Drugs and Behavior October 11th, 2006

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Drugs and BehaviorOctober 11th, 2006

• Synaptic Communication
• Steps in neurotransmission
• Neurotransmitters
• Drug Administration and Distribution
• Routes of Administration
• Distribution
• Metabolism
• Mechanisms of Drug Action
• Receptors and sites of drug action
• Agonists
• Antagonists
• Tolerance and Withdrawal
• Physiological Tolerance
• Psychological Tolerance the role of learning
• Classes of Drugs

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Synaptic Communication

• Release of neurotransmitter
• Exocytosis
• Release
• Binding
• Deactivation

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Synaptic Communication

• Binding Revisited - Receptor Types
• Ionotropic
• Metabotropic

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Synaptic Communication

• Receptor Types
• Ionotropic
• Example acetylcholine

http//www.blackwellpublishers.co.uk/matthews/neur
otrans.html
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Synaptic Communication

• Receptor Types
• Ionotropic
• Example acetylcholine
• Meatobotropic
• Example norepinephrine

http//www.blackwellpublishing.com/matthews/neurot
rans.html
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Synaptic Communication

• Inhibitory Receptors
• Example GABA

http//www.blackwellpublishing.com/matthews/neurot
rans.html
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Synaptic Communication

• Neurotransmitter synthesis
• Classes of Neurotransmitters

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Synaptic Communication

• Neurotransmitter synthesis
• Classes of Neurotransmitters
• Synthesis

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Drugs and Behavior

• What is a drug?

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Drug Administration and Distribution
Where do drugs act to affect behavior? How do
they get there? How are the eliminated?
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Drug Administration and Distribution
Where do drugs act to affect behavior?
The synapse..
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Drug Administration and Distribution
How do they get there?
The blood..
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Drug Administration and Distribution

• How do they get there?
• Routes of administration
• Oral
• Inhalation
• Intranasal
• Transdurmal
• Intravenous
• Intramuscular
• Subcutaneous

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Drug Administration and Distribution

• How do they get there?
• Routes of administration
• Oral
• Inhalation
• Intranasal
• Transdurmal
• Intravenous
• Intramuscular
• Subcutaneous

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Drug Administration and Distribution

• How are they eliminated?
• Metabolism
• Liver enzymes
• Enzymes in the brain

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Mechanisms of Drug Action
A Reminder Synaptic Transmission
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Mechanisms of Drug Action

• Receptors and sites of drug action
• Categories of Neurotransmitters

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Mechanisms of Drug Action

• Receptors and sites of drug action
• Categories of Neurotransmitters
• What defines a neurotransmitter?

• A neurotransmitter is defined as a substance
• that is synthesized in the neuron.
• that is released in a quantity sufficient to
  produce an effect on the post synaptic neuron.
• where there is a mechanism for terminating its
  action.
• whose effect can be mimicked by activating its
  receptors.

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Mechanisms of Drug Action

• Receptors and sites of drug action
• Categories of Neurotransmitters
• What defines a neurotransmitter?
• Where are they located in the brain?

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Mechanisms of Drug Action

• Receptors and sites of drug action
• Categories of Neurotransmitters
• What defines a neurotransmitter?
• Where are they located in the brain?

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Mechanisms of Drug Action
Receptors and sites of drug action
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Mechanisms of Drug Action
Receptors and sites of drug action Agonists
mimic the effect of the endogenous
neurotransmitter
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Mechanisms of Drug Action
Receptors and sites of drug action Antagonists
block the effect of the endogenous
neurotransmitter
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Mechanisms of Drug Action
Receptors and sites of drug action
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Tolerance and Withdrawal

• Tolerance
• More drug needed to achieve the same effect
• Metabolic Tolerance
• Functional Tolerance
• Cross Tolerance
• Sensitization

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Tolerance and Withdrawal

• Withdrawal
• Adverse effects of discontinuing drug use

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Tolerance and Withdrawal
Withdrawal from Alcohol

• Mild to moderate psychological symptoms
• Feeling of jumpiness or nervousness
• Feeling of shakiness
• Anxiety
• Irritability or easily excited
• Emotional volatility, rapid emotional changes
• Depression
• Fatigue
• Difficulty with thinking clearly
• Bad dreams
• Mild to moderate physical symptoms
• Headache - general, pulsating
• Sweating, especially the palms of the hands or
  the face
• Nausea
• Vomiting
• Loss of appetite
• Insomnia, sleeping difficulty
• Paleness

• Severe symptoms
• A state of confusion and hallucinations (visual)
  -- known as delirium tremens
• Agitation
• Fever
• Convulsions
• "Black outs" -- when the person forgets what
  happened during the drinking episode

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Tolerance and Withdrawal
Withdrawal from Cocaine
depressed mood fatigue generalized malaise vivid
and unpleasant dreams agitation and restless
behavior slowing of activity increased
appetite craving suicidal thoughts (in some
people)
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Tolerance and Withdrawal
Withdrawal from Heroin
elevation in blood pressure elevation in
elevation in pulse, elevation in respiratory
rate elevation in body temperature. goose
bumps watery eyes runny nose Yawning loss of
appetite Tremors panic chills Nausea muscle
cramps Insomnia depression
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Tolerance and WithdrawalPsychological Effects
and the role of Learning
Withdrawal from Heroin
Effects of Heroin
increase pain sensitivity elevation in blood
pressure elevation in elevation in
pulse elevation in respiratory rate elevation in
body temperature. loss of appetite Insomnia depre
ssion
decrease pain sensitivity decrease in blood
pressure decrease in pulse decrease in
respiratory rate decrease in body temperature
increase appetite wakefulness euphoria

• Users
• administer larger doses in drug-associated
  environments (increased tolerance).
• are more likely to overdose in unfamiliar
  environments.
• experience more intense craving in in
  drug-associated environments.
• the case of returning Vietnam veterans

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Tolerance and WithdrawalPsychological Effects
and the role of Learning
Withdrawal from Heroin
Effects of Heroin
increase pain sensitivity elevation in blood
pressure elevation in elevation in
pulse elevation in respiratory rate elevation in
body temperature. loss of appetite Insomnia depre
ssion
decrease pain sensitivity decrease in blood
pressure decrease in pulse decrease in
respiratory rate decrease in body temperature
increase appetite wakefulness euphoria

• In rats
• maximum tolerance to morphine is found in the
  drug-associated environment (Adams et al, 1969).
• rats given the usual dose of morphine but in an
  unfamiliar environment, overdose (Seigel, 1977).
• rats will show more withdrawal in the environment
  where morphine was consistently administered
  (Falls et al, 1989).

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Pavlovian Conditioning
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Pavlovian Conditioning
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Pavlovian Conditioning
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Pavlovian Conditioning
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Acquisition of Conditioned Salivation
Pavlovian Conditioned Salivation
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Drops of Saliva Occurring During the
Tone CS
10
5
0
1
2
3
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5
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Trial Number (tonefood pairing)
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Pavlovian Drug Conditioning
Conditional Stimulus (environment)

reduced pain!
Unconditional Response (pain reduction)
Unconditional Stimulus (morphine)
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Pavlovian Drug Conditioning
Conditioning
Testing
Conditional Stimulus (environment)
Conditional Stimulus (environment)

How much pain relief does that dose of morphine
produce?
Unconditional Stimulus (morphine)
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Pavlovian Drug Conditioning
Conditioning
Testing
Conditional Stimulus (environment)
(Neutral Environment)

Unconditional Stimulus (morphine)
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Pavlovian Drug Conditioning
Conditional Stimulus (environment)
Increased pain!
Conditional Response (increased pain sensitivity)
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Pavlovian Drug Conditioning
Testing
Conditional Stimulus (environment)

saline
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Pavlovian Drug Conditioning
Conditional Stimulus (environment)
Conditional Response
increase pain sensitivity elevation in blood
pressure elevation in elevation in
pulse elevation in respiratory rate elevation in
body temperature. loss of appetite Insomnia depre
ssion
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Classes of Drugs

• Stimulants
• Caffeine
• Nicotine
• Amphetamine
• Cocaine
• Depressants (sedatives)
• Alcohol
• Barbiturates
• Anxiolytic drugs
• Valium
• Buspar

• Narcotics
• Morphine
• Codeine
• Heroin
• Methadone
• Demerol
• Fentanyl
• Hallucinogens
• LSD
• Marijuana
• Mescaline
• MDMA
• Ketamine

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Classes of Drugs

• Stimulants
• Caffeine adenosine agonist
• Nicotine acetylcholine agonist
• Amphetamine dopamine agonist
• Cocaine dopamine agonist
• Depressants (sedatives)
• Alcohol GABA agonist and glutamate antagonist
• Barbiturates glutamate antagonist
• Anxiolytic drugs
• Valium GABA agonist
• Buspar serotonin agonist

• Narcotics
• Morphine opiate agonists
• Codeine
• Heroin
• Methadone
• Demerol
• Fentanyl
• Hallucinogens
• LSD serotonin agonist
• Marijuana cannabiniod agonist
• Mescaline serotonin agonist
• MDMA serotonin agonist
• Ketamine glutamate antagonist

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Cocaine
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CocaineBehavioral Effects
Short-term Effects Increased energy Decreased
appetiteMental alertnessIncreased heart rate
and blood pressureConstricted blood
vesselsIncreased temperatureDilated pupils
Long-term Effects AddictionIrritability and
mood disturbancesRestlessnessParanoiaAuditor
y hallucinations
Medical Complications disturbances in heart
rhythm heart attacks chest pain respiratory
failure strokes seizures and headaches
abdominal pain nausea
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CocainePhysiological Effects
Cocaine blocks the reuptake of dopamine. As a
consequence, dopamine stays in the synapse longer.
cocaine
http//abdellab.sunderland.ac.uk/lectures/addictio
n/animations/DrugsOnDA/index.html
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Behavioral Effects of DADrug Abuse
Dopamine Pathways in the Brain
Drug effects on the Dopamine Synapse
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Behavioral Effects of DADrug Abuse

• Olds and Milner (1954) showed that rats would
  administer bursts of electrical stimulation to
  their own brains. This phenomenon was termed
  intracranial self-stimulation (ICSS)
• Many sites throughout the brain supported ICSS
  including the hypothalamus, septum and nucleus
  accumbens and ventral tegmentum.

• Rats would undergo painful stimulation to receive
  ICSS.
• Rats would press a lever thousands of times an
  hour, suggesting a very powerful motivation for
  pressing.
• Olds and Milner argued that the brain sites
  supporting ICSS were those that normally mediated
  the pleasurable effects of natural rewards.

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Behavioral Effects of DADrug Abuse

• However..
• Rats stop pressing the lever when the electrical
  current is shut off.
• Self-stimulation did not start immediately after
  the current is turned back on. Rats needed to be
  primed.

Because rats pressing a lever for food, water or
sex extinguish slowly and do not need to be
primed, Olds and Milners interpretation of ICSS
was challenged.. .. But, if rats WERE NOT food
or water deprived, the differences between ICSS
and natural reinforcers disappeared.
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Behavioral Effects of DADrug Abuse

• The Contribution of Dopamine to ICSS..
• .
• Many areas that support ICSS are close to or
  within the mesolimbic and mesolimbocortical
  pathways this pathway passes through the medial
  forebrain bundle, the most effective site for
  ICSS.

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Behavioral Effects of DADrug Abuse

• The Contribution of Dopamine to ICSS..
• .
• Many areas that support ICSS are close to or
  within the mesolimbic and mesolimbocortical
  pathways this pathway passes through the medial
  forebrain bundle, the most effective site for
  ICSS.
• ICSS produces an increase in DA release in the
  striatum, particularly the nucleus accumbens.

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Behavioral Effects of DADrug Abuse

• The Contribution of Dopamine to ICSS..
• .
• Many areas that support ICSS are close to or
  within the mesolimbic and mesolimbocortical
  pathways.
• ICSS produces an increase in DA release in the
  striatum, particularly the nucleus accumbens.
• Dopamine agonists increase ICSS.

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Behavioral Effects of DADrug Abuse

• The Contribution of Dopamine to ICSS..
• .
• Many areas that support ICSS are close to or
  within the mesolimbic and mesolimbocortical
  pathways.
• ICSS produces an increase in DA release in the
  striatum, particularly the nucleus accumbens.
• Dopamine agonists increase ICSS.
• Lesions of the mesolimbocortical pathway
  interfere with ICSS.
• Dopamine antagonists blocked the effects of
  ICSS..

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Behavioral Effects of DADrug Abuse

• The Contribution of Dopamine to reward..
• .
• Dopamine agonists produce conditioned place
  preference.

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CocainePhysiological Effects
Cocaine blocks the reuptake of dopamine. As a
consequence, dopamine stays in the synapse longer.
http//abdellab.sunderland.ac.uk/lectures/addictio
n/animations/DrugsOnDA/index.html
57
CocainePhysiological Effects
Cocaine works in the mesocorticolimbic dopamine
pathway. He projections from the from the
ventral tegumentum to nucleus accumbens play an
important role in cocaine addiction.
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CocainePhysiological EffectsCocaine abusers
have a decrease in DA
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CocainePhysiological EffectsCocaine abusers
have a decrease in DA and a decrease in DA
receptors