Trends in Biomedical Science

1
Trends in Biomedical Science

• Diseases of the Brain 1
• Non-prescription drugs

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• We will study some brain diseases.
• I will try to present them in order of their
  importance to society.

3

• We will study some brain diseases.
• I will try to present them in order of their
  importance to society.
• For this reason we will study non-prescription
  drugs first.

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• References
• Brain facts http//www.sfn.org/index.aspx?pagename
  brainfacts
• especially Neural Disorders Advances and
  Challenges
• Drugs alter the Brains Reward Pathway
• http//learn.genetics.utah.edu/content/addiction/d
  rugs/index.html

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• Facts and figures
• We know what can be done to help reduce
  psychoactive substance use.
• We know what needs to be done to help reduce
  psychoactive substance use.

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• Facts and figures (US figures)
• At least 15.3 million persons have drug use
  disorders.
• Injecting drug use is reported in 148 countries,
  of which 120 report HIV infection among this
  population.

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• The leading causes of death in 2000 were tobacco
  (435 000 deaths 18.1 of total US deaths), poor
  diet and physical inactivity (400 000 deaths
  16.6), and alcohol consumption (85 000 deaths
  3.5). Other actual causes of death were
  microbial agents (75 000), toxic agents (55 000),
  motor vehicle crashes (43 000), incidents
  involving firearms (29 000), sexual behaviors (20
  000), and illicit use of drugs (17 000).
• JAMA AH Mokdad et al Actual Causes of Death in
  the United States, 2000

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• The following is an example of the Australian
  problem.
• Australia has half the size of Koreas population.

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• The costs of tobacco, alcohol and illicit drug
  abuse to Australian society in 2004/05

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Disease Number Yearly Cost
Drugs - Illegal 22,000,000 276,000,000,000
Drugs Nicotine (US) 70,000,000 138,000,000,000
Drugs Nicotine Korea 3,920,000,000,000 won
Drugs - Alcohol (US) 14,000,000 185,000,000,000
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Disease Number Yearly Cost
Drugs - Illegal 22,000,000 276,000,000,000
Drugs Nicotine (US) 70,000,000? 138,000,000,000
Drugs Nicotine Korea 3,920,000,000,000 won
Drugs - Alcohol (US) 14,000,000 185,000,000,000
Alzheimer 5,000,000 100,000,000,000
Pain 97,000,000 100,000,000,000
Major Depression 70,000,000,000
Trauma 1,400,000 60,000,000,000
Stroke 700,000 51,200,000,000
Dyslexia 60,000,000
Anxiety 24,800,000
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• Smoking in South Korea is the leading preventable
  cause of death in the country, with more than
  40,000 people dying every year from smoking-relate
  d diseases.

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• Lets look at constructing a pedigree for
  possible addiction to nicotine.
• http//learn.genetics.utah.edu/content/addiction/p
  i/
• And here we can look at finding candidate genes.
• http//learn.genetics.utah.edu/content/addiction/c
  andidate/

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• Drug abuse is one of the worlds most serious
  health problems.
• In the US, 9, more than 22 million people, abuse
  drugs on a regular basis.
• Recent estimates show that the abuse of drugs,
  including alcohol and nicotine, costs more than
  276 billion each year.

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• If continued long enough, drug abuse often
  defined as harmful drug use can eventually
  alter the structure and chemical makeup of the
  brain, producing a true brain disorder.
• This disorder is called drug addiction or drug
  dependence.

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• Drug addiction is a pathological desire for
  drugs, such that drug seeking and drug-taking
  behaviors take up too much of an persons time
  and thoughts and these behaviors continue despite
  many bad consequences.
• Addicts also have difficulty controlling
  frequency of use and stopping use, despite
  wanting to.

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• Abused drugs alter the ways neurotransmitters
  carry their messages from neuron to neuron.
• Some drugs mimic neurotransmitters, whereas
  others block them.
• Still others alter the way neurotransmitters are
  released or inactivated.
• In all cases, the brain reward system is
  activated because drugs alter the chemical
  messages sent among neurons in this circuit.

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• The reward circuit is at the heart of our mental
  activity and guides all our behaviors. This
  circuit is complex, but it contains a central
  link that is very important.

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• This link consists of the nerve connections
  between two particular small groups of neurons.
  One of these groups is located in the ventral
  tegmental area (VTA), and the other in the
  nucleus accumbens.

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• The chemical messenger that makes the connections
  between these two groups of neurons is dopamine.
  This is the site where most drugs act and cause
  dependencies.

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• Dopamine is a chemical messenger
  (neurotransmitter) that is not very common in the
  brain. Only 0.3 of the neurons in the brain
  produce dopamine. These neurons play an essential
  role in many of our behaviors.

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• Other parts of the brain connect directly
  to dopamine neurons

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• Green dots represent neurons providing inputs to
  dopamine neurons in the ventral tegmental area
  (VTA, processes rewards), while red dots
  represent neurons providing inputs to substantia
  nigra (SNc, motor control) dopamine neurons.

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• Some dopamine-producing neurons act when the
  person experiences desire or pleasure.

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• The Reward Pathway Reinforces Behavior
• The following information about the brains
  rewards system comes from http//learn.genetics.ut
  ah.edu/content/addiction/rewardbehavior/

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• The reward system reinforces behavior.

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• The brain is divided into several regions that
  are each responsible for performing different
  functions. In the center of the brain is the
  reward pathway, which is responsible for driving
  our feelings of motivation, reward and behavior.

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• The reward pathway makes us feel good when we do
  behaviors that are necessary for our survival.
• These behaviors include eating, drinking and sex.

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• The reward pathway connects to several other
  important areas of the brain.
• These connections bring information about what is
  happening outside of the body, and strengthen
  brain circuits that control good behavior.

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• Imagine you havent eaten all day and someone
  gives you a nice sandwich. Your five senses
  gather information from your surroundings and
  send signals to the brain letting it know that
  there is a delicious sandwich in front of you.

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• In another part of your brain is the memory that
  when you eat a sandwich, you will no longer be
  hungry and you will feel good. Based on this
  information, the brain tells the body to pick up
  the sandwich and eat it.

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• The senses tell the brain that the body is eating
  some good tasting food and the stomach is filling
  up. Special neurons in the reward pathway release
  the chemical dopamine. The release of dopamine
  gives you a little push of pleasure. Thats your
  reward for eating the sandwich.

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• In addition to making you feel good when you
  engage in good behavior, the reward pathway is
  responsible for trying to make sure  you repeat
  the behavior whenever possible. It does this by
  connecting to regions of the brain that control
   memory and behavior.

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• When the reward pathway signals brain regions
  involved in memory, it enables the brain to
  create the memory that eating food makes you feel
  good. This increases the chance that you will eat
  the food again.

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• When the reward pathway signals the brains motor
  center, it strengthens the neuron networks for
  behaviors that help you achieve your reward. In
  this case, picking up the sandwich, chewing it
  up, and swallowing it.

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• By giving us a push of pleasure, the reward
  pathway works to make us repeat behaviors which
  are necessary for survival.

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• A central group of structures is common to the
  actions of all drugs.
• These structures include a collection of
  dopamine-containing neurons found in the ventral
  tegmental area.
• These neurons are connected to the nucleus
  accumbens and other areas, such as the prefrontal
  cortex.

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• Cocaine exerts its effects mainly through this
  central system.

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• Opiates act in this system and many other
  regions, including the amygdala, that normally
  use opioid peptides.
• Opioids are naturally occurring brain chemicals
  that induce the same actions as drugs, such as
  heroin and morphine.

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• Alcohol activates the core reward system and
  additional structures throughout the brain
  because it acts where GABA and glutamate are used
  as neurotransmitters.
• GABA and glutamate are widely distributed,
  including in the cortex, hippocampus, amygdala,
  and nucleus accumbens.

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• Common Features of Addiction.
• Many substances found in nature leaves, seeds,
  and roots of plants, and some animal products
  had medicinal qualities.

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• Common Features of Addiction.
• Some of these produced pleasure when eaten,
  drunk, or smoked. Perhaps the first one that
  people discovered, is ethyl alcohol.

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• For example,
• Asians - the opium poppy and the tea plant,
• Indians - cannabis,
• South Americans - coca leaves and coffee beans,
• North Americans - the tobacco plant.

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• Many of these drugs are poisons that protect the
  plants from animals that eat them.
• People learned how to take these drugs in amounts
  that would not make them ill.
• The effects of these drugs on the brain rewards
  us for taking the drug.

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• Agonist something which makes it work better or
  more
• Antagonist something which makes it work less

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• GABA RECEPTORS GABA (gamma-aminobutyric acid)
  affects the GABA receptors. 
• These receptors are macromolecular complexes with
  several sub-units.
• The GABA-A receptor is 5 sub-units surrounding a
  channel for chloride ions (and bromide ions).

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• The GABA-A receptor also has secondary binding
  sites for molecules that modulate GABAs effects.
  Examples are benzodiazepines, barbiturates,
  convulsants, steroids, and alcohol.

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• These molecules change GABAs efficiency by
  changing the protein shape of the GABA-A complex.
  The size of the channel changes, and the neurons
  permeability to chloride ions. Negative chloride
  ions then hyperpolarize the neuron.

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• The result is an inhibition of neuronal activity
  and a general anxiolytic effect.
• Treatment with benzodiazepines helps to reduce
  anxiety by increasing the effect of GABA, and by
  making the chloride channel open more frequently.

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• However, in the absence of GABA at the primary
  site on the GABA-A receptor, the modulating
  molecules have no effect on the neurons chloride
  permeability.

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• Addictive drugs have reinforcing effects.
• These effects include activating the reward
  mechanism.
• The reward strengthens the action that was just
  made.
• If the drug was taken by a fast-acting route, the
  last action will be taking the drug, so that will
  be reinforced.

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• Drug users prefer heroin to morphine because
  heroin has a faster effect.
• Heroin is converted to morphine as soon as it
  reaches the brain. But heroin is more lipid
  soluble, it passes through the bloodbrain
  barrier more rapidly, and its effects on the
  brain are felt sooner than those of morphine.

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• The biggest reinforcement occurs when drugs
  produce sudden changes in the activity of the
  reward mechanism slow changes are much less
  reinforcing.
• A person taking an addictive drug seeks a sudden
  rush produced by a fast-acting drug.

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•  Different methods of delivery smoking,
  injecting, or snorting largely influence how
  quickly a drug reaches the brain.
• http//learn.genetics.utah.edu/content/addiction/d
  elivery/

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• Food for a hungry animal, water for a thirsty
  one, or sexual contact have one effect in common
  they cause the release of dopamine in the nucleus
  accumbens.

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• The nucleus accumbens is an important part of the
  reward system.

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• Addictive drugs including amphetamine, cocaine,
  opiates, nicotine, alcohol, PCP, and cannabis
  trigger the release of dopamine in the nucleus
  accumbens.
• Different drugs stimulate the release of dopamine
  in different ways.

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• The first changes appear to take place in the
  ventral tegmental area (VTA).
• A single dose of an addictive drug (cocaine,
  amphetamine, morphine, alcohol, or nicotine)
  increased the strength of excitatory synapses on
  dopaminergic (DA) neurons in the VTA in mice.
• This change is by putting more AMPA receptors
  into the postsynaptic membrane of the DA neurons.
• Dopaminergic means related to dopamine

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• When people first take an addictive drug, they
  experience pleasure.
• If they continue to take the drug and become
  addicted a different part of the brain becomes
  developed.

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• Then they take the drug, not for the pleasure,
  but because drug-related cues means they want to
  seek drugs.
• Drug addicts are aroused and motivated when they
  are seeking a drug but are withdrawn and dull
  when they are in a drug-free environment.

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• Most people who take addictive drugs do not
  become addicted.
• The chance of becoming addicted is a function of
  heredity, age (adolescents are most vulnerable),
  and environment (such as access to drugs and
  stressful life events).

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• The role of the prefrontal cortex in judgment,
  risk taking, and control of inappropriate
  behaviors may explain why adolescents are much
  more vulnerable to drug addiction than are
  adults.

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• Adolescence is a time of fast and large change in
  the brainparticularly in the prefrontal cortex.

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• Before these circuits reach their adult form,
  adolescents are more likely to display increased
  levels of impulsive, novelty-driven, risky
  behavior, including experimentation with alcohol,
  nicotine, and illicit drugs.

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• Addiction in adults most often begins in
  adolescence or young adulthood.
• Approximately 50 percent of cases of addiction
  begin between the ages of 15 and 18, and very few
  begin after age 20.

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• A behavior that turns off (or reduces) an bad
  stimulus will be reinforced.
• This phenomenon is known as negative
  reinforcement.

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• Negative Reinforcement
• the removal or reduction of an bad stimulus that
  depends on a particular response, with an
  increase in the frequency of that response

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• People who abuse some drugs become physically
  dependent on the drug that is, they show
  tolerance and withdrawal symptoms.
• Tolerance is the decreased sensitivity to a drug
  that comes from its continued use the user must
  take larger and larger amounts of the drug for it
  to be effective.

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• If a person has taken an opiate regularly enough
  to develop tolerance, that person will have
  withdrawal symptoms if he stops taking the drug.
• Withdrawal symptoms are the opposite of the
  effects of the drug itself.
• The effects of heroin feeling good,
  constipation, and relaxation lead to the
  withdrawal effects of feeling bad, cramping and
  diarrhea, and agitation.

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• Positive reinforcement supports drug taking.
• Reduction of withdrawal effects can maintain
  someones drug addiction.
• The withdrawal effects are unpleasant, but as
  soon as the person takes some of the drug, these
  effects go away, producing negative reinforcement.

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• Negative reinforcement could also explain some
  drug addictions.
• If a stressed person is suffering from some
  unpleasant feelings and then takes a drug that
  eliminates these feelings, the persons drug -
  taking behavior is likely to be reinforced.
• For example, alcohol can relieve feelings of
  anxiety.
• If a person finds himself in a situation that
  makes him anxious, he might find that having a
  drink or two makes him feel much better.

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• The presence of drug-related stimuli can start
  cravings and drug-seeking behavior.
• Stressful situations can cause former drug
  addicts to relapse.
• These effects have been observed in rats that had
  previously learned to self-administer cocaine or
  heroin.

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• For example, put new rats with rats that had been
  trained to win fights.
• After being defeated by the fighting rats, the
  socially stressed rats became more sensitive to
  the effects of cocaine and showed
  self-administration of larger amounts of the drug.

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• Stress that occurs early in life can have
  long-lasting effects.
• Infant rats were stressed by isolating them from
  their mothers and littermates for one hour per
  day for eight days.
• When these rats were given the opportunity in
  adulthood to inject themselves with cocaine, they
  quickly acquired the habit and took more of the
  drugs than did control rats that had not been
  stressed.

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• An important link between stressful experiences
  and drug craving is provided by corticotropin
  releasing hormone, or CRH.

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• CRH helps make bad effects on health produced by
  stress, and helps development of anxiety
  disorders.
• Just as giving a drug or stimuli previously
  associated with drug-taking behavior can cause
  relapse, so can stressful experiences

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• Summary
• Addictive drugs are those whose reinforcing
  effects are so strong that some people who are
  exposed to them dont like not taking the drugs
  and whose lives become organized around taking
  them.
• Fortunately, most people who are exposed to drugs
  do not become addicted to them.

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• If a person regularly takes some addictive drugs,
  the effects of the drug show tolerance, and the
  person must take increasing doses to get the same
  effect.
• If the person then stops taking the drug,
  withdrawal effects, opposite to the primary
  effects of the drug, will occur.
• However, withdrawal effects are not the cause of
  addiction the addiction of a drug is related to
  its ability to reinforce drug-taking behavior.

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• The drugs themselves change the brain in complex
  ways, leading to symptoms of addiction.
• The brain regions that are changed by drugs
  include the brain reward system as well as brain
  regions involved in executive functions and
  judgment.
• These brain systems control behavior and are used
  in making decisions.

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• The process of becoming addicted is influenced by
  many factors.
• Genetic susceptibility and environmental factors,
  such as stress, alter the way that people respond
  to drugs.
• The types of the drugs themselves, how quickly
  they enter the brain, also play a role in
  addiction.

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• The development of tolerance the progressive
  need for a higher drug dose to achieve the same
  effect varies in different people, as does drug
  dependence the adaptive physiological state
  that results in withdrawal symptoms when drug use
  stops.

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• Tolerance and dependence are standard responses
  of the brain and body to the presence of drugs.
• However, addiction requires that these occur
  while a motivational form of dependence the
  feeling that a person cant live without a drug
  also is developing.

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• It is important to understand how these many
  factors interact to push individuals to
  addiction and how to protect them.
• This understanding will lead to new therapies.

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• Not all drugs increase dopamine levels in the
  brain in the same way.
• Some substances imitate natural neuromediators
  and take their place on their receptors.
  Morphine, for example, binds to the receptors for
  endorphin (a natural "morphine" produced by the
  brain), while nicotine binds to the receptors for
  acetylcholine.

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• Other substances increase the secretion of
  natural neuromediators. Cocaine, for example,
  mainly increases the amount of dopamine in the
  synapses, while ecstasy mainly increases the
  amount of serotonin.
• Still other substances block a natural
  neuromediator. Alcohol, for example, blocks the
  NMDA receptors. 

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• Alcohol
• Nearly 14 million people (US) abuse alcohol or
  are alcoholic.
• Fetal alcohol syndrome, affecting about 0.5 to 3
  of every 1,000 babies born in the United States,
  is the leading preventable cause of mental
  retardation.
• Cirrhosis and other liver diseases are
  responsible for more than 25,000 deaths each
  year.
• The annual cost of alcohol abuse and addiction is
  estimated at 185 billion.

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• Alcohol activates the endogenous opioid system so
  that susceptible individuals may feel an opioid
  like euphoria from their own endorphins when they
  drink.
• Opiate receptors are involved in the
  dopamine-reward activation of alcohol.
• Naltrexone, a medication developed for heroin
  addiction, is used to treat alcoholics.

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• Here is an animation of the effects of alcohol.
• http//thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03
  _m_par/i_03_m_par_alcool.htmldrogues
• Describe what happens and suggest why.

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• Ethanol, the active ingredient in alcoholic
  beverages, reduces anxiety, tension, and
  inhibitions.
• In low doses, it may act as a stimulant, whereas
  at higher doses, it acts as a depressant.
• It alters mood and behavior.
• It can also cause heat loss and dehydration.

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• The drug, which is easily absorbed into the
  bloodstream and the brain, affects several
  neurotransmitter systems.
• Alcohols interaction with the gamma-aminobutyric
  acid (GABA) receptor can calm anxiety, impair
  muscle control, and delay reaction time.

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• At higher doses, alcohol also decreases the
  function of N-methyl-d-aspartate (NMDA) receptors
  that recognize the neurotransmitter glutamate.
• This interaction can cloud thinking and
  eventually lead to coma.

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• Nicotine
• In 2003, more than 70 million people smoked, at
  least occasionally, making nicotine one of the
  most widely abused substances.
• Tobacco kills more than 430,000 U.S. citizens
  each year more than alcohol, cocaine, heroin,
  homicide, suicide, car accidents, fire, and AIDS
  combined.

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• Tobacco use is the leading preventable cause of
  death in the United States.
• Smoking is responsible for approximately 7
  percent of total U.S. health-care costs, an
  estimated 80 billion each year.
• The direct and indirect costs of smoking are
  estimated at more than 138 billion per year.

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• In Korea, the major preventable health problem is
  tobacco.
• The smoking rate for women was the lowest in the
  OECD area in 2007 at 5, the rate for men was the
  third highest at 47.

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• Smoking is associated with high rates of lung and
  stomach cancer, making a significant cost for
  Korea.
• The estimated cost of diseases due to smoking in
  Korea in 2001 was a total of 3.92 trillion won
  3.72 trillion won for males and 0.20 trillion won
  for females.

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• Nicotine acts through the cholinergic nicotinic
  receptor.
• Nicotine can act as both a stimulant and a
  sedative.
• Nicotine stimulates the adrenal glands, and the
  resulting discharge of epinephrine causes a
  sudden release of glucose with an increase in
  blood pressure, respiration, and heart rate.

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• Nicotine also suppresses insulin output from the
  pancreas, which means that smokers are always
  slightly hyperglycemic.
• In addition, nicotine releases dopamine in the
  brain regions that control motivation, which is
  one reason that people continue to smoke.

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• Here is an animation of the effects of nicotine
• http//thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03
  _m_par/i_03_m_par_nicotine.htmldrogues

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• Replacements, such as nicotine gum, transdermal
  patches, nasal sprays, and inhalers are equally
  effective in treating nicotine addiction.
• These are used to relieve withdrawal symptoms and
  produce less severe problems than tobacco-based
  systems.

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• The first non-nicotine prescription drug,
  bupropion, an antidepressant, has been approved
  for use as a pharmacological treatment for
  nicotine addiction.

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• Varenicline for smoking cessation, directly
  interacts with the cholinergic nicotinic receptor
  and prevents nicotine from activating the brains
  reward circuit.
• Varenicline is a good example of how basic
  science research can lead to the production of
  new medications.

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• HOW COCAINE AFFECTS THE BRAIN
• The basis for increased pleasure occurs at the
  synapse.
• Dopamine-containing neurons normally relay their
  signals by releasing dopamine into many synapses.
  
• Dopamine crosses the synapse and fits into
  receptors on the surface of the receiving cell.
• This triggers an electrical signal that is
  relayed through the receiver.

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• Then, to end the signal, dopamine molecules break
  away from the receptors and are pumped back into
  the nerve terminals that released them.
• Cocaine molecules block the pump or
  transporter, causing more dopamine to
  accumulate in the synapse.
• Pleasure circuits are stimulated again and again,
  producing euphoria.

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• Cocaine effects
• http//thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03
  _m_par/i_03_m_par_cocaine.htmldrogues