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Psychopharmacology

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Title: Psychopharmacology


1
Psychopharmacology
  • The study of the effects of drugs on the nervous
    system and behavior

2
Neurochemistry and psychopharmacology
  • Ligand any substance that will act on a
    receptor
  • Exogenous ligand originating outside the body
  • Endogenous ligand originating within the body
  • Exogenous drugs work on endogenous
    neurotransmitter/modulator systems

3
Psychopharmacology
  • Drug effects
  • The changes a drug produces in an animals
    physiological processes and behavior.
  • Drugs must reach sites of action, where they can
    exert an effect
  • Effectiveness depends on
  • Site of action
  • Affinity
  • Expectations
  • Pharmacokinetics
  • The entry, distribution, metabolisation and
    excretion of drugs through the body.

4
Sites of drug actions
  • Different drugs work at different sites in the
    brain
  • Not ALWAYS as ligands at the post-synaptic
    receptors!
  • All drugs affect synaptic transmission in one of
    two ways
  • Agonists __________ synaptic transmission
  • Antagonists ________ synaptic transmission

5
Effects on production of neurotransmitters
  • In the soma or axon terminal, precursors are
    synthesized into NT
  • Some drugs act as precursors
  • Increase NT production
  • AGONISTS
  • Some drugs inactivate the enzymes required for NT
    synthesis
  • Decrease NT production
  • ANTAGONISTS

6
Effects on storage of neurotransmitters
  • NTs are packaged into vesicles by transporter
    molecules on the vesicles membranes
  • Some drugs inactivate these transporter
    molecules, preventing storage
  • Vesicles are empty no NT is released into the
    synapse
  • ANTAGONISTS

X
7
Effects on release of neurotransmitters
  • Drugs may deactivate the ions that allow the
    vesicle to fuse with the presynaptic membrane
  • Inhibits NT release
  • ANTAGONISTS
  • Other drugs may cause the vesicles to fuse and
    rupture
  • Increases NT release
  • AGONISTS

X
8
Effects on receptors
  • Direct agonists
  • Bind with the postsynaptic receptors and mimic
    the actions of NTs
  • Open ion channels
  • Results in a PSP
  • Direct antagonists
  • Bind with the postsynaptic receptor and block it
  • Do NOT open ion channels
  • Prevent NTs from binding with the receptor

X
9
Effects on receptors
  • Noncompetitive binding drug ligands may bind at
    sites on the receptor that are different from the
    binding sites for NTs
  • Indirect agonists use noncompetitive binding to
    open ion channels
  • Indirect antagonists use noncompetitive binding
    to prevent the opening of ion channels

10
Effect on autoreceptors
  • Autoreceptors on the presynaptic membrane limit
    the amount of NT released
  • Some drugs act on the autoreceptors
  • Drugs that activate the autoreceptor decrease the
    NT released
  • ANTAGONISTS
  • Drugs that block the autoreceptor increase the NT
    released
  • AGONISTS

11
Effects on reuptake or enzymatic deactivation
  • Some drugs work by inactivating the transporter
    molecules responsible for reuptake or by
    deactivating the enzymes that break down NT
  • Keeps the NT in the synapse longer
  • AGONISTS

12
Neurotransmitters Neuromodulators
13
Acetylcholine
  • Excitatory neurotransmitter responsible for
    muscle contractions
  • Neuromuscular junctions
  • Target organs of the parasympathetic nervous
    system

14
Acetylcholine
  • Originates in cell bodies located in
  • Motor neurons
  • Ach originating here controls ______________
  • Pons
  • ACh originating here controls ______________
  • Basal forebrain
  • ACh originating here facilitates ______________
  • Medial septum
  • ACh originating here modulates ______________
  • ACh axons distribute widely throughout the brain

15
Acetylcholine
  • Two types of ACh receptors
  • Nicotinic receptors ionotropic
  • Fast acting
  • Located on muscle fibers and in the CNS
  • Muscarinic receptors metabotropic
  • Slow, prolonged action
  • Located in the CNS and PNS

16
Drug effects on ACh system
  • Botulinum toxin (Botox) - prevents the release of
    Ach
  • Causes paralysis
  • Black widow spider venom - stimulates the release
    of ACh
  • Causes severe muscle contractions
  • Nicotine (tobacco) - stimulates nicotinic
    receptors
  • Increases CNS function
  • Curare (extracted from plants) - blocks nicotinic
    receptors
  • Causes paralysis

17
Drug effects on ACh system
  • Muscarine (found in many mushrooms) - stimulates
    muscarinic receptors
  • Causes convulsions
  • Atropine - blocks muscarinic receptors
  • Nerve block, used to dilate pupils, increase
    heart
  • rate, and decrease lung secretions
  • Neostigmine deactivates AChE, blocking the
    breakdown of ACh in the synapse
  • Results in more ACh remaining in the synapse
  • Used to treat myasthenia gravis

18
Monoamines
  • Major class of compounds
  • Each derived from a single amino acid
  • Two subclasses
  • Catecholamines (derived from tyrosine)
  • Dopamine
  • Norepinephrine
  • Epinephrine (hormone)
  • Indolamines (derived from trytophan)
  • Serotonin
  • Melatonin (hormone)

19
Catecholamines
  • Catecholamies are all synthesized in the same
    process

20
Dopamine
  • DA neurons comprise 3 major
  • systems in the brain
  • Mesostriatal (or nigrostriatal)
  • system originates in the substantia nigra
  • Axons project to the _______________________
  • Mesolimbic system originates in the ventral
    tegmental area
  • Axons project to the _______________________
  • Mesocortical system originates in the ventral
    tegmental area
  • Axons project to the _______________________

21
Dopamine
  • DA is both excitatory and inhibitory, depending
    on the receptors activated
  • All DA receptors are metabotropic
  • There are several types of DA receptors found
    throughout the brain
  • D1 receptors are located only on postsynaptic
    membranes
  • D2 receptors are located on both pre- and
    postsynaptic membranes

22
Drug effects on the DA system
  • Levodopa (L-Dopa) increases DA production
  • Parkinsons treatment
  • Improves motor function
  • Reserpine prevents storage of all monoamines in
    synaptic vesicles
  • Formerly used as an antipsychotic, to decrease DA
    availability

23
Drug effects on the DA system
  • Amphetamine Cocaine
  • Stimulates DA release
  • Blocks reuptake of DA by reversing (amphetamine)
    or inactivating (cocaine)
  • the DA transporter molecule
  • Effects
  • Highly addictive
  • Can cause psychosis, loss of DA neurons
    throughout the brain

24
Drug effects on the DA system
  • Monoamine oxidase-inhibitors (MAO-I) destroy
    monoamine oxidase
  • MAO limits DA
  • MAO-I increase DA that may be released
  • Many antipsychotic drugs block DA receptors
  • Chlorpromazine
  • Clozapine
  • Methylphenidate - blocks reuptake of DA
  • Inactivates transporter molecule
  • Increases DA in the synapse
  • Increases attention

25
Norepinephrine
  • Also called noradrenaline
  • Cells originate in the medulla, pons and thalamus
  • Locus coeruleus dorsal pons nucleus
  • Responsible for ________________
  • Axons project widely throughout the brain

26
Norepinephrine
  • NE is released from axonal varicosities
  • Adrenergic receptors are sensitive to both
    norepinephrine and epinephrine
  • Entirely metabotropic

27
Drug effects on the NE system
  • Methamphetamine - releases/prevents reuptake of
    both DA and NE by reversing the transporter
    molecules
  • Highly addictive
  • Effects
  • Chronic use results in
  • Bupropion (Wellbutrin/Zyban) blocks reuptake of
    both NE and DA by inactivating the transporter
    molecule and blocks the nicotinic ACh receptors.
  • Anti-depressant
  • Anti-smoking drug

28
Epinephrine
  • Also known as adrenaline
  • Hormone, produced by the adrenal glands
  • Acts as a ligand in the brain
  • At adrenergic receptors

29
Serotonin (5-HT)
  • Involved in regulation of mood, control of
    appetite, sleep, dreaming, arousal and pain
    regulation.
  • Synthesized from ___________
  • Neurons in the _________ nuclei of the midbrain
  • 5-HT neurons project to the cortex, basal ganglia
    and hippocampus
  • Nine types of 5-HT receptors found throughout
    the brain

30
Drug effects on the serotonin system
  • LSD stimulates 5-HT2A receptors in the
    forebrain
  • Powerful agonist causes hallucinations
  • MDMA (Ecstasy) reverses the 5-HT and NE
    transporter molecules, releasing serotonin and
    norepinephrine and inhibiting reuptake
  • Effects
  • Causes permanent damage to 5-HT neurons
    cognitive impairment

31
Drug effects on the serotonin system
  • Fluoxetine (Prozac), Paroxetine (Paxil),
    Sertraline (Zoloft) inhibit 5-HT reuptake by
    the transporter molecule
  • Used to treat
  • Fenfluramine stimulates 5-HT release and
    inhibits reuptake
  • Used as

32
Amino acid neurotransmitters
  • Amino acids produced by cell metabolisation may
    also act as neurotransmitters
  • 3 major amino acid neurotransmitters
  • Glutamate
  • GABA
  • Glycine

33
Glutamate
  • Major excitatory NT in the brain
  • Acts on postsynaptic receptors and directly
    affects other axons
  • ________ the threshold of excitation, so that
    ________ depolarization is needed to produce an
    action potential

34
Glutamate
  • Four types of glutamate receptors
  • AMPA receptor ionotropic
  • Opens a ______ channel produces EPSPs
  • Kainate receptor ionotropic
  • Opens a ______ channel produces EPSPs
  • NMDA receptor ionotropic
  • Contains 6 binding sites (4 outside, 2 inside)
  • Controls an ion channel specific for both
    ____________
  • Only opens in the presence of both glutamate and
    glycine molecules at binding sites
  • Metabotropic glutamate receptor metabotropic
  • Controls both ____________ channels

35
Drug effects on Glutamate
  • Alcohol blocks glutamate at the NMDA receptor
  • Phencyclidine (PCP) acts at the PCP receptor
  • Blocks the Ca2 channel of the NMDA receptor
  • Hallucinations
  • Ketamine acts at the PCP receptor
  • Blocks the Na channel on the NMDA receptor
  • Dissociative interrupts memory and thought

36
GABA (gamma-aminobutyric acid)
  • Major inhibitory neurotransmitter in the brain
  • Produced throughout the CNS
  • Inhibitory influence throughout the brain
  • Acts on receptors as well as directly on axons
  • __________ the threshold of excitation -
    __________ depolarization is needed to produce an
    action potential.

37
GABA
  • Two known GABA receptors
  • GABAA receptor ionotropic
  • Controls _____ channel
  • Contains 5 binding sites
  • GABAB receptor metabotropic
  • Controls _____ channel
  • Both postsynaptic receptors and autoreceptors

38
Drug effects on the GABA system
  • Benzodiazepines, alcohol, barbiturates and
    steroid hormones
  • Indirect agonists on GABAA receptor
  • Baclofen, alcohol, gamma-hydroxy butyric acid
    (GHB)
  • Stimulate the GABAB receptor
  • All GABA agonists are CNS depressants
  • Produce sleep, anxiety relief, muscle relaxation,
    seizure alleviation

39
Glycine
  • Inhibitory neurotransmitter found in the
    brainstem and spinal cord
  • Involved in the inhibition of muscle contractions
    in the periphery
  • Glycine receptor ionotropic
  • Drug effects
  • Tetanus bacteria prevents glycine release
  • Strychnine blocks the glycine receptor

40
Neuropeptides
  • Composed of two or more amino acids
  • Released from vesicles from the entire terminal
    button
  • Diffuse widely, affecting other neurons in the
    vicinity
  • Some are neurotransmitters, some are
    neuromodulators

41
Endogenous opioids
  • Well-known neuropeptides
  • Endogenous ligands for the opiate receptors
  • Ligands Enkephalins, Dynorphin
  • Receptors mu, delta, kappa
  • Major effects of endogenous opiates
  • Analgesia (pain relief)
  • Reinforcement
  • Inhibition of species-specific defensive responses

42
Drug effects on the endogenous opioid system
  • Opium, morphine and its derivatives
  • (heroin, oxycodone, other narcotics) stimulate
    opiate receptors
  • Effects ___________________________
  • Rapidly lead to tolerance and intense withdrawal
    symptoms
  • Naloxone, Naltrexone block the opiate receptors
  • Used to treat opiate addiction

43
Endocannabinoids
  • Lipid-based molecules that transmit messages
    between cells
  • Act on cannabinoid receptors (named for their
    affinity for tetrahydrocannabinol)
  • Anandamide first natural ligand for the
    cannabinoid receptor
  • Receptors
  • CB1 receptors found throughout the brain
  • Role in modulating most brain functions
  • CB2 receptors found outside of the brain

44
Endocannabinoids
  • Produced and released on demand, not stored in
    vesicles
  • Retrograde transport - endocannabinoids are
    released by the postsynaptic cell, travel
    backward, act on the axon membrane of the
    presynaptic cell

45
Drug effects on the endocannabinoid system
  • THC stimulates the cannabinoid receptors
  • Produces analgesia and sedation, stimulates
    appetite, reduces nausea and vomiting, relieves
    asthma attacks, decreases symptoms of glaucoma,
    certain motor disorders, wasting syndrome,
    depression, decreases anxiety, insomnia,
    arthritis pain
  • Prevents excitotoxicity
  • Interferes with concentration, memory, perception
    of time, visual and auditory perception.
  • Effects depend on ____________________,
    _______________, and _________________
  • Rimonabant blocks the CB1 receptor
  • Used as
  • Results in depression

46
Dependence
47
Addiction
  • Dependence on a particular substance or activity
  • Takes two forms
  • Physical dependence
  • Psychological dependence

48
Repeated drug administration
  • Repeat administration of a drug will change the
    effect of the drug
  • Tolerance _________ behavioral effectiveness
  • Metabolic tolerance
  • Functional tolerance
  • Greater amounts of the drug are needed
  • Withdrawal symptoms occur in response to
    _________
  • Specific effects

49
Repeated drug administration
  • Sensitization __________ behavioral
    effectiveness
  • Smaller amounts of the drug will produce the same
    initial effects
  • Results from long-term structural changes in the
    brain
  • Many drugs result in both tolerance and
    sensitization

50
Physical dependence
  • Withdrawal symptoms opposite from the drugs
    effects
  • Due to the body and brain adjusting to the
    presence of the drug
  • The drug becomes necessary to function at normal
    levels
  • Reduction of physical withdrawal symptoms becomes
    the reason for continued use of the drug

51
Psychological dependence
  • Why do drug users reach the point of withdrawal
    symptoms?
  • Drugs are ______________
  • Drugs that are abused act __________
  • Reinforcement (of ALL drugs) comes via increased
    dopamine in the mesolimbic system
  • DA acting at the nucleus accumbens produces
    positive, reinforcing feelings
  • Results in the desire to take the drug again
  • Removal of withdrawal symptoms is also
    psychologically reinforcing

52
Psychological dependence
  • Exists when a person needs to use a drug to gain
    the psychological effects that it produces
  • Results in craving
  • MUCH harder to overcome than physical dependence
  • Cravings persist after long periods of abstinence
  • Not all drugs are physically addictive, but all
    addiction has a psychological component.

53
Genetics and addiction
  • Research on alcoholism and other drugs suggests
    genetic components to addiction
  • Common genetic factors
  • Specific genetic factors
  • Every body responds to drugs differently, based
    on genetically determined traits
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