Understanding the neurobiology of addiction, it’s important to know that the brain

reacts to all pleasure in the same way. Whether it’s in response to a long jog, a raise in pay at
work, a drink of whiskey or even smoking a cigarette, pleasure has a unique signature in the
brain.

A cluster of nerve cells underneath the cerebral cortex, near the front of the brain, is so
associated with good feelings that neuroscientists refer to this region, the nucleus
accumbens, as the “pleasure center.”

Dopamine, a naturally occurring chemical in the brain, floods the “pleasure center”
when substances like alcohol, cocaine or nicotine are ingested. This brings on feelings of
euphoria and wellbeing.

The likelihood that a person will become addicted to a substance or behavior is

directly related to how fast and reliable these things create the release of dopamine in the
brain. A stronger, faster dopamine release will generally lead to abuse and dependency
problems.

Newer studies have shown that dopamine, which is also associated with remembering
and learning, may in fact lay down memories of the speedy satisfaction drugs and alcohol
generate, conditioning the brain to crave the substance. The brain is then chemically
motivated to seek out whatever causes the pleasure.

The natural release of dopamine isn’t as quick and intense as it is with drugs and
alcohol, and the consistent use of addictive substances makes it even more difficult to
experience naturally occurring pleasures.

With substance abuse, the brain adapts to the regular release of dopamine and causes a
tolerance, meaning individuals have to use more and more of a substance to achieve a similar
“high.”

Scientists have shown that once the brain has memories of the “high” and has gone on
to create a tolerance, compulsion takes over.

Compulsion occurs when the pleasure from a behavior or a drug is gone, but there is a
persistent, often overpowering, drive to recreate the good feelings regardless of the
consequences.

https://www.inspiremalibu.com/blog/alcohol-addiction/understanding-addiction-
reward-and-pleasure-in-the-brain/
Three particular areas in the brain play a key role in developing an addiction:

1. Basal Ganglia – The Basal Ganglia is an important part of the brain’s rewards system,
which sends signals telling the individual to continue the addictive behaviors. It also
contributes to brain functions like motivation, routines behaviors and patterns.
https://www.ncbi.nlm.nih.gov/books/NBK424849/
2. Extended Amygdala – This part of the brain is responsible for regulating stress and
fight or flight response. Research indicates that this part of the brain is key to
developing drug dependence. https://www.ncbi.nlm.nih.gov/books/NBK424849/
3. Prefrontal Cortex – The Prefrontal Cortex affects decision-making and regulates
impulses. This is why people continue to engage in addictive behavior, despite the
consequences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201373/

The effects of substance abuse and addiction aren’t limited to just these areas, though.
The human brain functions as a network of interconnected parts. Changes to one region of the
brain will impact others.

What causes addiction in the brain?

Both genetics and environmental factors play a role in how addictions develop.

Genetic – If either of your parents has been addicted to drugs, your chances of being
addicted increase. The presence of other genetic mental disorders also plays a role in how
likely you are to become addicted to drugs or alcohol.
 There is no single gene that causes addiction, though. A combination of multiple
genetic factors determines your risk.

Environmental– This accounts for all the outside influences that can lead someone
into addiction. If you grow up in a household where drugs are around, you’re statistically
more likely to develop an addiction.

Other environmental factors that contribute to addiction include:

 Peer pressure
 Past traumatic experiences
 Socioeconomic factors
 Availability of support & treatment

Having parents with an addiction problem or growing up around drugs does not
necessarily mean that you will become an addict yourself, though. It only increases your
chances.

Which neurotransmitters are involved in drug addiction?

A neurotransmitter is chemical signal allows brain cells to communicate with each other.
Dopamine is the primary neurotransmitter involved in addiction. Dopamine is responsible for
many of the pleasurable feelings we experience as humans, like eating good food or laughing
with friends. It’s also closely associated with addiction.

Drugs work by mimicking dopamine, increasing dopamine levels or by increasing the

sensitivity of dopamine receptors. The surge of pleasure from dopamine is what convinces the
brain that a drug is rewarding, and it wants more.
 Other neurotransmitters like serotonin, GABA and acetylcholine also impact how
addiction is formed. For example, serotonin plays an important role in how people form habits
and behaviors that contribute to substance abuse. In alcoholics, low serotonin levels are
correlated with a stronger compulsion to drink.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC80880/

https://journeypure.com/ask-our-doctors/uncategorized/how-does-addiction-affect-the-brain/
https://www.boardpreprecovery.com/rehab-blog/why-cant-he-quit/

Brain Circuits Associated with Addiction

 The brain circuits that are involved in addiction have been characterized in preclinical
studies and in human imaging studies. The four interacting circuits that can be involved, to
varying extents, in different persons and different addictions are shown in the above figure.

The reward circuit (indicated in green) is a dopamine pathway from the ventral
tegmental area to the nucleus accumbens (NAcc, also known as ventral striatum), which
subsequently outflows through the ventral pallidum (VP). This pathway plays a role in
responding to rewards and guiding behavior towards them.

The encoding and reactivation of memories of drug use are regulated by the red areas.
The hippocampus (HIP) is involved in place memories of drug use as well as the amygdala
(Amyg) for the emotional aspects of these. Drug memories are known to be some of the most
powerful aspects and they are extremely hard to overwrite or dislodge.

The purple areas of the anterior cingulate gyrus (ACG) and prefrontal cortex (PFC) are
responsible for cognitive control and depend on a suitable balance of glutamate and GABA
interactions, allowing this region to exert "top-down" control on the pleasure and motivation
areas.

The orbito-frontal cortex (OFC) evaluates the value of rewards or salience and the
decision to use.

Generally, these areas are in balanced condition, with the OFC having the final "say"
in behavioral control, that is, "NO-GO" for drug use. This balance is disrupted in addiction,
and the motivation to use drugs become stronger, drug memories become more dominant, and
the "top-down" mechanisms become weaker such that drug use cannot be controlled, leading
to a "GO" take drugs state.

Fig 2. A comparison of the brain circuits in a normal brain with the brain circuits in an
addicted brain. Image credit: Tocris Bioscience

Classes of Addictive Drugs

Stimulants are drugs that function by releasing dopamine and, in some instances,
blocking its reuptake. This class contains amphetamine and its derivatives, for example,
methylphenidate and methamphetamine (crystal meth), cocaine (and crack), and some
cathinones, for instance, mephedrone. Their actions are based on the speed of brain
penetration, with IV injection and smoking being the most addictive routes, but are highly
unaffected by dopamine receptor antagonists. Other effects of neurotransmitters, such as
endorphin release, could then describe their addictive properties.

Fig 3. The effect of stimulants on neurotransmitters. Image credit: Tocris Bioscience

Drugs that imitate the actions of the endogenous opioid endorphin peptides are called opioids.
They comprise of morphine, codeine, heroin, fentanyl, and methadone. They differ with
respect to efficacy and affinity at the µ opioid receptor, which happens to be their site of
action in reward. They are strong analgesics yet can lead to lethal respiratory depression.
Buprenorphine, an example of partial agonists, are safer. These actions are blocked by
antagonists such as naltrexone, nalmefene, and naloxone.

Fig 4. The effect of opioids on neurotransmitters. Image credit: Tocris Bioscience

Alcohol and other sedatives function mainly through the GABA receptor. Alcohol appears to
improve the actions of both GABAB and GABAA receptors and at higher doses also blocks
NMDA glutamate receptors, influences dopamine release, and stimulates 5-HT3 5-
HT3receptors. Benzodiazepines are selective positive allosteric modulators (PAMs) of the α1,
2, 3, and 5 subunits of the GABAA receptor. Although a GABAB agonist, GHB also acts on
GHB receptors. Barbiturates are GABAA PAMs, which at anesthetic doses also open the
GABAA chloride ionophore directly.
 Fig 5. The effect of alcohol and sedatives on neurotransmitters. Image credit: Tocris
Bioscience

Psychoactive cannabinoids, specifically ∆9 THC (the “stoning” element of herbal cannabis),

imitate the effects of endogenous cannabinoids, for example, diacylglycerol and anandamide
that are formed by the breakdown of phospholipids in cell membranes. The brain effects of
cannabinoids are regulated through CB1 receptors, which are found at high concentrations in
brain areas related to reward and motivation. They also act on CB2 receptors that are mostly
found in the immune system. Another cannabinoid—cannabidiol — acts in some ways that
oppose those of THC through mechanisms that are yet to be understood.

Fig 6. The effect of cannabinoids on neurotransmitters. Image credit: Tocris Bioscience

Ketamine, and previously PCP, are dissociative respiratory-sparing anesthetics that also treat
chronic pain and acute depression. Conversely, they are addictive and can cause psychosis.
They function as glutamate NMDA receptor antagonists but since several of these receptors
are present presynaptically on GABA interneurons and on glutamate neurons, the ketamine
blockade results in increased glutamate transmission, which, in turn, stimulates AMPA
receptors. This consecutively can increase dopamine, which may be reinforcing.
Fig 7. The effect of ketamine and PCP on neurotransmitters. Image credit: Tocris Bioscience

https://www.news-medical.net/whitepaper/20190311/The-Biological-Mechanisms-
Behind-Addiction.aspx

The brain can experience pleasure from all sorts of things we like to do in life; eat a
piece of cake, have a sexual encounter, play a video game. The way the brain signals pleasure
is through the release of a neurotransmitter (a chemical messenger) called dopamine into the
nucleus accumbens, the brain’s pleasure center. This is generally a good thing; it ensures that
people will seek out things needed for survival. But drugs of misuse, such as nicotine, alcohol,
and heroin, also cause the release of dopamine in the nucleus accumbens, and in some cases
these drugs cause much more dopamine release than natural, non-drug rewards.

Below is a picture (helpguide.org) of the brain and the nucleus accumbens, in addition
to some other brain regions that are affected by addition.
The brain’s nucleus accumbens activated by alcohol (Gilman et al., 2008)

Addictive drugs can provide a shortcut to the brain’s reward system by flooding the
nucleus accumbens with dopamine. Additionally, addictive drugs can release 2 to 10 times the
amount of dopamine that natural rewards do, and they do it more quickly and reliably.

Over time, drugs become less rewarding, and craving for the drug takes over. The
brain adapts to the effects of the drug (an effect known as tolerance), and because of these
brain adaptations, dopamine has less impact. People who develop an addiction find that the
drug no longer gives them as much pleasure as it used to, and that they have to take greater
amounts of the drug more frequently to feel high.
 There is a distinction between liking and wanting the drug; over time, the liking decreases and
the wanting increases. Individuals with a substance use disorder continue to seek and use the
substance, despite the negative consequences and tremendous problems caused for themselves and for
their loved ones, because the substance allows them to simply feel normal.

. There is evidence that the brain does recover; the image below shows the healthy
brain on the left, and the brain of a patient who misused methamphetamine in the center and
the right. In the center, after one month of abstinence, the brain looks quite different than the
healthy brain; however, after 14 months of abstinence, the dopamine transporter levels (DAT)
in the reward region of the brain (an indicator of dopamine system function) return to nearly
normal function (Volkow et al., 2001).
 PET
SCAN: The right scan is the brain of an individual with chronic cocaine use disorder. Compared to the
control on the left, the PET image on the right has less red, indicating that the brain of the individual
with cocaine use disorder has less glucose and is less active. Lower activity in the brain disrupts many
of the brain's normal functions.

https://www.recoveryanswers.org/recovery-101/brain-in-recovery/

Stages of the Addiction Cycle of alcohol

Addiction can be framed as a repeating cycle, with three stages. Each stage is linked to
and feeds on the others. These stages primarily involve three domains: incentive salience,
negative emotional states, and executive function. The domains are reflected in three key
regions of the brain: the basal ganglia, the extended amygdala, and the prefrontal cortex,
respectively. A person may go through this three-stage cycle over the course of weeks or
months, or progress through it several times in a day. Note also that a person can enter the
cycle of addiction at any one of the following stages:

1. Binge/Intoxication Stage: reward, incentive salience, and pathological habits

 During this stage, a person experiences the rewarding effects of alcohol, such as
euphoria, the reduction of anxiety, and the easing of social interactions.
  Repeated activation of the basal ganglia’s reward system reinforces alcohol drinking
behavior, increasing the likelihood of repeated consumption. The basal ganglia play an
important role in motivation as well as in the formation of habits and other routine
behaviors.
 This repeated activation of the basal ganglia also ultimately triggers changes in the
way a person responds to stimuli associated with drinking alcohol, such as specific
people, places, or alcohol-associated cues such as certain glassware or images or
descriptions of drinking. Over time, these stimuli can trigger powerful urges to drink
alcohol.
 Repeated alcohol consumption also results in changes in the basal ganglia that lead to
habit formation, ultimately contributing to compulsive use.

2. Negative Affect/Withdrawal Stage: reward deficits and stress surfeit

 When a person who is addicted to alcohol stops drinking, they experience withdrawal
symptoms—or symptoms that are opposite to the positive effects of alcohol that are
experienced when drinking it. These symptoms can be physical (sleep disturbances,
pain, feelings of illness) and emotional (dysphoria, irritability, anxiety, and emotional
pain).
 The negative feelings associated with alcohol withdrawal are thought to come from
two sources. First, a diminished activation in the reward systems—or a reward deficit
—of the basal ganglia makes it difficult for people to experience the pleasures of
everyday living. Second, an increased activation of the brain’s stress systems—or a
stress surfeit—in the extended amygdala contributes to anxiety, irritability, and
unease.
 At this stage, the person no longer drinks alcohol for the pleasurable effects (“high”),
but rather to escape the “low” feelings to which chronic alcohol misuse has
contributed.

3. Preoccupation/Anticipation Stage: craving, impulsivity, and executive function

 This is the stage at which an individual seeks alcohol again after a period of
abstinence. A person becomes preoccupied with alcohol and how to get more of it, and
looks forward to the next time he or she will consume it.
 The prefrontal cortex—an area of the brain responsible for executive function,
including the ability to organize thoughts and activities, prioritize tasks, manage time,
and make decisions—is compromised in people experiencing alcohol addiction. As a
result, this area of the brain plays a key role in this stage.

Hyperkatifeia is a word that can be used to describe the

negative emotional state associated with drug withdrawal.
This overactive negative emotional state is hypothesized to
drive the consumption of alcohol to find relief from this
emotional state, and it may be caused by profound changes in
the brain reward and stress systems
 https://www.niaaa.nih.gov/publications/cycle-alcohol-
addiction