Lecture 2: Drug Addiction Flashcards

1
Q
Defining Addiction
Is there a single definition?
(A) 
(B)
(C)
A

*There is no single, universally accepted definition of addiction

“The compulsive seeking (drug craving) and
administration of a drug despite grave
adverse consequences or as a loss of
control over drug intake” (Nestler, 2004)

• i.e., when I drink coffee, it doesn’t have
grave consequences so is not an addiction
under this definition. This definition is
missing the physiological aspect, get a
headache as a withdrawal symptom which is
a sign your body is saying they need the
chemical (caffeine) and to drink a cup of
coffee.

“a term used to indicate the most severe,
chronic stage of substance-use disorder, in
which there is a substantial loss of self-
control, as indicated by compulsive drug-
taking despite the desire to stop taking the
drug” Volkow, Koob, and McLellan (2016)

• A second definition. coffee is not extreme
and not an addiction under this definition.
Chronic – repeated and uncontrollable
behaviour. To take drug to stop withdrawal
symptoms and feed cravings despite
negative consequences and desire to stop.
Classifies it as a part of substance use
disorder (qualifies it)

“a chronic, relapsing brain disease that is
characterized by compulsive drug seeking
and use, despite harmful consequences”
National Institute for Drug Abuse (NIDA)

• Third definition: brain disease (chemical
reactions in the brain, every sense of you
are, belief, memory, needs, or behaviour
starts in the brain)

“addiction is, at its core, a consequence of
fundamental changes in brain function
means that a major goal of treatment must
be to either reverse or compensate for
those brain changes”
(Alan Leshner in 1997)

• Criticists argue that the disease model
disregards human decision making and
choice
• Fourth: changes in brain function.
• Problem with calling ‘alcoholism’ a brain
disease? Argues the addictive behaviour is
the physiological consequence of a brain
disease. It implies that the person was born
with a brain with genetic make-up that made
them predisposed to addiction and removes
the nurture/choice behaviour which results
in addiction.
• We need to separate the brain from being a
physiological organ and a mechanism that
makes decisions. The brain is you; it makes
your decisions, and you are your
decisions/thoughts. If we say someone has
stage four cancer, we do not say hey man
you could’ve pulled through if you just
thought positive thoughts. When we say
alcoholism, we say there was a choice, you
had a choice to drink.
• Like cancer and addiction (depending on
circumstance but in general) there is an
initial choice, the initial behaviour to smoke
which lead to the unintended and
uncontrollable consequence of either
addiction or cancer. If there was no cocaine
in the world, then they could not be
addicted to cocaine. However, it could
manifest in another way with another
substance if it is a disease. Addiction is not
just about the drug. It’s about the self-
destruction. They know it is wrong and they
should stop but they can’t get rid of the drug
taking lifestyle, they are not looking for the
chemical, but the ability to
forget/escape/numb themselves to pain.

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2
Q

Drug overdose deaths in the USA

A

• More common for males to overdose than
women
• Overall, 91,000 people overdosed in 2020
• Alarming that this is such a prevalent issue
and trend is increasing. Clearly,
punishment/arrests are not working at
preventing drug use. It seems anything else
could be better. Would legalizing drugs be
better?

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3
Q

Opioids in New Zealand

A

• Different drugs are more prevalent in
different geographical locations in New
Zealand.
• Guessing the reason, would be that
Northland have a social problem (low ses is
linked to drug use; gangs & violence; MDMA
in cities with clubs/universities).
• Opioids = despair & low socioeconomic
status

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4
Q

Classifying addiction (DSM-V)

A

• Substance-related and addictive disorders
o Substance induced disorders
o Substance use disorders

*There are many things you can be addicted
to that are not substances (i.e., pornography,
gambling etc. which do NOT include
chemicals). Substance – chemicals
ingested/injected/snorted into the body
*DSM-5 uses addiction and substance use
disorder synonymously

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5
Q

Substance-induced disorders

A

• Substance intoxication (drink too much and
get sick)
• Substance withdrawal (headaches, pain, get
sick)
• Substance/medication-induced mental
disorders (i.e., psychosis)

*physiological & psychological symptoms

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6
Q

Substance use disorders

A
• Cluster of cognitive, behavioral, and 
  physiological symptoms  
• Continued use of a substance despite 
  significant substance-related problems 
  (continue using despite consequences)

*Behavioural changes

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7
Q

(9) Drugs included in Substance Abuse Disorder

A
  1. Alcohol
  2. Cannabis
  3. Hallucinogens
  4. PCP
  5. Opioids
  6. Inhalants
  7. Sedatives
  8. Stimulants
  9. Tobacco

*A variety of drugs people can be addicted
to. People are usually addicted to one not
all of them. Indicating that they have their
own pathways, mechanisms, chemical
reactions, and physiological changes.
*Makes it harder to fix when there are so
many and not a single substance
(prevention wise)

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8
Q

General criteria of substance use disorders

*How to determine when someone has a substance use disorder

A
  1. Increasing larger amounts of use of the
    substance (i.e., tolerance builds and more is
    needed too feel good, do it in the morning,
    most of the day)
  2. Unsuccessful efforts to decrease use
    (relapse/withdrawal/cravings so continue to
    use)
  3. Drug craving (always wanting to do it that is
    hard to resist, harder when near it or in
    same place you usually ingest it in)
  4. Impairment in occupational, home, or social
    functioning (whole life becomes about using
    the drug)
  5. Substantial time spent procuring or
    recovering from use
  6. Risky use of the substance
  7. Use of the substance despite negative
    consequences (more you do it, the drug
    becomes the number one priority and are
    less concerned about the consequences,
    continue to use it despite them).

*Tolerance and withdrawal are additional
criteria for substance use disorders but are
not required for the diagnosis!

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9
Q

Tolerance

A

Increased amounts of the substance are needed to achieve the desired effect (or a substantially reduced effect when the usual amount is taken)

*Tolerance: body uses a compensatory
response to counteract the drug and
maintain homeostasis, so you need to take a
higher dosage to get the same effect of the
drug. They are chasing the high of the first
use that they will never get.
*Physiology changes: receptors, dopamine
change with continued use.
*Pentanol: is a synthetic opioid people use
when they have built a tolerance, leads to
overdose, due to our body not being able to
handle the repeated physiological changes
results in heart attacks etc.
*Tolerance varies among individuals

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10
Q

Withdrawal

A

Aversive physiological effects that ensue when the addictive substance is removed or reduced and may include insomnia, anxiety, agitation, and digestive problems

• Symptoms vary substantially across drugs!
And not all substances are associated with
withdrawal symptoms.
• Withdrawal: when the body has undergone
physiological changes to maintain
homeostasis after repetitive drug use,
when the cues for drug using are present
but a drug is not ingested, you go through
withdrawal and crave the drug to make it
go away.
• When drugs are removed the body tries to
reach a new equilibrium which results in
withdrawal physiological symptoms. Pretty
bad in opioids, they will vary across
substances. E.g., caffeine withdrawal is
headaches till the new equilibrium is
reached.

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11
Q

Prevalence

A

• ~10% of individuals 12 years of age or older
(22 million people in the U.S.) are addicted
to alcohol or other drugs
• Cannabinoids, depressants, hallucinogens,
opioids, stimulants, alcohol, PCP, nicotine
are commonly abused (worldwide)

*High prevalence. Terrifying that some 12- 
 year-olds use substances.
*It is a worldwide issue
*A solution/prevention strategy can be 
 implemented worldwide
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12
Q

Prevalence (alcohol)

A

• Alcohol use disorder affects 7.8% of men
and 1.5% of women worldwide
• 8.5% of adults and 4.6% of adolescents in
the United States

*men > women (alcohol)
*Early onset of drug use is associated with
heavy drug use in adulthood

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13
Q

Prevalence (opioids)

A

• Opioid addiction rates continue to increase
o prescription opioid use has increased by
500% in the last 7 years
o ~Two million (0.8%) of the U.S. population
is addicted to prescription opioids
o In 2015 one in three Americans were
prescribed opioids

Class Discussion:
• Drug use is increasing (upward trend)
• Pentanol is included here
• Wisdom tooth taken out and given pain
reliever (oxycodone) is that a problem.
Adderall and Ritalin are methamphetamines.
People assume if it is given to you at the
doctors the drug is different than getting it
on the street corner. The brain chemistry
changes, and the chemical is the same.
• Still get hooked if it is given to you at the
doctors, they won’t prescribe anymore, so
you go to the streets to compensate. Street
drugs are laced with rat poison, or other
drugs (fentanyl) which can cause you to OD
and get hooked on their strain or bulk up
product to make a profit.
• Ritalin = methamphetamine salts (cleaner
but not better)

*People can get addicted to their prescription
without realizing because people deny that
you can be addicted to prescriptions (i.e.,
pain meds, wine)

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14
Q

Withdrawal Symptoms

A
• Not associated with some types of 
   hallucinogens 
o	LSD
o	Mescaline
o	Psilocybin (mushrooms) 

*Withdrawal symptoms are not associated
with these drugs!
*Some students do micro dosing of
psychedelics to improve academic
performance, every day, without being
addicted. No convincing evidence of it
reliably improving performance.
*All drugs have the same effect prescribed or
not.
*Hallucinogens are not considered addictive

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15
Q

Addictive Substances

A

*highly addictive substances include, alcohol,
benzodiazepines, nicotine, and opioids.
*cigarette smoking is the most prevalent
addiction (22.5% adults), alcohol (7.8% men;
1.5% women)

Five substances with the highest potential for addiction worldwide
Criteria:
• the extent to which the drug activates the
brains dopamine system
• degree of pleasure experienced from the
drug
• the degree to which the drug causes
withdrawal symptoms
• the degree of physical and cognitive harm
caused by the drug
• how quickly the drug results in addiction

Substances
•	heroin
•	alcohol
•	nicotine
•	cocaine 
•	sedatives
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16
Q

Comorbidity

A

• Commonly co-occurs with psychiatric
disorders
• Increases the complexity of providing
effective treatment interventions
• Study: 400 patients - 54% exhibited
comorbid psychiatric and substance use
disorders (a larger % of public health
patients meet the criteria for comorbidity
than those from the substance abuse
settings)
• The presence of co-occurring psychiatric
disorders (bipolar disorder, major
depressive disorder) increases the risk of a
poor prognosis

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17
Q

Epidemiological studies

A

• Males are more likely than females to
suffer from substance-related disorders
o However, the prevalence gap appears to
be narrowing as substance use disorders
are increasing among females (study in
2017)
• Initiation of substance use is occurring at
younger ages

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18
Q

Males vs. Females

A
•  Females appear to have:
o Accelerated progression to dependence
o More severe adverse medical, psychiatric, 
   and functional consequences
o More vulnerable to medical, physical, 
   mental, and social consequences of 
   substance use and dependance
o potential risk of drug-induced 
   complications during pregnancy
• However, no differences in treatment 
   outcomes detected between males and 
   females
• Boys and girls aged 12–17 years have 
  comparable rate of use and initiation for 
  alcohol, cocaine, heroin, and tobacco
• ~5% of pregnant women abuse illicit drugs 
   during their pregnancy (other studies found 
   higher rates of opioid use in low 
   socioeconomic status women)
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19
Q

Do most people who take addictive substances become addicted?

A

• The majority of individuals who use drugs
do not become addicted suggesting that
some people are more susceptible to
addiction than others
§ Genetic?
§ Environmental?
§ Social?

  • What is the cause? Genetic (allele),
    environment (ACEs), social? (gang/drug
    presence). No, it is the combination of all of
    them
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20
Q

Percentage of people who become addicted?

A

• ~10% of individuals are highly susceptible to
addiction
• This varies across drug types
• 23% of individuals who try heroin become
addicted (80% of heroin users started with
prescription opioids first)
• less than 1% of prescription benzodiazepine
(Valium, Xanax, Ambien) users become
addicted
• The interaction between genetics,
environment, and social factors influences
susceptibility to addiction

• First Experiment (humans)
• Vietnam soldiers took heroin during the war
and the military were concerned when they
came back the the US would be addicts
with guns. However, only 5% of them
continued to take heroin but 35-38%, who
had physiology changes and liked it,
stopped because the environmental factors
which induced the need to take drugs was
gone. 8-12% of those who misuse
prescription opiates become addicted.
• It is never entirely genetics, it’s the gene-
environment interaction!
• Second Experiment Bruce Alexander
• Mice put into a cage and was trained to
push the lever for cocaine to be released
into the brain. The article stated that the
behaviours related to cocaine addiction and
found that mice will press the lever until
they die (overdose). He re-did the
experiment with the rat in the park with
more stimuli in the cage, press the lever for
cocaine, he found a significantly smaller
percentage rats pressed the lever.
Introducing social, mating, sensory
stimulation changed their behaviour (80 vs
20%). Drugs is only a small percentage of
addiction. Unless you change the social
environment, you are not going to be able
to change addictive behaviour (it is not the
chemical in the drug, it is the combination of
the chemical and the environment).

• Gin Craze (London 18th Century)
• People moved from rural to urban areas.
Struggled to adjust and started to consume
gin (opioids). People blamed gin for the high
rates of death.
• The problem is the environment, the
stress/trauma of the environment, leads you
to addictive behaviours

• Experiment 3 (NZ is liberal; Switzerland is
conservative)
• Switzerland late 1990’s had huge heroin
problem. The government responded by
punishing people who take heroin (shame,
prison, you can say no in USA) they
legalized it rather than criminalized it.
Anyone who wants to do it goes to the
clinic and for free (clean needles, in a safe
place) people were fearful of the
chaos/violence would rise BUT the number
of overdoses was 0, there was less crime
(no need to steal, sell body, be violent), and
they engaged with the addicts and helped
them by social working, find job,
counselling, which was way more effective
than US’s response.

*Conditions to how drugs should be legal,
clinical safe spaces with treatment without
punishment or shame. We don’t want
unknown people selling unknown drugs to
unknown people.
*Is addiction an illness? Is it their fault/choice
or a mental illness that needs treatment? If
it’s a gene-environment then there is no
choice. Like depression, social anxiety,
cancer, bipolar, addiction is NOT a choice!

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21
Q

Impact of trauma

A

• Exposure to child maltreatment increases
the risk of lifetime substance use disorders
o 50% - 75% of college students with
substance use problems have a history of
adverse childhood experiences
• Physical abuse, sexual abuse, and parental
violence are correlated with substance use
disorder are similar across race and
ethnicities

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22
Q

Addiction in childhood associated with…

A

• Intention to use substances in childhood is
related to subsequent use
• Adolescents are vulnerable to addiction
due to
o Environmental factors
o Psychosocial factors
o Brain development factors
• Elementary school students intentions and
prevalence of substance use increased with
grade level. Intentions to use cigarettes and
alcohol early on were associated with
substance use in subsequent grades (i.e.,
intention is a warning sign)
• College students are at high-risk population
for use of alcohol and illicit drugs
o ~98% of drug users ingest more than one
substance
o At risk of using prescription stimulants
without a valid prescription (especially
lower point grade averages and
psychological difficulties)

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23
Q

Multicultural Findings

A
• Alcohol is the most frequently used 
  substance (3.6% of the world population 
  between the ages of 15-64 being 
  alcoholics)
o	Eastern Europe 10.9% (highest)
o	Americas 5.2%
o	Africa 1.1%
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24
Q

Multicultural Findings (alcohol)

A

• Within the USA the prevalence rates of
alcohol use disorder vary across race and
ethnicity
o Native Americans and Alaska Natives:
12.1% (highest)
o Whites: 8.9%
o Hispanics: 7.9%
o African Americans: 6.9%
o Asian Americans and Pacific Islanders:
4.5% (lowest)

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25
Multicultural Findings (cannabis)
• Within the USA the prevalence rates of cannabis use disorder vary across race and ethnicity o Native Americans and Alaska Natives: 3.4% (highest) o African Americans: 1.8% o Whites: 1.4% o Hispanics: 1.2% o Asian Americans and Pacific Islanders: 1.2% (lowest)
26
Multicultural findings (longitudinal study)
• Steady and steep reduction of heavy drinking in white men and women in 20s • Black men and women heavy drinking increased in frequency during their mid 20s • Blacks and Hispanics (compared to whites) showed a slower decline in heavy drinking over time *However, stimulants and opioids misuse are higher among whites! *mixed findings on whether individuals with disabilities are at risk of substance misuse
27
Onset of Substance Use Disorders
• Development and course of substance use disorders varies among individuals and the substance used • Onset for alcohol use disorder typically occurs in late teens to mid-20s (can occur in late teens) and majority of alcohol use disorders are developed by their late 30s • Onset (abuse and dependence) for most drugs occurs in 20s to 40s • Substance use disorder is chronic with periods of exacerbation and remission
28
Psychosocial factors | Two predictors of drug use/relapse
• Psychological factors influence the course and outcomes of substance use disorders • Depression (and drug cravings) are major triggers for relapse in both men and women • Age is another predictor factor: the earlier the onset the higher the relapse rate (and physical and psychological comorbidity)
29
Inebriated Mice Chow Down (Reading)
• Inject mice with the equivalence of two bottles of wine per day over three consecutive days to mimic a weekend of heavy drinking (experimental). Control mice were injected with saline. • Results indicate that both male and female intoxicated mice consumed far more chow food than control mice. • Autopsies of their brain revealed alcohol (ethanol) induced activation of specialised neurons called agouti-related protein (AgRP). These neurons typically become activated following fasting or release of hunger hormones in the brain. The researchers concluded that increased AgRP following alcohol consumption plays a critical role in alcohol-induced binge eating
30
Initiation and Maintenance of Addiction Theories: How does the addiction cycle begin? (A) Reinforcement Theories
*There is no single cause of substance use disorders or additive behaviours (i.e., combination of physiology and environment interactions). Our knowledge is based on animal models but some argue that addiction is a uniquely human condition which animal models cannot fully capture. 1. Pleasurable effects reinforce initial drug use - Positive reinforcement of initial drug use (reading) - Negative reinforcement in those who use drugs to escape emotional distress, negative affect, or stress (lecture) 2. Rewarding effects are reduced and compulsive drug-taking behavior begins - Overtime the rewarding effects of drug use are reduced and compulsive drug-taking behaviour results from a need to achieve a state of homeostasis (i.e., to feel normal, alleviate pain, discomfort, and withdrawal symptoms) - The rewarding properties of the drugs do not justify the negative consequences which accompany their repeated use. However, Classical Conditioning theories argue that environmental stimuli can be paired with drug use, becoming conditioned stimuli which triggers drug- taking behaviours. 3. Impaired cognitive processes - Salience attribution (i.e., attention towards stimuli heightened towards drug- associated cues) - response inhibition (i.e., inhibiting behaviour which interferes with goal- directed behaviour)
31
Reinforcement Theories (anatomy)
• Salience attribution, response inhibition, drug reward, drug cravings are mediated by the mesocorticolimbic pathway o Striatum o Midbrain o Limbic system o Prefrontal regions Mesocorticolimbic Pathway: Rodents • Connections between striatal, midbrain, limbic, and prefrontal regions o Addictive drugs activate “reward pathways” o Release of dopamine • After 60 years of investigation, details concerning the specific functioning of these pathways remains poorly understood. However, what is in common among all addictive drugs is that they activate ‘reward pathways’ in the brain by triggering the release of neurotransmitter dopamine (linked to experiencing pleasure or reward) • mesocorticolimbic system involves several interconnected brain regions including the ventral tegmental area (VTA), substantia nigra, caudate nucleus, and putamen (striatum), nucleus accumbens, amygdala, and frontal cortical regions that correspond to a rats prefrontal cortex or a humans anterior cingulate (READING) Addiction Study (Rats) • Rats learn to press self-administer cocaine o Will do so despite adverse consequences o Will do so in lieu of drink or food o Mothers will abandon their newborn pups in order to self-administer drugs Addiction Study (Rats) • Self-administer bursts of electrical stimulation to brain sites that mediate pleasurable effects of natural rewards like food, water, and sex (i.e., intracranial self- stimulation) • Dopamine levels in the nucleus accumbens increases during intravenous cocaine administration • Administering dopamine antagonists decreased lever-pressing behaviour and lesioning of the nucleus accumbens drastically reduced the rate of drug self- administration which strongly supports the role of dopamine and the mesolibiccortico pathways in drug addiction PET and fMRI: Humans • Increases in dopamine levels in the nucleus accumbens, caudate, and putamen during amphetamine administration • Dopamine release is increased in the nucleus accumbens and striatum in anticipation of drug administration and drug cues • Differences in brain activation patterns in the mesolimbiccortico pathway in participants with cocaine use disorder while at rest, compared to participants without cocaine addiction
32
Orbitofrontal Pathways
• Frontal regions are important for regulating higher-order cognitive functions o Response inhibition o Decision making o Working memory • Extensive connections with midbrain, limbic, and subcortical structures • Increased activation of the pre-frontal cortex in drug users relative to controls during fMRIs when drug related cues are presented
33
Executive Function Deficits
• Executive functioning deficits are common in individuals with addictions (executive control is mediated by frontal regions) o Motivation o Craving o Withdrawal symptoms • Study o Increased blood flow activity in orbitofrontal cortex and striatum in healthy volunteers while they eat chocolate and rated eating the chocolate as “very pleasant” o No changes in activity when participants did not find the experience pleasurable (i.e., were satiated)
34
Stage Theory of Addiction
1. Binge and intoxication 2. Withdrawal and negative affect 3. Preoccupation and anticipation (or craving) *Each stage activates specific neurobiologic circuits ``` Stage Theory of Addiction • All addictive drugs trigger the release of dopamine • Repeated environmental stimuli elicit conditioned surges of dopamine release in anticipation of the drug • This repetitive surge in dopamine in anticipation of the drug results in a physiological desire for the drug (i.e., drug craving) • Continued use of drugs results in reduced dopamine release and less pleasurable effects • Lack of drug consumption leads to: o Negative affect o Increased reactivity to stress o Withdrawal symptoms ```
35
Timeline
• As the process of addiction progresses from using drugs to get high to using drugs to escape dysphoria and withdrawal symptoms. • As drug addiction continues, dopamine down-regulation continues resulting in impaired functioning of the Orbitofrontal pathways which results in: o Poor decision making o Poor self-regulation o Poor inhibition of impulsive response • As a result individuals with addiction succumb to desire, cravings, and continue to use drugs despite their intention to stop and the negative consequences of their actions.
36
Challenge to unitary theory of addiction
o Addiction to a drug such as cocaine has different neurobiological effects than addiction to other drugs such as opioids o There may be a high degree of overlap regarding cellular adaptations with the use of these drugs. Although different drugs may produce different behavioural and psychological effects, they may share core underlying neurobiological substrates of addiction.
37
Dopamine
• Addictive drugs effect dopamine and mesolimbic pathways by: o activating neurons in the mesolimbic and projecting systems o results in increase firing of dopamine- releasing neurons o are associated with increased dopamine levels in extracellular space o are self-administered o often result in relapse after detoxification • Dopamine antagonists block drug effects (cocaine and amphetamines) • Patients with Parkinson’s disease have compromised level of dopamine in the nucleus accumbens and mesolimbic pathways and experience reduced effects of stimulants. • Complex relationship between dopamine and other neurotransmitter systems o Drug addiction is often characterized by anhedonia (failure to experience rewarding stimuli) linked to reduced serotonin (i.e., based on depression research).
38
Other systems involved (GABA)
• Opioid receptors located on GABA neurons in the ventral tegmental are activated, dopamine cell activity is enhanced and dopamine is subsequently released in the nucleus accumbens. • Opiates increase dopamine by removing the inhibitory effect of GABA neurons on dopamine releasing neurons • GABA agonist: e.g., gabapentin o Reduce drinking o Decrease craving o Improve sleep and affect in participants with alcohol use disorder
39
Other systems involved (Glutamate)
• Lower glutamate levels in the forebrain (dorsal anterior cingulate region) in participants with alcohol use disorder • Glutamate signaling in the prefrontal region has been implicated in nicotine, amphetamine, cocaine, and opioids addiction
40
Brain stimulation methods
``` *Which interfere with dopamine release and/or cellular functioning in the mesocorticolimbic pathways • Opiate antagonists injected into the nucleus accumbens block the rewarding effects of opiates in rats ```
41
Brain stimulation methods (Naltrexone)
``` *Which interfere with dopamine release and/or cellular functioning in the mesocorticolimbic pathways • A pharmacological treatment for human alcohol and opiate addiction is daily administration of naltrexone – an opioid mu receptor antagonist ```
42
Brain stimulation methods (Baclofen)
• Baclofen is a GABA receptor agonist • Reduced drug-seeking behavior in rats (controversial in humans) by reducing the propensity of conditioned stimuli that induce drug-seeking behaviour *Mesocorticolimbic dopamine activation plays a critical role in the rewarding effects of drugs and, over time, chronic drug use leads to cellular adaptations.
43
Cellular Adaptation
*Chronic drug use leads to internal processing of cells as well as morphological changes • Research supports that chronic drug use leads to enduring changes in: 1. Synaptic plasticity 2. Changes in white and gray matter 3. Up/down-regulation of receptors 4. Changes in internal cellular processing
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Rapid Detox (Opiates)
• Chronic use of opiates results in cellular adaptation and as the opiate receptors become less sensitive to the drug, tolerance occurs, followed by withdrawal symptoms in the absence of the drug. • Withdrawal symptoms for opiates tend to be severe and long-lasting (i.e., nausea, vomiting, chills, insomnia, depression) which complicates detoxification treatment. • Detoxification treatments include: o abrupt cessation (cutting cold turkey), o tampering with other drugs used to minimise withdrawal symptoms, pharmacological substitution (e.g., methadone), o or rapid detox (i.e., a medical procedure designed to avoid physiological discomfort of withdrawal whilst under anaesthesia. An opioid antagonist like naltrexone or naloxone is administered so the patient can go with rapid and painless withdrawal)
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Rapid Detox (Success)
• Detox session vary in terms of o Length of hospital stay o Safety o Cost o Pre-evaluation measures o Follow-up interventions o Actual detox method • Typically last 4-6 hours • Opiate antagonists are generally prescribed for several weeks to a year post-detox to reduce cravings and likelihood of relapse. • Rapid detox is a medical procedure (invasive; with risks associated with anesthesia) so psychological treatment is often needed to address the emotional and behavioral aspects of addiction • Study: Compared relapse rates of 30 opiate-dependent individuals who underwent rapid detox with and without a 9-month follow-up course of naltrexone: o 34% of the subjects overall relapsed within 13 months but no significant difference between treatment with and without naltrexone. o More research is needed to understand the benefits and limitations
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Genetic Findings | Family and Twin Findings
``` • Influenced by both genetic and environmental factors o Genetic factors influence the: • Metabolism • Sensitivity • Effects of drugs • Relatives have increased risk of substance use disorders including: o Alcohol o Cannabis o Cocaine o Hallucinogens o Sedatives o Stimulants o Opiates • Genetic factors account for 40% to 60% of a person’s vulnerability to addiction • Alcohol: Siblings elevated rates of dependence o 50% for men and 25% for women • First-degree relatives of those with opioid, cannabis, or cocaine use disorders have an eightfold increased risk ```
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Environmental experiences
``` • Determines the specific type of substance an individual will use or misuse • Environmental experiences include: o Age of exposure o Route of administration o Stress o Family o Peers o Community factors ```
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Genetics (Study)
• 3,372 twin pairs • 10.1% of the sample addicted to at least one illicit drug (i.e., substance disorders typically involve the misuse of more than one substance) o Monozygotic 26.2% o Dizygotic 16.5% o Supporting the genetic influence in addiction
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Heritability
Heritability estimates vary across drugs: o marijuana .33 o opiates .43 o stimulants .44 o general drug use .34 • slightly higher heritability estimates in twins for alcohol and marijuana (.56 and .50) • high degree of comorbidity between substance use disorders and psychological disorders including depression, anxiety, PTSD, and, personality disorders.
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Personality traits (predictive)
• Novelty seeking • Harm-avoidance • Low cooperation • Impulsivity • In childhood, externalizing disorders such as conduct disorder and antisocial behaviors are associated with early use of drugs and alcohol • Neither family history nor use of drugs or a combination of genetic risk and exposure necessarily lead to addiction! *individuals with this family/genetic history, who are depressed or possess certain personality traits that are even higher risk for substance abuse disorders, particularly when onset use occurs during adolescence or childhood. Linkage, candidate, and genome wide studies are needed to identify the specific genes linked to substance use disorder
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Linkage Studies (chromosomes)
*Identify specific chromosomes and chromosome locations that may harbor susceptibility genes involved in substance disorders. • Chromosome 4 (in loci 4q, 4p) has been linked to alcohol use disorder • A different locus on chromosome 4 has been linked to opioid use disorder • Chromosomes 6, 7, 11, and 17 have also been linked to opioid use disorders *There have been conflicting findings, and they are correlational not causal in nature
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3 main Candidate Genes
*Identifying specific genes linked to substance disorder • two main approaches: o exploring the role of genes that regulate neurotransmitter systems o exploring specific genes associated with specific genes associated with specific drugs and their potential role in substance use disorders • Genes involved in regulating monoamine neurotransmitters (dopamine, serotonin, norepinephrine) that are commonly studied in the addiction literature include COMT, SLC6A, and MAO-A genes. • polymorphisms of COMT (enzyme which breaks down dopamine; Val158Met) is associated with lower dopamine levels in mesocroticolimbic regions of the brain. occurs in more in individuals with substance use disorder (controversial). Val158Met is associated with increased white matter alterations in the prefrontal cortex and increased risk of addiction. • SLC6A gene regulates serotonin levels and the reuptake process by encoding a membrane protein involved in serotonin transporter. Polymorphisms of this gene is linked to increased risk of substance use disorders. • Variants of the MAO-A gene that encodes enzymes which break down monoamines have also been implicated in substance use disorders, including nicotine, opioids, and other substances.
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Alcohol-metabolizing enzymes genes
• Polymorphisms of ADH1B and ALDH2 influence alcohol consumption o Polymorphism of the ALDH2 gene results in acetaldehyde not being broken down in ~10% of the Asian population leading to an aversive response to alcohol consumption o when carriers of this gene drink alcohol, the acetaldehyde build up causes unpleasant side effects, including nausea, dizziness, skin flushing which significantly reduces alcohol drinking behaviour. o ALDH2 is protective against alcoholism but does not prevent other addictive behaviours from forming.
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Genes (Opioids)
• Dopaminergic system plays an important role in the rewarding effects of addictive drugs like opioids. • DRD4 gene more common in heroin users (controversial) • Meta-analyses have concluded variants of the D2 receptor gene are associated with several addiction disorders o Alcoholism o Cocaine o Nicotine o Opioids • Others include: VEGFR, CLOCK, PDCL2, NMU, NRSF, IGFBP7, KCNC1, KCN2
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Genes (Stimulants)
• Dopamine transporter protein (DAT1) polymorphisms are associated with crack- cocaine addiction *mixed findings overall *No single gene, or group of candidate gene have been identified that confer strong and reliable risk for any substance use disorder
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Genome-Wide Association Studies
*observe the entire genome of different populations to determine whether specific gene variants are associated with a particular substance use disorder. genome wide association studies are able to detect smaller effects in chromosome regions • No particular marker is causally related to “addiction” or to all substance use disorders • genes expected to be related to substance use disorders based on theory and linkage studies are often not identified in genome- wide studies • genes involved in regulating monoamines (dopamine, serotonin) were not associated with substance use disorder (those that were related to cell adhesion molecules were significant).
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Summary of Genetic Studies:
(A) Substance disorders are not caused by a single gene; multiple genes likely interact with constitutional (i.e., personality traits) and environmental factors. (B) No single gene or group of genes has been identified as causing a particular substance disorder and the amount of genetic variance accounted for by genetic factors appears to be relatively small. 95% of the genetic variance remains unaccounted for, indicating that most of the genetic risk factors for addictions have not been discovered.
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Neurotransmitter Findings:
• Drugs exert their effects by enhancing (agonist) or interfering (antagonist) the brains neurotransmitter systems. • These effects occur at the level of the synapse • Depending on the drug the mode of action varies
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Neurotransmitters (Agonists & Antagonists)
• Opiates attach to opioid receptors and mimics the effects of naturally occurring opioids • Nicotine is an agonist at the level of the nicotinic receptor (acetylcholine) • Alcohol is a GABA agonist attaches to a portion of the benzodiazepine receptor and enhance the effects of GABA (agonist) • Alcohol can also have an antagonist effect by inhibiting the functioning of NMDA Glutamate receptor which is associated with the intoxicating effects of alcohol
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Neurotransmitters
• Stimulants like cocaine prevents reuptake of dopamine (to a lesser extent serotonin and norepinephrine) • Barbituates and benzodiazepines are GABA agonists • Cannabinoids attach to Cannabinoid CB1 receptors that activate second messenger systems which enhance the release of dopamine in the midbrain and forebrain
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Neurotransmitters (Opioids)
• Receptors for various neurotransmitters are differentially distributed throughout the brain and their effects on behaviour differ based on the brain region of interest it targets. • Opioid receptors are located in various brain regions and include different subtypes: mu, delta, and kappa o These receptors are heavily concentrated in CNS particularly in the locus coeruleus, brain stem, and spinal cord o Explains why opiates such as morphine and oxycotin can impact respiration
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Neurotransmitters Modulatory Effects
• It is important to note that neurotransmitters can have modulating effects on the dopaminergic system and are implicated in drug addiction. • serotonin receptor agonist (psilocybin) on dopamine receptor (D2) binding found that serotonin receptor activation helped to modulate (increase) dopamine release in the striatum. • cocaine is associated with alterations in serotonergic function • cocaine effects hippocampal GABA and glutamate synapses by directly modulating production and degradation of enzymes that are important to the functioning of the dopamine system. • opioids modulate glutamate-releasing neurons in mesolimbic system and increase inhibition of GABAergic synapses • multiple neurotransmitter systems are involved in chronic use of ecstasy, alcohol and other substances
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Functional Findings (Alcohol substance abuse)
• Children from families with one or both parents are alcohol-dependant are at heightened risk for substance use disorders during adolescence and adulthood and this risk may be related to early childhood brain differences o Smaller volumes of the orbitofrontal cortex during childhood and adolescence predict alcohol (and cannabis) use disorder • Thinner and lower volume of prefrontal cortex and cerebellum • Decreased white matter • Elevated brain activity in fronto-parietal regions during working memory, inhibitory control, and verbal learning tasks • Males with a history of alcoholism have fewer dopamine receptors in the striatum which is correlated with alcohol craving severity • Increased activation in mesolimbic regions (striatum, anterior cingulate cortex, hippocampus, amygdala) in college students predict future heavy drinking • Individuals with a family history of alcoholism showed increase activation in reward pathways in response to sugar pill relative to HCs (oral sucrose response might be an endophenotypic marker of alcoholism risk).
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Pharmacological Treatment | Medications
• Decrease alcohol and drug craving by blocking dopamine release and neuronal activity in the mesolimbic regions o Naltrexone (Opiate receptor antagonist; FDA approved opioid treatment; blocks the release of dopamine in the nucleus accumbens in response to alcohol by occupying the opioid mu and delta receptors and reduces cravings; reduced binding of these receptors in alcohol use disorder in the right frontal, parietal, and dorsal lateral precortex linked to higher levels of cravings) o Bupropion hydrochloride (Nicotine receptor antagonist) o Baclofen (GABA receptor agonist) o Methadone (Opiate receptor agonist) o Varenicline (Nicotine receptor antagonist) • Modafinil improves cognitive and impulse control • Disulfiram: used to deter alcohol use by inhibiting the enzyme that clears acetaldehyde from the body, resulting in highly unpleasant physiological reactions of nausea and vomiting if alcohol is consumed *Chicken and the egg. Does addiction or the morphological and functional brain changes come first?
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Is Tylenol Just as Effective as Oxycodone?
• Despite the opioid crisis. Opioids remain the first line of defence for severe acute pain in emergency rooms. • Are non-opioid medications as effective as opioids in managing acute pain? • Study: Experimental groups o Opioid free (ibuprofen and acetaminophen- paracetamol) o 5 mg of oxycodone (opioid) and 325 mg of acetaminophen o 5 mg of hydrocodone (opioid) and 300 mg of acetaminophen o 30 mg of codeine (opioid) and 300 mg of acetaminophen *No difference in pain reduction! this suggests that ibuprofen + acetaminophen is a viable alternative to opioids. different types of pain can be treated with non- addictive medications than prescription opioids
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Opioids Extracted from... Two types...
• Opioids is extracted from poppy seeds and is a highly effective but addictive pain reliever • opioids include: o Endogenous opioids § Enkephalins § Endorphins o Synthetic opioids § Heroin § Oxycontin (oxycodone) § Vicodin (hydrocodone) § Sublimaze (fentanyl) • Oxycodone is the most prescribed in the US and overdose rates are increasing. There are individual differences in response to opioids, not everyone becomes addictive. • Opioids systems in the CNS, opioids occupy and activate opioid receptors (mu, delta, kappa) and stimulate mesolimbic pathways o mu receptors (molecular gate for opioid addiction) in the VTA stimulate dopaminergic neurons while activation of the kappa opioid receptor inhibits dopaminergic neurons • Visual cues (videos and pictures) of opioids activated regions rich in dopamine and opiate receptors (ventral tegmental area, mesolimbic system) in participants with opioid use disorders and these findings correlate with cravings. • Cravings and addiction are normal brain regions which are activated significantly greater in individuals with substance abuse • increased activation in the right caudate while at rest may serve as a biomarker for opioid relapse • Naltexone is an opioid receptor antagonists which reduces activation in the dorsal striatum in response to heroin related cues o Reduced drug craving *These studies show greater activation in brain regions linked to opioid drug use and that salient environmental cues are also activate these same regions. these neuroimaging findings help explain how cues can elicit cravings and conditioned emotional reactions that increase the risk of relapse.
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Safe Injection Sites
• In January 2018, Philadelphia announced “supervised injection sites” o Safe place and clean needles to inject illicit drugs o Trained staff to administer naloxone (narcan) a drug that reverses overdose o They significantly reduce the rate of death, spread of disease, and refer individuals to substance abuse treatment
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Stimulants
• Stimulants increase arousal in the CNS by increasing dopamine release o Cocaine inhibits dopamine reuptake by binding to dopamine transporter o Amphetamines induces a reversal of the transporter causing more dopamine to be released into the extracellular fluid • even after abstinence chronic cocaine use is associated with widespread reductions in cerebral glucose metabolism in the prefrontal regions • at least 50% occupancy of the dopamine transporter was required to induce a high • lower functional connectivity in the midbrain, cingulate, and cerebellum predicted poor performance on attention task (chronic cocaine use) • both drugs and food increase dopamine neurons in the mesolimbic pathway • when it becomes more chronic blunting dopamine release in mesolimbic system leads to compulsive drug-seeking behaviour. *neuroimaging studies support that stimulant use is initially associated with increased release and availability of dopamine in extracellular fluid leading to rewarding effects of drugs. With chronic use, however, dopamine release is diminished.
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Pharmacological Treatment
• Despite the prevalence of cocaine and amphetamine addiction, no pharmacological treatment is available o Several studies have reported that naltrexone reduces craving in adults addicted to cocaine
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Cannabis
* Psychoactive effects attributed to THC (cannabinoid) * cannabinoid like THC is inhaled or ingested and attaches to CB1 endogenous receptors in brain regions associated with memory, perception, appetite, and motor control. * High to moderate concentrations of CB1 receptors in the hippocampus, amygdala, cerebral cortex, stratium, globus pallidus, cerebellum, and brain stem * ~5–10% of the population, worldwide, who regularly use cannabis will develop cannabis use disorder and experience tolerance, craving, and withdrawal. * mixed findings on structural and functional changes * longitudinal study shows regular cannabis use in adolsebce and adulthood is associated with abnotmal activity in the fronto-parital region in cannabis users (especially heavy users) and in some cases this pattern of activation corresponded with reduced performance on memory and inhibition tasks
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Cannabis functional study
• Under the influence: o Higher activation in the dorsal striatum, insula, posterior parietal regions, anterior and posterior cingulate, and dorsolateral prefrontal o participants who decline cannabis use exhibited activation in different brain regions leading to 100% accuracy classification rate (neural signature of decisions to smoke cannabis)
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Medicinal Cannabis
• those who smoke cannabis for medicinal purposes may have different brain activation responses • longitudinal study compared fMRI scans of medicinal cannabis users after three months of treatment, improved task performance was associated with activation in the cingulate cortex and frontal regions. Non-medicinal marijuana users have shown to exhibit decrements in task performance accompanied by altered brain activation. Marijuana medicinal users had activations closer to HCs than non-users. • cannabis used for medicinal reasons may normalise brain function back to baseline.
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Pharmacological Treatment
• Relapse rate of ~70% for cannabis users (adults seeking treatment who have smoked daily for 10 years have relapsed 6 or more times) • No FDA drugs have been approved • Chronic cannibals use leads to the downregulation and desensitization of the CB1 receptors (i.e., neuroplastic changes) leads to cannabis dependence • CB1 antagonists that block the effects of THC and CB1 agonists which compete with cannibals for occupying the receptors. • e.g., dronabinol and nabilone are synthetic THC and THC agonists that have been found to reduce cannabis withdrawal • fatty acid amide hydrolase (FAAH) inhibitor for treatment for adults is undergoing clinical trials • The main form of treatment for cannabis disorders are psychosocial interventions
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Cellular Adaptations
1. Synaptic plasticity 2. Dendritic size and spines 3. Changes in white and gray matter 4. Up/down-regulation of receptors 5. Changes in internal cellular processing
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(1) Synaptic Plasticity
Synaptic Plasticity • Strengthening or weakening of synapses as a result of increased or decreased activity o Receptors change in quality o Increased or decreased sensitivity or responsivity to neurotransmitter substances (Hebb, 1949) AMPA glutamate receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) • Drugs of abuse result in up-regulation of AMPA receptors o Increase in the number of receptors • After cessation of abused drug, AMPA activity remains enhanced Long term potentiation • Cocaine use results in LTP in the ventral tegmental area • Opioids, Cannabis, and alcohol elicit LTP in mesocorticolimbic structures • LTP: Strengthening of synapses based on recent patterns of activity
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(2) Dendritic Plasticity
• Cocaine: Increases dendritic spine density in the NA • Alcohol: Decreases dendritic spine density and alters size and shape of spines • Opioids: Smaller dendrites, decreased density of dendritic spines, and reduced size of neurons and cell bodies of dopaminergic neurons in VTA
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(3) Gray Matter
Gray Matter • Volume reductions in the prefrontal regions and mesocorticolimbic structures • Drug craving is negatively associated with gray-matter volume Gray Matter (marijuana) • Inconsistent findings o Longitudinal studies are needed! White Matter • Reduced white matter in people with substance use disorders • Alcohol: Loss of cerebral white matter found in postmortem and living individuals o Reduced total brain volume • Reduced white matter, particularly in the hippocampus of adolescents • Cannabis use in adolescents associated with white matter reduction • Children exposed to cocaine, tobacco, marijuana, or alcohol in utero have smaller head circumference and white and gray matter! • Opioid use disorder is associated with white matter (and gray matter) changes in brain regions implicated in addiction
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(4) Receptors and Transporters
``` • Decreased density of postsynaptic dopamine receptors (D2) o Study: Reduced D2 receptors in individuals with alcohol use disorder • Reduced dopamine transporter density and reduced dopamine D2 receptors in the striatum of participants addicted to methamphetamine ```
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(5) Glial Cells
Glial Cells • Stimulants, opioids, and alcohol increase the expression of glial fibrillary acidic protein o Protein found in the cytoskeleton of astrocytes • Morphological changes in astrocytes that connect with blood vessels • Reduction of neurotrophins (BDNF - protein) ``` Internal Changes • Decrease in the amount of neurofilament proteins o Transport of substances from the soma to the terminal button o Up-regulation of the cyclic adenosine monophosphate (cAMP – second messenger) ``` CREB • Reduced phosphorylation of the protein CREB (cyclic adenosine monophosphate response element binding protein) o Initiates intracellular events that lead to long-term changes in cellular function cAMP (Opiates) • Exposure to opiates decreases cAMP levels • Chronic exposure increases levels of cAMP levels • Up-regulation of cAMP increases the firing of neurons in the locus coeruleus (norepinephrine) o Brain’s effort to establish homeostasis? Sensitivity (Tolerance) • Larger amounts of the drug are required to achieve a desired effect o Long-lasting intracellular, enzymatic, and genetic changes modulated by CREB may lead to tolerance
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Summary
• prominently involved in addiction is the dopaminergic system, including the mesolimbic system and associated ascending and descending pathways and connecting prefrontal and subcortical regions. • dopamine and other neurotransmitter systems (i.e., endogenous opioids, GABA, Serotonin, and glutamate) which play a poorly understood modulating role in addiction. • intercellular transcription factors, such as CREB and delta FosB, appear to play an integral role in altering gene expression that contributes to drug addiction. • molecular and neuroplastic changes including alterations in synaptic plasticity, dendritic size and density of spines, white and gray matter, and up/downregulation of receptors contribute to drug craving, withdrawal, and relapse. • No single drug addiction genes has been identified. it is likely a complex interaction between genetics-environment.