Discussion # 3
Drugs, Addiction, and Reward
Chapter 5
Psychoactive Drugs
A drug is any substance that changes the body or its functioning
Agonists mimics or enhances a neurotransmitter
Antagonists may reduce release of neurotransmitter or block receptors
Psychoactive drugs are those that have psychological effects, such as anxiety relief or hallucinations
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Addiction is identified by
Preoccupation with obtaining a drug
Compulsive use of the drug in spite of adverse consequences
A high tendency to relapse after quitting
Withdrawal
Negative reaction that occurs when drug use is stopped
Psychoactive Drugs
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Tolerance
Person becomes less responsive to the drug, requiring increasing amounts of the drug to produce the same results
Is a significant reason for overdose
Psychoactive Drugs
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Psychoactive Drugs: Overview
Opiates
Analgesic: pain relief
Hypnotic: sleep-inducing
Euphoria: strong feelings of happiness
Depressants
Sedation: calming, reduces agitation and irritability
Anxiolytic: anxiety reduction
Hypnotic: sleep inducing
Stimulants
Increased arousal and alertness
Euphoria
Psychedelics
Perceptual distortions and hallucinations
Marijuana
Temporary memory, cognitive, and IQ deficits;
Impaired prefrontal functioning.
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Opiates
Analgesic: pain relief
Hypnotic: sleep-inducing
Euphoria: strong feelings of happiness
Depressants
Sedation: calming, reduces agitation and irritability
Anxiolytic: anxiety reduction
Hypnotic: sleep inducing
Stimulants
Increased arousal and alertness
Euphoria
Psychedelics
Perceptual distortions and hallucinations
Marijuana
Temporary memory, cognitive, and IQ deficits
Impaired prefrontal functioning
Psychoactive Drugs: Overview
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Psychoactive Drugs: Opiates
Opiates have high abuse potential, since they mimic endogenous opioids (natural pain killers called endorphins)
Examples
Morphine
Heroin was synthesized from morphine
Oxycontin
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FIGURE NOTE: An opium poppy
Psychoactive Drugs: Opiates
Examples in fiction
Wizard of Oz field of poppies
Game of Thrones’ “Milk of the Poppy”
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FIGURE NOTE: An opium poppy
Heroin is particularly dangerous because:
Produces intense euphoria
Crosses the blood brain barrier
Tolerance develops rapidly
Conditioned or learned tolerance also is a problem
A learned association between tolerance and the environment in which it develops
When a drug is taken in a different setting, it is more likely to result in an overdose
Psychoactive Drugs: Opiates
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Endorphins
Produce pain relief by stimulating these opioid receptors
Produce additional positive effects by indirectly stimulating dopamine pathways
Psychoactive Drugs: Opiates
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Psychoactive Drugs: Depressants
Depressants are drugs that reduce nervous system activity
Sedation: calming, reduces agitation and irritability
Anxiolytic: anxiety reduction
Hypnotic: sleep inducing
Alcohol, or ethanol, is the most commonly used and abused depressant
Used throughout history in cultural and social practices
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Alcohol has many effects on behavior
Stimulant by turning off cortical inhibition, reducing social constraints and anxiety
Higher doses produce sedative and hypnotic effects
Alcohol has negative effects on health
Acute effects include alcohol-induced coma or death.
Chronic effects include liver damage and brain damage associated with Korsakoff’s syndrome
Psychoactive Drugs: Depressants
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In the U.S. and Canada a person is considered too impaired to drive at a blood alcohol concentration of 0.08%.
Withdrawal is dangerous, and may produce a condition known as delirium tremens
Hallucinations, delusions, confusion, and, in extreme cases, seizures and possible death
Psychoactive Drugs: Depressants
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In the U.S. and Canada a person is considered too impaired to drive at a blood alcohol concentration of 0.08%.
Psychoactive Drugs: Depressants
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FIGURE NOTE: A Normal Brain and an Alcoholic Brain.
Both brains are from 53-year-old men. In the alcoholic brain note the smaller corpus callosum, as well as the enlarged ventricles, sulci, and fissures, which indicate reduced brain tissue.
Alcohol inhibits glutamate (excitatory transmitter)
Alcohol part of the GABAA receptor complex (inhibitory effects)
Effect is sedation, anxiolytic, muscle relaxation, and inhibition of cognitive and motor skills
Psychoactive Drugs: Depressants
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FIGURE NOTE: The GABAA Receptor Complex.
The complex has binding sites for GABA, barbiturates, benzodiazepines, and alcohol.
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Psychoactive Drugs: Depressants
Alcohol’s pleasurable effects likely due to stimulation of opiate, serotonin, and cannabinoid receptors
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FIGURE NOTE: The GABAA Receptor Complex.
The complex has binding sites for GABA, barbiturates, benzodiazepines, and alcohol.
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Barbiturates
Previously drug of choice for treating anxiety and insomnia
Prescribed doses not addictive, but tolerance may lead to increased consumption
Can open chloride channels without GABA
Psychoactive Drugs: Depressants
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Benzodiazepines are safer drugs for treating anxiety
Effects due to decreased activity in the limbic system, hippocampus, brain stem, and cortex
Psychoactive Drugs: Depressants
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Psychoactive Drugs: Stimulants
Stimulants activate CNS to produce arousal, increased alertness, relieves fatigue, decreased appetite, and elevated mood
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FIGURE NOTE: Advertisement from around 1900 for cocaine-based product
Previously included in Coca-Cola
Psychoactive Drugs: Stimulants
Cocaine: extracted from coca plant
Blocks dopamine and serotonin reuptake
Dopamine removes inhibition on lower structures
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FIGURE NOTE: Advertisement from around 1900 for cocaine-based product
Previously included in Coca-Cola
Cocaine was believed to be safe
Freud initially endorsed use
Users have deficits in executive functions that involve the pre-frontal cortex
Psychoactive Drugs: Stimulants
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FIGURE NOTE: A Normal Brain and a Brain on Cocaine.
The upper two scans show activity in a cocaine-free individual. The remaining scans show reduced activity in the brain of a cocaine abuser 10 days and 100 days after last cocaine use.
Injection and smoking produce an immediate and intense euphoria, which increases the addictive potential of cocaine. After the end of a cocaine binge, the user crashes into a state of depression, anxiety, and cocaine craving that motivates a cycle of continued use. Withdrawal effects are typically mild, involving anxiety, lack of motivation, boredom, and lack of pleasure
Addictive due to intense euphoria and craving during abstinence
Difficult to treat because many users have comorbid conditions
Psychoactive Drugs: Stimulants
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FIGURE NOTE: A Normal Brain and a Brain on Cocaine.
The upper two scans show activity in a cocaine-free individual. The remaining scans show reduced activity in the brain of a cocaine abuser 10 days and 100 days after last cocaine use.
Injection and smoking produce an immediate and intense euphoria, which increases the addictive potential of cocaine. After the end of a cocaine binge, the user crashes into a state of depression, anxiety, and cocaine craving that motivates a cycle of continued use. Withdrawal effects are typically mild, involving anxiety, lack of motivation, boredom, and lack of pleasure
Amphetamines are a group of synthetic drugs that produce euphoria and increase confidence and concentration
E.g., Benzedrine, dexadrine, and methamphetamine
Increase the release of norepinephrine and dopamine
Heavy use can cause symptoms that resemble schizophrenia
Have been used in weight-loss drugs, to postpone sleep, and to treat narcolepsy
Psychoactive Drugs: Stimulants
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Safety concerns have been raised in recent years by bath salts, a variety of synthetic derivatives of the Catha edulis plant (khat).
Bath salts produce positive effects similar to those of amphetamines, they can also lead to hallucinations, delusions, paranoia, anxiety, or depression, as well as impaired memory, attention, and concentration; seizures and death have also been reported
Nicotine is the primary psychoactive and addictive agent in tobacco
Stimulates nicotinic acetylcholine receptors
In periphery, activates muscles and may cause twitching
Centrally, produces increased alertness and faster response to stimulation
Withdrawal symptoms are mild, but contribute to a 7% increase in workplace accidents during the United Kingdom’s “No Smoking Day”
Only 20% of attempts to stop are successful after two years
Psychoactive Drugs: Stimulants
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The dangers of smoking are mostly due to the compounds in tobacco smoke, not nicotine
These include
Various cancers
Buerger’s disease
Reduced birth weight
Smoking is the primary cause of preventable death in the world
480,000 premature deaths annually in the U.S.
6 million worldwide
Psychoactive Drugs: Stimulants
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Buerger’s disease, constriction of the blood vessels that may lead to gangrene in the lower extremities, requiring progressively higher amputations
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Caffeine is the active ingredient in coffee
Produces arousal, increased alertness, and decreased sleepiness
Blocks receptors for the neuromodulator adenosine, increasing the release of dopamine and acetylcholine
Because adenosine has sedative and depressive effects, blocking its receptors contributes to arousal
Withdrawal symptoms include headaches, fatigue, anxiety, shakiness, and craving
Psychoactive Drugs: Stimulants
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Because 80% of Americans drink coffee, researchers at the Mayo Clinic once recommended intravenous administration of caffeine to patients recovering from surgery to eliminate postoperative withdrawal headaches !
Psychoactive Drugs: Psychedelics
Psychedelic drugs are compounds that cause perceptual distortions
Often referred to as hallucinogenic
Light, color, and details are intensified
Objects may change shape, sounds may evoke visual experiences, and light may produce auditory sensations
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Examples:
Examples of psychedelic drugs include:
LSD, which resembles serotonin and stimulates serotonin receptors;
LSD-like drugs from mushrooms, such as psilocybin and psilocin;
Mescaline, from the peyote cactus;
Ecstasy, which also has stimulant properties; [STARRED- SEE NEXT PAGE]
PCP, which increases dopamine and blocks glutamate.
Psychoactive Drugs: Psychedelics
Examples
LSD
Mushrooms
Mescaline
PCP
Ecstasy
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Examples:
Examples of psychedelic drugs include:
LSD, which resembles serotonin and stimulates serotonin receptors;
LSD-like drugs from mushrooms, such as psilocybin and psilocin;
Mescaline, from the peyote cactus;
Ecstasy, which also has stimulant properties; [STARRED- SEE NEXT PAGE]
PCP, which increases dopamine and blocks glutamate.
Ecstasy (or MDMA) is popular among young people
Psychomotor stimulant at low doses (releases dopamine)
Hallucinatory at higher doses (releases serotonin)
Chronic use may cause impairment in serotonin functioning
Cognitive deficits such as memory loss
In monkeys, MDMA destroys serotonergic neurons
Psychoactive Drugs: Psychedelics
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Phencyclidine (PCP)
Addictive through activating dopamine pathways
Inhibits glutamate receptors, causing “model psychosis,” with significant implications for theories of schizophrenia
Psychoactive Drugs: Psychedelics
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FIGURE NOTE: Brain Damage Produced by the Drug Ecstasy.
These brain sections have been stained with a chemical that makes neurons containing serotonin turn white. Photos in the top row are from a normal monkey; those below are from a monkey given MDMA a year earlier.
Marijuana: dried leaves and flowers of Cannabis sativa
Delta-9-tetrahydrocannabinol (THC)
Binds to endogenous cannabinoid receptors
Cannabinoids regulate presynaptic transmitters
Psychoactive Drugs: Psychedelics
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FIGURE NOTE: A marijuana plant
Effects on brain and mind
Mildly addictive
Memory, cognitive, IQ deficits
Hippocampus, amygdala reductions (possible)
Impaired prefrontal functioning in offspring when smoked during pregnancy
Psychoactive Drugs: Psychedelics
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FIGURE NOTE: A marijuana plant
Addiction
Addiction and withdrawal are independent processes; they even occur in different parts of the brain.
Rats will self-inject morphine into the ventral tegmental area, which indicates the area is involved in addiction
However, blocking opiate receptors there does not produce withdrawal
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Addiction
Rats will not press a lever to inject morphine into the periventricular gray, so it is not involved in addiction
But once rats are addicted, blocking opiate receptors in the periventricular gray produces signs of withdrawal
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Addiction: Neural Basis
A hypothesized basis for addiction is reward
The positive effect an object or condition (drug, food, sex, etc.) has on the user
The mesolimbocortical dopamine system is usually considered the major reward system
The dopamine system is implicated in the rewarding effects of drugs, food, sex, and electrical stimulation of the brain (ESB)
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Major structures of this system are the nucleus accumbens, medial forebrain bundle, and ventral tegmental area (VTA).
Virtually all abused drugs increase dopamine in the VTA.
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Addiction: Neural Basis
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FIGURE NOTE: The Mesolimbic and Mesocortical Dopamine Systems.
The mesolimbic system projects from dopamine (DA) neurons in the ventral tegmental area (VTA) to the nucleus accumbens; the mesocortical system projects from DA neurons in the VTA to the frontal cortex. Together, they form the mesolimbocortical dopamine system, so named because it begins in the midbrain (mesencephalon) and projects to the limbic system and prefrontal cortex.
Chronic exposure to abused drugs changes the brain
Baseline levels of dopamine activity decrease in the system
Tolerance and decreased response to normal rewarding stimuli
But, the drug/drug-related stimuli produce greater increases in dopamine
This sensitization can last long after the person stops taking the drug
Addiction: Neural Basis
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Sensitization makes individual prone to relapse
Frontal regions include: prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex - control working memory, attention, behavioral inhibition, and the individual’s response to the environment
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Another effect is hypofrontality, reduced activity in frontal regions
Creates impulsivity and compulsivity
Stopping the drug activates neurons in the amygdala
Mediate fear and other aversive states, producing the negative emotions and many of the bodily symptoms that characterize withdrawal
Addiction: Neural Basis
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Sensitization makes individual prone to relapse
Frontal regions include: prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex - control working memory, attention, behavioral inhibition, and the individual’s response to the environment
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Addiction: Neural Basis
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FIGURE NOTE: Reduced Dopamine D2 Receptors in Drug Abusers.
The researchers imaged the brains using PET and an agent that binds to dopamine D2 receptors. The predominance of yellow in place of red in the scans of the drug abusers’ brains indicates fewer of the D2 receptors than in the control subjects’ brains.
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Learning produces brain changes, creating lifelong addiction
Repeated use leads to enduring neural changes
Increased dendrite length and complexity in nucleus accumbens
Craving – hyperactivity in areas involved in learning and emotion (e.g., hippocampus)
Addiction
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Addiction
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FIGURE NOTE: The Brain of a Cocaine Abuser During Craving.
PET scans are shown at two depths in the brain. Notice the increased activity during presentation of cocaine-related stimuli. Frontal areas (DL, MO) and temporal areas (TL, PH) are involved in learning and emotion.
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Addiction: Treatment
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Figure Note: Sigmund Freud and Relapse of Smoking Addiction.
Notice in the graph that the two legal drugs have relapse rates equal to that of heroin.
He smoked as many as 20 cigars a day and commented that his passion for smoking interfered with his work. Although he quit cocaine with apparent ease, each time he gave up smoking he relapsed. He developed cancer of the mouth and jaw, which required 33 surgeries, but he continued smoking
Agonistic treatments mimic the drug’s effects
Example: Methadone for opiate addiction
Serve as “replacement” for drug
Addiction: Treatment
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Figure Note:Effects of a GABAA Receptor Blocker.
The two rats received the same amount of alcohol, but the one on the right received a drug that blocks the effect of alcohol at the GABAA receptor.
Antagonistic treatments block drug effects
Examples: naltrexone is used for opiate and alcohol addiction
Antagonistic treatments don’t replace the drug, so compliance depends on the addict’s motivation to quit
Addiction: Treatment
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Figure Note:Effects of a GABAA Receptor Blocker.
The two rats received the same amount of alcohol, but the one on the right received a drug that blocks the effect of alcohol at the GABAA receptor.
Aversive treatments cause an unpleasant reaction when the addict uses the drug
Example: antabuse (that blocks the enzyme aldehyde dehydrogenase or ALDH) for alcohol addiction causes immediate hangover effects
Treatment compliance depends on the addict’s motivation to quit
Addiction: Treatment
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(Serotonin helps regulate the mesolimbocortical dopamine system.)
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Anti-drug vaccines stimulate the immune system to make antibodies that degrade the drug
Reduced serotonin is found across several addictions
Drugs that potentiate serotonin have shown some usefulness
Addiction: Treatment
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(Serotonin helps regulate the mesolimbocortical dopamine system.)
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Addiction: Treatment
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Table 5.1 Medications Approved by the U.S. Food and Drug Administration for Treating Drug Addictions.
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Behavioral management for heroin addiction has a 10% to 30% success rate; combined with methadone, success rises to 60–80%
Pharmacological treatment is controversial due to belief that recovery should involve the exercise of will and that it is wrong to give an addict another drug, such as methadone
Drug treatment is cost effective: addiction costs $600 billion a year in the U.S., but every dollar invested in treatment saves $7
Addiction: Treatment
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The Role of Genes in Addiction
Alcoholism heavily studied
Two types of alcoholism
Type 1
Cautious and emotionally dependent
Drinking began after 25
Abstinence mixed with binge drinking
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Alcoholism heavily studied
Two types of alcoholism
Type 2
Impulsive, uninhibited, confident, socially detached
More likely male
Bar fights and reckless driving
The Role of Genes in Addiction
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People who do not respond to the negative effects of alcohol, such as motor impairment, are 4x more likely to become alcoholic later
The inheritable ability to eliminate aldehyde is associated with alcoholism and vulnerability to other drugs
A genetic deficiency in the ability to metabolize nicotine protects some people from nicotine addiction
The Role of Genes in Addiction
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The Role of Genes in Addiction
A number of genes are common to drug dependence and the personality characteristics associated with it – impulsivity, risk taking, novelty seeking, and stress responsiveness
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Genes that contribute roughly 50% to addiction
Increase vulnerability
Involved with neurotransmitter systems
Affect how the individual responds to the drug
Environmental influences
Stress, social pressure, drug exposure
The Role of Genes in Addiction
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Example: people with a particular allele of the CHRNA5 acetylcholine receptor gene get a pleasurable rush during early experimentation with tobacco and are more likely to become heavy smokers
An allele of the opioid receptor gene OPRMI confers a similar euphoria from drinking and triples the risk of alcohol abuse
This discussion would be incomplete if we left the impression that the link between genes and drug use is unidirectional; drugs also change the way our genes function. A recent study of smokers and former smokers found more than 7,000 genes whose functioning had been modified by the process of methylation (Joehanes et al., 2016); methylation is the attachment of a methyl group to DNA, which suppresses a gene’s activity
Genes involved in alcohol addiction alter the way the brain functions
Increased high frequency EEG occurs in alcoholics and their offspring
Alcoholics and their offspring also show a reduction in the normal “dip” in the P300 wave
The Role of Genes in Addiction
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These EEG abnormalities are not specific to alcoholism
Often occur in disorders characterized by behavioral disinhibition, such as conduct disorder, antisocial behavior, and other types of drug abuse
The Role of Genes in Addiction
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The Role of Genes in Addiction
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FIGURE NOTE: Evoked Potentials in Children at High Risk and Low Risk for Alcoholism.
Evoked potentials were elicited by high-pitched tones occurring among low-pitched tones. The usual dip of the P300 wave is diminished in the high-risk children.
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Addiction research has broad implications for understanding vulnerability and behavioral inheritance
Behavior results from an interplay between environment and genetics
It is not enough to assign relative roles to environment and heredity; we must then understand the mechanisms – the neurotransmitters, receptors, pathways, enzymes, an so on
The Role of Genes in Addiction
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