Psychopharmacology

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Psychopharmacology

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

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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

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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.

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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

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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

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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
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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
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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
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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

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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

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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

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Neurotransmitters Neuromodulators
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Acetylcholine

• Excitatory neurotransmitter responsible for
  muscle contractions
• Neuromuscular junctions
• Target organs of the parasympathetic nervous
  system

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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

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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

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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

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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

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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)

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Catecholamines

• Catecholamies are all synthesized in the same
  process

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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 _______________________

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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

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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

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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

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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

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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

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Norepinephrine

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

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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

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Epinephrine

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

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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

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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

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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

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Amino acid neurotransmitters

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

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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

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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

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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

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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.

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GABA

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

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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

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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

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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

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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

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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

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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

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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

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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

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Dependence
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Addiction

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

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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

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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

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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

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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

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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.

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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