Drugs, Addiction, and Reward

1
CHAPTER 16

• Drugs, Addiction, and Reward
• Psychoactive Drugs

2
Psychoactive Drugs

• Drug a substance that on entering the body
  changes the body or its functioning.
• An agonist mimics or enhances the effect of a
  neurotransmitter.
• An antagonist may occupy the receptors without
  activating them, simultaneously blocking the
  transmitter from binding to the receptors.
• Psychoactive drugs are those that have
  psychological effects, such as anxiety relief or
  hallucinations.

3
Psychoactive Drugs opiates

• Opiates
• derived form the opium poppy.
• Can also be synthetically made
• Act on opiate receptors or endorphin receptors
• Several important effects
• analgesic (pain relieving)
• hypnotic (sleep inducing)
• produce a strong euphoria (sense of happiness of
  ecstasy).
• Types of opiates
• Morphine pain relief, surgical pain relief,
  cancer
• Derivatives include codeine, vicodin, oxycotin,
  etc...
• Heroin
• synthesized from morphine
• marketed as an over-the-counter analgesic until
  its dangers were recognized
• now it is an illegal drug in the U.S.

4
Opiate drug action

• Endorphins
• body produces its own natural opiates, which are
  neuromodulators
• Released when in pain, motor exertion, stress
• Endogenous opiates
• Endogenous made by the body.
• Opiate drugs are effective because they mimic
  endorphins
• Because of CNS effects and cognitive effects,
  very high likelihood of abuse.

5
Psychoactive drugs the depressants

• Depressants
• drugs that reduce central nervous system
  activity.
• Sedatives calming drugs
• Barbiturates including amobarbital (Amytal)
  pentobarbital (Nembutal) secobarbital (Seconal)
  and Phenobarbitol (Luminal)
• Anxiolytic anxiety-reducing drugs
• Benzodiazepines ("minor tranquilizers") including
• Klonopin diazepam (Valium) estazolam (Prosom)
  flunitrazepam (Rohypnol) lorazepam (Ativan)
  midazolam (Versed) nitrazepam (Mogadon)
  oxazepam (Serax) triazolam (Halcion)
  ttemazepam (Restoril , Normison, Planum Tenox,
  Temaze) chlordiazepoxide (Librium)

6
Psychoactive drugs the depressants

• Hypnotic drugs induce sleep-like states
• Nonbenzodiazepines
• Zolpidem Zaleplon Zopiclone Eszopiclone
• Antihistamines
• Diphenhydramine Doxylamine Hydroxyzine
  Promethazine
• Others
• gamma-hydroxybutyric acid (Xyrem)
• Glutethimide
• Chloral hydrate
• Ethchlorvynol
• Levomepromazine
• Chlormethiazole

7
Sedative effects on cns

• Barbiturates
• Suppress inhibitory centers
• in small amounts act selectively on higher
  cortical centers, especially those involved in
  inhibiting behavior
• In low doses
• produce talkativeness
• increased social interaction,
• Higher doses
• sedatives and hypnotics.
• Barbiturates do not reduce pain, but they do
  reduce the anxiety associated with pain.
• Barbiturates produce their effects by decreasing
  glutamate activity and increasing GABA activity.
• They operate at the barbiturate receptor on the
  GABAA complex.

8
Benzodiazepines- an alternative to barbiturates?

• A few decades ago
• Barbiturates drug of choice for treating
  anxiety
• Also as most common drug for situations requiring
  sedation.
• BUT high liability
• potential for addiction
• High rate of accidental or intentional death.
• Benzodiazepines largely replaced barbiturates
• produce anxiety reduction,
• Also induce sedation and muscle relaxation.
• operate at the benzodiazepine receptor on the
  GABAA complex.
• At first, thought non-addictive
• Today know that are highly addictive

9
Psychoactive drugs Alcohol

• Ethanol, or alcohol
• is a drug
• fermented from fruits, grains, and other plant
  products.
• Is a DEPRESSANT
• It acts at many brain sites to produce euphoria,
  anxiety reduction, sedation, motor
  incoordination, and cognitive impairment
• Why is it a depressant?
• Depresses CNS
• Inhibits areas of the brain that inhibit acting
  out, inappropriate behavior, etc..

10
How does alcohol affect the CNS?

• Alcohol inhibits the release of glutamate (the
  most prevalent excitatory neurotransmitter).
• glutamate reduction produces a sedating effect
• Chronic use results in a compensatory increase
  in glutamate receptors,
• probably accounts for the seizures that sometimes
  occur during withdrawal.
• Alcohol also increases the release of
  gamma-aminobutyric acid (GABA
• the most prevalent inhibitory neurotransmitter).
• Alcohol specifically affects the A subtype of
  GABA receptor.
• The combined effect at these two receptors is
• sedation,
• anxiety reduction,
• muscle relaxation,
• inhibition of cognitive and motor skills.

11
(No Transcript)
12
Alcohol abuse effects

• Cirrhosis of the liver,
• Common side effect of chronic alcoholism
• in its severest form is fatal.
• Vitamin B1 deficiency
• associated with chronic alcoholism
• can produce brain damage and Korsakoffs syndrome
• Korsakoffs syndrome
• Neurological syndrome due to alcohol damage, B1
  deficiency
• involves severe memory loss along with sensory
  and motor impairment.
• Alcohol withdrawal symptoms
• involves tremors, anxiety, and mood and sleep
  disturbances
• Delirium tremors
• more severe reactions
• hallucinations, delusions, confusion, and in
  extreme cases, seizures
• possible death.

13
(No Transcript)
14
Psychoactive stimulants

• Stimulants
• activate the central nervous system to produce
• arousal,
• increased alertness,
• elevated mood
• Typically affect dopamine, norepinephrine and
  serotonin
• Several drugs in this category
• Cocaine
• Amphetamine
• Methamphetamine
• Ritalin
• Adderal,
• Most ADHD medications
• Ephedrine

15
Psychoactive stimulants

• Cocaine,
• extracted from the South American coca plant,
• produces
• Euphoria
• decreases appetite,
• increases alertness
• relieves fatigue.
• Cocaine blocks the reuptake of dopamine and
  serotonin at synapses,
• Potentiating effect of these neurotransmitters
• Makes neurotransmitter remain longer in synapse.
• Presumably, cocaine produces euphoria and
  excitement because dopamine removes the
  inhibition the cortex usually exerts on lower
  structures.

16
Cocaine user
Normal
17
Psychoactive Drugs

• Amphetamines
• group of synthetic drugs
• Again produce euphoria
• increase confidence
• concentration.
• increase the release of norepinephrine and
  dopamine
• Common examples
• Amphetamine (Adderal) Dextroamphetamine
  (Dexedrine, Dextrostat)
• Methamphetamine (Desoxyn)
• Highly relatedRitalin
• Ritalina, Rilatine, Attenta, Methylin, Penid,
  Rubifen) and the sustained release tablets
  Concerta, Metadate CD, Methylin ER, Ritalin LA,
  and Ritalin-SR. Focalin

18
Amphetamine Action

• DA neurons release DA into the synapse From
  there 1 of 3 things can happen
• DA can then attach to the post-synaptic membrane
• DA can be degraded by enzymes
• DA can be taken back up by the pre-synaptic
  membrane.
• Amphetamine appears to affect all three
  mechanisms
• Promotes release of DA into the synapse
• Inhibits the DA degredative enzyme, monoamine
  oxidase (MAO),
• Blocks the uptake proteins in the pre-synaptic
  membrane
• The result Amphetamine effectively promotes a
  flood of DA into the brain reward center
• Nucleus Accumbens or Nac
• This area is highly involved in both learning and
  reward.

19
Amphetamine Action

• Amphetamine and related compounds elicit a
  variety of dose-dependent deleterious effects.
• low doses of AMPH may improve attention and
  vigilance
• improve vigilance
• At high doses over-stimulation of the motor and
  cognitive systems
• behavioral stereotypy, repetitive thoughts and
  even hallucinations.
• In rodents, a high AMPH dose elicits behavioral
  stereotypy
• continuous digging Searching Licking Gnawing
  Circling
• In humans, high doses of AMPH may elicit
• psychotic state,
• High rates of locomotion and repetitive behavior
• high potential for self-injury or injury to
  others

20
A normally moving rat
21
A rat given 8.0 mg/kg amphetamine
22
Psychoactive Drugs Nicotine

• Nicotine
• primary psychoactive and addictive agent in
  tobacco
• Also in chewing tobacco, nicotine gum, etc.
• It stimulates nicotinic acetylcholine receptors.
• In the periphery,
• it activates muscles
• may cause twitching.
• In CNS
• produces increased alertness
• Also faster response to stimulation.

23
Psychoactive Drugs Caffeine

• Caffeine
• active ingredient in coffee, many soda pops
  teas energy drinks, etc.
• produces arousal, increased alertness, and
  decreased sleepiness.
• Action blocks receptors for the neuromodulator
  adenosine
• This increases the release of dopamine and
  acetylcholine.
• Because adenosine has sedative and depressive
  effects, blocking its receptors contributes to
  arousal
• Acts like amphetamine in releasing DA.

24
Psychodelic Drugs

• Psychedelic drugs
• compounds that cause perceptual distortions in
  the user.
• May be referred to as hallucinogenic
• Not really inducing hallucinations, but
  distortions in perception
• Light and color details are intensified,
• objects may change shape,
• sounds may evoke visual experiences,
• light may produce auditory sensations.

25
Psychoactive Drugs

• lysergic acid diethylamide (LSD)
• best-known psychedelic
• is structurally similar to serotonin
• stimulates serotonin receptors
• Appears to disrupt the brain stems ability to
  screen out irrelevant stimuli.
• psilocybin and psilocin
• Another serotonin-like psychedelics
• both derived from the mushroom, Psilocybe
  mexicana
• Mescaline
• the active ingredient in peyote (the crown or
  button on the top of the peyote cactus),
• psychedelic properties result from stimulation of
  serotonin receptors.

26
Psychoactive Drugs Ecstasy

• Ecstasy
• street name for a drug developed as a weigh-loss
  compound
• methlenedioxymethamphetamine (MDMA).
• At low doses
• psychomotor stimulant
• Increases energy, sociability, and sexual
  arousal.
• At higher doses
• produces hallucinatory effects like LSD.
• Also can overstimulate muscles resulting in
  locked or frozen muscles
• MDMA stimulates
• the release of dopamine which accounts for muscle
  and arousal effects
• the release of serotonin, which probably accounts
  for the hallucinatory effects.

27
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.
28
Psychoactive Drugs PCP

• Phencyclidine (PCP)
• Developed as an anesthetic typically used by
  veterinarians
• was abandoned for human use because it produces
  schizophrenia-like disorientation and
  hallucinations.
• PCP increases activity in the dopamine pathways
• This stimulates motivation system
• Also, drugs motivating properties apparently are
  partly due to its inhibition of a subtype of
  glutamate receptors.

29
marijuana

• Marijuana
• is the dried and crushed leaves and flowers of
  the Indian hemp plant, Cannabis sativa.
• The major psychoactive ingredient is
  delta-9-tetrahydrocannabinol (THC)
• .
• THC actions
• THC binds with cannabinoid receptors, which
  ordinarily respond to endogenous cannabinoids.
• Two known cannabinoids receptors
• anadamide
• 2-arachidonyl glycerol, or 2-AG.
• These receptors are found on axon terminals
• Unusual action
• cannabinoids are released by postsynaptic neurons
  
• act as retrograde messengers, regulating the
  presynaptic neurons release of neurotransmitter.

30
Addiction

• Reward refers to the positive effect an object or
  condition such as a drug, food, sexual contact,
  and warmth has on the user.
• Drug researchers have traditionally identified
  the mesolimbicortical dopamine system as the
  location of the major drug reward system.
• It takes its name from the fact that it begins in
  the midbrain (mesencephalon) and projects to the
  limbic system and prefrontal cortex.
• The most important structures in the system are
  the nucleus accumbens, the medial forebrain
  bundle, and the ventral tegmental area.

31
Virtually all the abused drugs increase dopamine
levels in the nucleus accumbens
32
Psychoactive Drugs

• Addiction
• preoccupation with obtaining a drug
• compulsive use of the drug in spite of adverse
  consequences
• high tendency to relapse after quitting
• Typically defined as an individual showing both
  withdrawal and tolerance.
• Withdrawal
• negative reaction that occurs when drug use is
  stopped
• Bodys compensatory reaction.
• Tolerance
• individual becomes less responsive to the drug
• requires increasing amounts of the drug to
  produce the same results.

33
Addiction

• Societal definition
• obsession, compulsion, or excessive physical
  dependence or psychological dependence,
• E.g., drug addiction, alcoholism, compulsive
  overeating, problem gambling, computer addiction,
  pornography, etc.
• Scientific definition of Addiction A state in
  which
• the body relies on a substance for normal
  functioning and develops physical dependence
• When the drug or substance on which someone is
  dependent is suddenly removed, it will cause
  withdrawal,
• increased drug tolerance.
• However, common usage spread to include
  psychological dependence, but brain doesnt
  recognize this distinction

34
Addiction

• Addiction and withdrawal take place in different
  parts of the brain and are independent of each
  other.
• The ventral tegmental area is suggested to be
  involved in addiction,
• Periventricular gray area produces classic signs
  of withdrawal.
• Not mean that addicts never take drugs to avoid
  withdrawal symptoms,
• Means that withdrawal is not necessary for
  addiction and avoidance of withdrawal is not an
  explanation of addiction.

35
Addiction pathways
36
Addiction involves Dopaminergic pathway

• mesolimbicortical dopamine system
• Major reward system
• Many drugs (especially stimulants) mimic effects
  of normal reward.
• begins in the midbrain (mesencephalon) and
  projects to the limbic system and prefrontal
  cortex.
• The most important structures in the system
• nucleus accumbens
• medial forebrain bundle
• ventral tegmental area.

37
Reward and the Dopaminergic pathway

• Schultz (2005) and others show
• Dopamine is not released as a reward
• Dopamine is a motivating neurotransmitter-
  produces increases in locomotion, action behavior
  that is oriented towards reward
• Thus when dopamine released, body moves towards
  or continues doing whatever it was doing to keep
  getting that Reward
• General DA reward system serves as feedback
  system that identifies
• need to continue or shift behavior depending on
  reward situation
• Helps select the appropriate response for the
  situation

38
Changing behavior with DA agonists

• Virtually all the abused drugs increase dopamine
  levels in the nucleus accumbens.
• Electrical stimulation of the brain (ESB),
• Stimulate Nucleus accumbens
• Animals press a level or engage in high rates of
  locomotion immediately after receiving
  stimulation
• Why? DA release elicits search behavior
• A reinforcer is any object or event that
  increases the probability of the response that
  precedes it
• Thus, must keep doing the behavior that got you
  the reinforcer
• DA maintains ongoing responses or kicks you into
  movement behaviors that increase likelihood of
  reward.

39
Changing behavior with DA agonists

• Think of symptoms of stimulant abuse/addiction
• Lots of motor movement
• Lots of perseverative motor behavior
• Nose wiping
• Tics
• Perseveration
• Paranoia is highly similar to schizophrenia
• Why? Too much dopamine is overstimulating
  circuits, cognitive areas of brain are
  hyperstimulated.
• What got you these feelings- the drug
• What do to keep these feelings- get more drug
• And, because you have replaced normal DA levels,
  now you will engage in seeking behaviors to
  maintain those levels!

40
Diminished dopamine?

• Chronic drug users show diminished DA release
  from DA receptors
• May be individual, and not the addiction
• Lower levels of D2 autoreceptors
• Note that those with high number of D2
  autoreceptors find DA drugs unpleasurable those
  with fewer report more pleasure
• D2 autoreceptors help regulate general DA tone in
  synapse, regulate reuptake and production of DA
• Thus, may be that DA-drug addicts have reward
  deficiency syndrome insufficient receptors to
  respond to DA, need more DA to get same effect

41
Step down reflex

• Addiction learning
• Learning produces changes in the brain
• Addiction produces same changes
• Drug release of DA
• US(drug)? UR(drug effects)
• Stimulus (CS) predicts drug that releases DA
• CS(cue? US(drug)? UR(drug effects)
• Anticipate DA release BUT Body prefers
  homeostasis no sudden changes, maintain level
• CS(cue? US(drug)? UR(drug effects)
• \
• ?CR(decrease DA release in anticipation of drug
  DA release)
• Thus body REDUCES dopamine in ANTICIPATION of
  increase in DA

42
Compensation tolerance and withdrawal

• Body REDUCES dopamine in ANTICIPATION of increase
  in DA
• No longer get same effect for drug
• Must take more
• This is called tolerance
• If stop taking the drug, no step-down reflex or
  compensation
• Now, reduction in DA
• Now have too little DA shaky, motor tremors,
  etc.
• This is called withdrawal Setting cues are
  critically important

43
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.
44
Evidence for Addiction?

• Nora Volkow and her colleagues, among others
• Transition from controlled drug use to compulsive
  drug intake involves pathological changes in
  communication between prefrontal cortex and the
  nucleus accumbens.
• addict returns to drug taking when stress or
  drug-related stimuli trigger increases in
  dopamine release in the prefrontal cortex and
  glutamate release in the nucleus accumbens.
• Prefrontal release produces a compulsive focus on
  drugs at the expense of other reinforcers
• Glutamate release cranks up the drive to engage
  in drug seeking.

45
Treating Addiction

• Agonist treatments replace an addicting drug with
  another drug that has a similar effect.
• Opiate addiction is often treated with a
  synthetic opiate called methadone.
• Antagonist treatments involve drugs that block
  the effects of the addicting drugs.
• Drugs that block opiate receptors are used to
  treat opiate addictions and alcoholism because
  they reduce the pleasurable effects of the drug.
• Antabuse for alcohol
• Another experimental strategy is to interfere
  with the dopamine reward system.
• Baclofen reduces dopamine activity in the ventral
  tegmental area by activating GABAB receptors on
  dopaminergic neurons.

46
(No Transcript)
47
The Role of Genes in Addiction

• If genetics plays such an important role in
  addiction, just what is inherited?
• Most research on the genetics of addiction
  implicates various neurotransmitter systems.
• Appears to be a syndrome or related group of
  dysfunction
• Addicts correlated with individuals who have
  family members with
• Schizophrenia, bipolar disorder, depression
• ADHD and related disorders
• Autism and autism-spectrum disorders.

48
The Role of Genes in Addiction

• Dopamine is one of the factors differentiating
  addictive from normal behavior.
• There are several alleles, or alternate forms, or
  the gene responsible for the development of the
  D2 subtype of dopamine receptor.
• Various alleles are associated with alcoholism,
  cocaine dependence, stimulant abuse, and multiple
  addictions.
• Serotonin is involved in drug abuse in general
• Also in mood,
• sexual behavior,
• aggression,
• the regulation of bodily rhythms and food and
  water intake.
• Bottom line May have a predisposition
• Stress bring out or turns on different coping
  mechanism
• Best way to avoid reduce stress avoid
  situations with drug availability

49
A Societal comment on drug usage from the onion!

• And now for something absolutely silly!
• http//www.theonion.com/content/video/fda_approves
  _depressant_drug_for