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Brain, Behavior, and Drugs

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Brain, Behavior, and Drugs

By Julie Myers, PsyD, MSCP

I.  The complex and adaptive brain

  1. Brain architecture:  gross anatomy, neurons
  2. How the brain communicates
  3. Adaptation and learning

II.  How drugs hijack the brain

  1. Pleasure and the reward center:  the dopamine connection
  2. What (or who) controls the reward center?:    bottom-up vs. Top-down
  3. Brain adaptation:   the change from use to abuse
  4. Binge, withdrawal, cravings, relapse, and the role of stress hormones
  5. Medication that can change the brain’s response

III:  Is addiction biology or just a bad habit?  The possibilities of change

I.  The Complex and Adaptive Brain

The brain is an extraordinarily complex organ.   Once thought to be essentially static after adulthood, we now know that the brain continues to adapt and change and even to grow new neurons.   This is important, as the formation and maintenance of addictive disorders depends not only on the environment, but on the molecular, genetic, and cellular adaptations of the brain.  Addiction to drugs follows a pattern of spiraling brain dysfunction, similar to that seen with gambling, compulsive exercise, binge eating, etc.  Let’s now look more closely at the structure of the brain itself in order to understand the way it processes information and how we become addicted.

A.  Brain architecture

Gross AnatomyThe brain lies nestled inside the protective skull, surrounded by the blood brain barrier, a filter that selects which chemicals/drugs to allow into the brain.  The largest part of the human brain is the cerebrum, and it is composed of four lobes (areas), each with their own specialization.   The outermost part of the cerebrum is the cerebral cortex, the part of the brain responsible for higher-order thinking.  The prefrontal cortex is in the front part of the cerebral cortex; it controls judgment, decision making, and emotional regulation.  Other structures of the brain important in addiction are the limbic system (made up of the hippocampus, and amygdala), ventral tegmental area (VTA), nucleus accumbens, and dorsal striatum.

NeuronsWithin the brain structures are clusters of neurons (nerve cells) called nuclei that govern specific brain processes.  They form routes that allow one part of the brain to communicate with another;  integrating, processing, interpreting, storing, and distributing information.  A neurons is made up of the cell body, axon, axon terminal, dendrites, and dendritic spines.  The neurons are separated by one another by a space called a synapse.



Within the axon terminal are small containers (vesicles) that store the brain chemical messengers called neurotransmitters.  Located on the dendrites are special proteins called receptors, which absorb the neurotransmitters into the cell.  Each receptor specializes in a particular chemical neurotransmitter.  The two most common neurotransmitters in the brain are glutamate and gamma-aminobutyric acid (GABA).  Drugs of abuse act on glutamate and GABA, but also on other neurotransmitters such as serotonin, norepinephrine, acetylcholine, and most importantly dopamine.

B. How the brain communicates

The brain does not act by a single process, but rather by millions of communication pathways made up of neurons and nuclei.  Neurons communication with one another via neurotransmission, which is carried out by the neurotransmitters   To better understand this communication, let’s first examine serotonin, a neurotransmitter important in the drug ecstasy.

Serotonin is synthesized within the neuron body and is stored in vesicles at the axon terminal.  When the neuron receives a signal to release serotonin, the vesicle moves to the interior membrane of the neuron (presynaptic membrane).  The vesicle fuses with the presynaptic membrane, releasing its contents into the synapse.  Once in the synapse, the serotonin travels to the dendritic spine of the receiving neuron, attaching to serotonin receptors.  It is then taken up into the cell by reuptake pumps, reducing the concentration of serotonin in the synapse.

In the receiving neuron, the serotonin may act to activate or inhibit enzymes, release ions, turn-on genes, or increase cyclic adenosine monophosphate (cAMP), which generates the neuronal electrical impulses that propagate communication through the nerve.  When an electrical impulse is generated, it travels down the axon toward the axon terminal, stimulating release of neurotransmitters from vesicles, which are then released to the next neuron to continue the communication pathway.  The electrical impulse transmission is very rapid, but transmission may also occur more slowly, particularly when hormones are stimulated for released by neurotransmitters.  As we will examine later, when drugs of abuse enter the brain, this delicate communication pattern is disrupted.


C.  Adaptation and Learning

The brain is able to adjust to both internal and external stimuli by forming new neuronal connection and by decreasing or increasing receptors, neurotransmitters, dendrites, and hormones.  This ability to adapt (neuroplasticity) helps to explain not only how we become addicted, but how we may unlearn addiction.  It even gives some hope for the possibility of the brain repairing itself from structural damage caused by drugs.

The brain responds to stimuli by generating new neuronal pathways.  For example, if you practice hitting a baseball, you become more skilled as the brain grows new dendritic spines and synapses, transmitting the learned sequence most efficiently.  Neurotransmitters decrease or increase to support this new structure.  The more the pathways are used, the more efficient they become and the stronger the neuronal connections become;  the less they are used, the more the skill (or habit) fades.  Habits can form from any repetitive action that stimulates the brain, such as checking our e-mail or drinking coffee.  Habits, particularly using drugs of abuse, involve the body’s natural hedonic reward system, or reward center.

II.  How drugs hijack the brain

The brain maintains an internal equilibrium by adjusting its structure and function to maintain homeostasis  (maintenance of normal body equilibria).  Although highly adaptive, when drugs of abuse enter the system, homeostasis can be disrupted.   Depending on the quantity, route of administration, and length of time the drug is used, disruption may be profound.   Drugs may come to dominate – or hijack – normal brain function, particularly in the reward center of the brain.

A. Pleasure and the Reward Center

We are hedonistically programmed to seek pleasure.  When the neurotransmitter dopamine is released into the brain, we experience it as pleasure.  Many things release dopamine, including natural highs like exercise, socializing, and sex, as well as all drugs of abuse.  Dopamine plays a dominate role in the reward center, which is controlled by the mesolimbic dopamine pathway.  This pathway starts in the VTA and connects to the limbic system.  The prefrontal cortex, our decision making center, is also involved in this pathway.


The mesolimbic dopamine pathway mediates pleasure using an array of natural chemicals, including endorphins (like morphine), anandaminde (like cannabis), acetylcholine (like nicotine), and dopamine (like cocaine/amphetamines).  When released naturally from neurotransmitter processes, these chemicals help regulate our mood and behavior and bring us pleasure.  However, when drugs of abuse are introduced, they hijack this system, bypassing our body’s own neurotransmitters and directly stimulating an explosive and large release of dopamine.  Such a large and quick release of dopamine dwarfs our natural hedonistic drive to seek pleasure from more sustainable, but smaller sources of dopamine.

Although all drugs of abuse result in a release of dopamine, they may also affect other neurotransmitters.   Cocaine works by a fairly simple mechanism:  It blocks dopamine transporter pumps from taking dopamine up into the neuron, thus increasing dopamine in the synapse.   Opiates affect the reward system via dopamine indirectly:   Opiates bind to a receptor, causing dopamine to be released, which then affects a nearby neuron containing GABA, which inhibits dopamine release thus increasing dopamine release.  Ecstasy binds to the serotonin transporter first, preventing transport and reuptake, which then increased serotonin is in the synapse,  causing activation of serotonin and dopamine receptors.

B. What (or who) controls the Reward Center?

Control of the mesolimbic dopamine pathway occurs at two levels:   Bottom-up control (originating at the level of stimulation) and top-down control (originating from brain cortical regions)

Bottom-up control

The amygdala — the area of the brain involved with memory and emotion – is connected to the mesolimbic dopamine pathway.  When a potentially pleasurable activity or substance is received (e.g., drugs), the amygdala signals neurons in the VTA and the nucleus accumbens.  Dopamine is released, and the stimulus is interpreted as pleasurable;  it becomes a “reward”.   The structures involved with this pathway “learn” that pleasure is created when the drug is introduced into the system.  The amygdala stores the “memory” of the drug, as well as associations of that drug, e.g., paraphernalia.   The brain learned how to acquire fast and large quantities of dopamine.  This reward-learning can be so powerful that the brain can forget how to acquire pleasure through natural engagement in everyday activities.  In essence, normal learning is short-circuited.

When we learn that a particular stimuli (reward) gives pleasure, it positively reinforces the behavior that produced it.  Positive reinforcement occurs on a small scale for everyday things we enjoy, for example, if we enjoy someone’s company, we seek them out.  Our choice to engage in repeated, pleasurable behaviors usually has a direct relationship to the amount of dopamine released.  Depending on individual brain make-up, drugs of abuse can be an extreme form of positive reinforcement (as may some activities such as sex, gambling, and food), driving us toward more drug seeking behavior.

The reward pathway for a particular stimuli can become so strong and automatic, that even when the stimuli is not so rewarding – or when there may be dire consequences – we continue to seek the stimuli.  Cravings arise out of these automatic pathways; the stronger and more fixed the pathways, the stronger our desire to seek the drug (reward).  Memory of the drug is stored in the amygdala, and when it receives information about the drug or its associations, it activates the reward system, triggering the neurons in the nucleus accumbens to procure that drug to seek pleasure.  The more we have used the drug and derived pleasure from it, the stronger will be the drive to complete the reward cycle.

Top-down control

Luckily humans possess a thinking brain, allowing interpretation and interruption of the automatic bottom-up pathway.   At the top of the reward center is the prefrontal cortex, which regulates impulse, analysis, flexibility, and integration of emotions.  At this level of reward center control, we are able to consciously make decisions to use (or not use) quick, dopamine releasing drugs or activities.  The strength of our top-down control system to override the impulses of the bottom-up control depends on our experience, our genetics, our learning about the benefits and cost of our decisions, and our ability to self-regulate.  It is this top-down control that is ultimately at the core of drug abuse treatment, which relies on the strengthening of the top-down control system to interrupt and reclaim bottom-up control.

C.  Brain Adaptation:   The progression from use to abuse

The neuroplasticity of the brain contributes to the progression from casual drug use to addiction.  Drugs of abuse cause short and long-term adaptation in a predictable succession (Koob, 2010), starting with the (1) mesolimbic dopamine pathways, moving to the (2) ventral striatum, (3) ventral striatum/ dorsal striatum/thalamus  (4) dorsolateral frontal cortex/inferior frontal cortex/hippocampus system, and finally the (5) extended amygdala.  This neuroadaptation reprograms the systems that process reward, motivation, memory, habituation, decision making, inhibition, self-awareness, and stress reactions.   This reprogramming leads to dysregulation of the brain reward center, causing compulsive drug use and loss of control.


Short-term change

All drugs of abuse have an immediate action on neurotransmission, particularly dopamine.  The opiates mimic neurotransmitters, which mimic dopamine.  Benzodiazepines enhance the receiving cells response to dopamine.  Cocaine hijacks the dopamine receptors, so that dopamine is not taken out of the synapse, and marijuana mimics cannabinoid neurotransmitters.  Other drugs alter neurotransmission by interacting with or interfering with the neurotransmission signals.  The quantity of drug taken, the metabolic breakdown of the drug, and route that the drug is taken all affect the strength of the dopamine reward (the faster the administration, the strongest reward).  The dopamine release is more prolonged and unregulated than natural stimuli, and the reinforcing effects from such large increases in dopamine in the brain affect the reward threshold.


Long-term change: 

As drug use continues, long-term structural changes occur in the brain, some of which may be permanent.  Simple structural changes include the up-regulation or down-regulation of receptors.  Up regulation means that when the neurons is exposed to too little neurotransmitter, more receptors are created to “capture” neurotransmitters in the synapse.  Down-regulation refers to the process where the number of receptors is reduced when exposed to too much neurotransmitter (or drugs mimicking the neurotransmitter).

Down regulation is especially important when drug use is stopped.  When a drug is actively being used, a lot of dopamine is in the synapse;  receptors down-regulate to adapt to the abundant dopamine.  If the drug is then stopped, less dopamine is available but few receptors are present.  Since neurons can’t up-regulate instantaneously, withdrawal symptoms are felt because of the relative reduction in dopamine.

More serious structural changes occur when drug use results in neuron death or loss of function. Neuroimaging of the brain (such as CAT scans or MRI) shows that some drugs can cause loss of brain structure and function.  Such loss may be caused by over-excitation of the neuron, which leads to apoptosis (cell suicide), and direct toxicity to the cell or dendrite.   Sometimes the brain can regrow dendrites, reversing drug damage and allowing the brain to return to normal;  in some cases damage is irreversible.

Most important of the long term adaptations is the change in the mesolimbic dopamine pathway, caused by dopamine that is released in a more prolonged and unregulated manner than natural stimuli.  The brain no longer responds to lower, slower levels of dopamine.   In other words, there is a recalibration of dopamine-activating (reward) thresholds for natural reinforcers.  This low dopamine tone contributes to the lack of motivation often seen in those using drugs.

The ability to choose between small, immediate rewards and large, deferred rewards is made in the prefrontal cortex.  With drug use, adaptations occur in the regulation of cognitive and emotional processes, which results in the overvaluing of drugs and the undervaluing of natural reinforcers.  There are deficits in inhibitory control of drug responses and an overall underperforming of the prefrontal cortex leading to poor impulse control.   With chronic drug exposure, the neurons responsible for memory and conditioned learning undergo abnormal neuroadaptations.

Binge, withdrawal, cravings, relapse, and the role of stress hormones

Each stage of the addiction cycle – binge, withdrawal, and cravings – is controlled by discrete brain system (Koons, 2010).  These systems play a role in developing and maintaining an addiction and they also contribute to relapse.

During the binging stage, the ventral tegmental area and the ventral striatum of the forebrain play dominate roles.  The acute reinforcing effects of drugs depends on immediate neurotransmitter release.  Impulsivity (the rapid, unplanned reactions to stimuli without regard for negative consequences) is the dominate behavior when a person first starts using drugs and is controlled by these brain areas.

With continued drug use, both compulsivity (repeated behavior in the face of adverse consequences) and impulsivity play roles in maintaining the addiction.  During the withdrawal stage, compulsivity changes from a behavior leading to positive reinforcement (i.e., the high of the drug use) to a behavior with negative reinforcement.  Negative reinforcement refers to the removal of an aversive stimulus, i.e., the removal of the negative emotional state that comes with withdrawal.   The negative emotional mood state is caused by decreased neurotransmitters:  Decreased dopamine and serotonin leading to dysphoria,  decreased opioid peptides causing pain, and decreased GABA, which results in anxiety and panic.  The extended amygdala, which plays an important role in pain and fear/stress processing, dominates the withdrawal stage.

Acute withdrawal is drug specific, but all drugs of abuse increase the stress response from release of stress hormones such as corticotropin releasing factor (CRF).  Dopamine is low in post-acute withdrawal, which increases sensitivity to environmental cues and decreases sensitivity to reward.   Changes in the prefrontal cortex follows, with impaired control of impulsivity.  The decrease in the reward system and the increase in stress sensitivity persist in post-acute withdrawal and play a role in relapse.

The preoccupation(cravings) stage is controlled by an variety of brain systems, including the prefrontal cortex, amygdala, and hippocampus.  Brain stress systems play a key role in the cravings stage, particularly from actions of CRF and norepinephrine in the extended amygdala.   Combined dopamine and glutamate neurotransmission in the dorsal striatum (involved with habit formation and action initiation) is involved when cravings, which are triggered by stimuli from external environmental cues and internal mood states of anxiety, irritability, and dysphoria.

Medication that can change the brain’s response

Research on ways to inhibit cue-conditioned dopamine and glutamate responses is a focus of current development of medication to treat addictions.   Treatments for binging and cravings include naltrexone (ReVia, Vivitrol), buprenorphine (Suboxone, Subutex), varenicline (Chantix), nicotine replacement, and methadone.  Treatments for negative mood state and cravings include methadone (Dolophine), buprenorphine (Suboxone, Subutex), varenicline (Chantix), nicotine replacement, acamprosate (Campral), and bupropion (Zyban).   There is optimism in the scientific community about the possibility that new drugs will be developed, which may help individuals gain and maintain control over addictive behaviors and substances.

III:  Is addiction biology or just a bad habit?  The possibilities of change

To what extent does genetics control the propensity to develop an addiction?   It has been shown that genetic factors, the environment, and the non-shared environment all had nearly equal influences on an individual’s risk of developing a drug use disorder (Tsaung, 1996).  There are also appear to be genetic and environmentalcharacteristics that make up a common vulnerabilityto abuse a range of illegal drugs (Tsuang, 1998).  That is, abuse of one drug is associated witha marked increase in the probability of abusing every othercategory of drug.  Also, drugs may “turn-on” genes to produce proteins, which cause changes in cell function or structure, which may lead to neuroadaptations.  Cocaine, for example, causes genes to produce the proteins necessary for new dendritic growth, and those who abuse alcohol are more likely to have different  dopamine receptor genes (Smith, 1992).

From scientific studies, we know that certain genetic factors may play a role in the development of an addiction;  some people may simply be more predisposed to developing an addiction.  We also know that in the development of addiction, there is a spiraling dysregulation of brain reward systems, producing short and long term changes in the brain.  Changes include both structural and functional changes in the brain, which reinforce the response to conditioned cues and maintain cravings, strengthened by the development of a stress sensitivity.   But does this mean that some of us are “programmed” to use drugs and that their use is predestined by genetics?  No.

We know that people do stop using drugs.   How do they do this if they are programmed to use the drug genetically or environmentally?  They change, because when stopping the drug becomes more important to them than continuing the drug, they can override and overcome the impulses generated by brain adaptations that maintain the abuse.   They are able to reengage the more sophisticated top-down control of the brain, overriding the bottom-up control of the more primitive parts of the brain.    Simply stated, we as humans are able to choose.

Julie Myers, PsyD, MSCP

Licensed Psychologist, MS Clinical Psychopharmacology, Master Addiction Counselor, Board Certified Biofeedbac  

Copyright 2011 Julie Myers, PsyD.  All Rights Reserved

Koob, G.F and N.D Volkow, Neurocircuitry of Addiction, Neuropsychopharmacology Reviews (2010) 35, 217–238

Koob, G.F. and Michel Le Moal (1997), Drug Abuse: Hedonic Homeostatic Dysregulation, Science, V. 278,

 Tsuang, M.T.,  Michael J. Lyons, Seth A. Eisen, et al. (1996)   Genetic influences on DSM-III-R drug abuse and dependence: A study of 3,372 twin pairs   .American Journal of Medical Genetics.  Volume 67, Issue 5, pages 473–477.

Tsuang,M.T.,  MD, PhD, DSc, FRCPsych; Michael J. Lyons, PhD; Joanne M. Meyer, PhD; Thomas Doyle; Seth A. Eisen, MD, MSc; Jack Goldberg, PhD; William True, PhD, MPH; Nong Lin, PhD; Rosemary Toomey, PhD; Lindon Eaves, PhD, DSc (1998).  Co-occurrence of Abuse of Different Drugs in Men  The Role of Drug-Specific and Shared Vulnerabilities, Arch Gen Psychiatry;55:967-972.

Stevens S. Smith, PhD; Bruce F. O’Hara, PhD; Antonio M. Persico, MD; David A. Gorelick, MD, PhD; David B. Newlin, PhD; David Vlahov, PhD; Liza Solomon, DrPH; Roy Pickens, PhD; George R. Uhl, MD, PhD, (1992).  The D2 Dopamine Receptor Taq I B1 Restriction Fragment Length Polymorphism Appears More Frequently in Polysubstance Abusers.  Arch Gen Psychiatry. 1992;49(9):723-727)


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