PS201418: Biological Psychology

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PS2014/18 Biological Psychology
Neuropharmacology
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Agonists, antagonists and partial agonists

• Prevents the native transmitter or any agonist
  from binding to the receptor

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Dose response curves for receptor interactions
Agonist plus antagonist
ED50
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Potency and efficacy

• Agonist A is more potent than agonist B
• A smaller concentration of the drug is required
  to give a specified effect
• The dose required to produce maximum effect is
  lower.
• Not to be confused with efficacy both drugs
  have the same efficacy
• Similar applies to antagonists
• Maximum effect occurs when all the available
  receptors are occupied.

• The concentration at which the maximum effect
  occurs is related to the binding affinity of the
  agonist to the receptor, measured as KD
• KD is inversely proportional to affinity
• The higher the affinity the lower the KD and the
  more potent the drug

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Receptor selectivity

• Receptor selectivity is the relative potency at
  different receptors
• Can refer to neurotransmitters or drugs (agonist
  or antagonist)
• Selectivity is not related to absolute potency
• You can have drugs which are highly selective,
  but not very potent and vice versa
• Drug selectivity is rarely absolute
• lt 100 X more potent at receptor A than B
  Non-selective
• 100 X to 10,000 X more potent at receptor A than
  B Selective
• gt 10,000 X more potent at A than B - Specific

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Presynaptic receptors
NT
NT
Precursor
Dopamine D2 5HT 5HT-1B Noradrenaline
alpha-2 Acetylcholine Muscarinic (M2)
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Drug action at autoreceptors
Autoreceptors inhibit the release of
neurotransmitter Therefore Agonists block
transmitter release Antagonists increase
transmitter release
X
NT
By blocking autoreceptors, a receptor antagonist
may have the opposite effect to that which is
expected. Instead of reducing the post-synaptic
effect it may increase it by blocking the
negative feedback.
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Therapeutic drugs acting at receptors

• Agonists
• Used to treat conditions involving underactivity
  of neurotransmitters
• e.g. Dopamine agonists in treatment of
  Parkinsons Disease
• Antagonists
• Used to treat conditions involving overactivity
  of neurotransmitters
• e.g. Dopamine antagonists in treatment of
  schizophrenia
• Actions at presynaptic receptors can complicate
  treatment strategies

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Drug action at receptors

• Neuroleptics (antipsychotics) antagonist at
  dopamine receptors
• Aripiprazole partial agonist at dopamine
  receptors
• Barbiturates and benzodiazapines
  (anticonvulsants, anxiolylics)
• increase GABA receptor function (allosteric
  binding site)

• Many plant derivatives
• atropine (belladonna from deadly nightshade)
  antagonist at acetylcholine receptors first
  pharmacological treatment for Parkinsons disease
• nicotine (from tobacco) agonist at
  acetylcholine receptors
• muscarine (from fungus) agonist at
  acetylcholine receptors

• Many venom toxins
• curare (from frogs) antagonist at
  acetylcholine receptors
• bungarotoxin (from cobras) antag at
  acetylcholine receptors

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Allosteric binding sites on receptors

• A second ligand binding site on the extracellular
  part of the receptor
• binding of the co-agonist alters the action of
  the main agonist
• e.g. Benzodiazipine binding site on GABA-A
  receptor benzodiazipines enhance the effects of
  GABA

Extracellular
Intracellular
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Benzodiazepines and barbiturates

• Benzodiazepines and barbiturates bind to
  allosteric binding sites
• Increase the binding affinity of the receptor for
  GABA
• Leads to an increase chloride influx
• Action of the two drug types is through separate
  binding sites
• Benzodiazipines increase the frequency of
  chloride channel openings, but do not change the
  duration of channel opening
• Barbiturates increase the duration of channel
  opening, but do not change the frequency

What are the endogenous ligands for
benzodiazepine and barbiturate receptors?
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Therapeutic uses of benzodiazepines and
barbiturates
Sedative-hypnotics and anxiolytics

• Barbiturates widely used in the past
• e.g. Pentobarbital, buspirone
• BUT can cause fatal respiratory depression high
  potential to produce dependence
• Now mainly used only as anticonvulsants and
  anaesthetics
• Introduction of benzodiazepines reduced the use
  of barbiturates
• e.g. Diazepam
• Much reduced (although still significant) risk of
  dependence
• Widely used in treatment of anxiety disorders,
  anaesthesia, insomnia

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Drugs affecting synaptic transmission
Action potential Neurotransmitter Change in
membrane potential
Reuptake and/or breakdown of neurotransmitter
neurotransmitter release
receptors
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Drugs affecting synthesis and storage

• Reserpine
• prevents vesicular storage of amine transmitters

• L-DOPA
• precursor for dopamine increases dopamine
  concentrations main therapeutic agent used in
  Parkinsons disease
• Tryptophan
• precursor for serotonin effective in treating
  some depression

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Drugs affecting neurotransmitter release

• Botulinum toxin
• Prevents acetylcholine release at neuromuscular
  junction (NMJ)

• Black widow venom toxin
• increases then eliminates acetylcholine release
  at NMJ

• ? Amantidine ?
• Mechanism uncertain, but may increase dopamine
  release used in the treatment of Parkinsons
  disease

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Drugs affecting reuptake and breakdown

• Monoamine reuptake inhibitors
• tricyclic antidepressants prevents reuptake of
  noradrenaline and serotonin
• fluoxitine (Prozac) prevents reuptake of
  serotonin

• Monoamine oxidase inhibitors
• prevent the breakdown of amine neurotransmitters
• Selegiline (deprynil) blocks dopamine
  breakdown used in the treatment of Parkinsons
  disease
• Phenelzine blocks breakdown of noradrenaline
  and serotonin antidepressant

• GABA transaminase (GABA-t) inhibitors
• prevent the breakdown of GABA anticonvulsant

• Amphetamine and cocaine
• Increase dopamine levels by blocking reuptake
  amphetamine also increases dopamine release and
  blocks monoamine oxidase

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Drug action at allosteric binding sites

• Benzodiazepines
• Anxiolytic (also anti-convulsants)
• Facilitate responses at GABA-A receptors

• Barbiturates
• Anxiolytic/hypnotic
• Toxic in overdose, and lead to dependence
• Facilitate responses at GABA-A receptors

• Drugs affecting glycine binding site on NMDA
  receptors
• ? Anticonvulsant, anti-ischeamic

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Actions of therapeutic drugs
Synthesis Release Receptor Clearance
NT
NT
NT
Tricyclic antidepressants MAO inhibitors GABA-t
inhibitors
Neuroleptics Anxiolytics Anticonvulsants
Tryptophan L-DOPA
Amantidine