugs to stave off withdrawal, instead of just wanting them to get high.

A byproduct of increasing tolerance is worsening physical withdrawal. Repeated binge-and-

withdrawal cycles also impels a corresponding defensive reaction, causing detoxes to become
progressively longer and more severe withdrawal stretches from one to two days, then to three
and four.6 The fear of withdrawal escalates as well, with good reason, a central reason addicts
keep using drugs in spite of worsening physical, social and psychological consequences.