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Year 2 Medicine > How Drugs Control the Brain > Flashcards

How Drugs Control the Brain Flashcards

1
Q

The GABAergic system

  • Widespread distribution throughout the brain
  • Inhibitory interneurons - keep the … in check
  • Synaptic inhibition must be tightly … in the brain
    • Too much GABA = loss of consciousness and coma
    • Too little GABA = leads to convulsions and seizures
  • (many … treatments act to enhance GABA transmission)
A
  • Widespread distribution throughout the brain
  • Inhibitory interneurons - keep the excitation in check
  • Synaptic inhibition must be tightly regulated in the brain
    • Too much GABA = loss of consciousness and coma
    • Too little GABA = leads to convulsions and seizures
  • (many epilepsy treatments act to enhance GABA transmission)
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2
Q

The GABAergic system

  • Widespread distribution throughout the brain
  • Inhibitory interneurons - keep the excitation in check
  • Synaptic inhibition must be tightly regulated in the brain
    • Too … GABA = loss of consciousness and coma
    • Too … GABA = leads to convulsions and seizures
  • (many epilepsy treatments act to … GABA transmission)
A
  • Widespread distribution throughout the brain
  • Inhibitory interneurons - keep the excitation in check
  • Synaptic inhibition must be tightly regulated in the brain
    • Too much GABA = loss of consciousness and coma
    • Too little GABA = leads to convulsions and seizures
  • (many epilepsy treatments act to enhance GABA transmission)
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3
Q

Too much GABA = loss of … and …

A
  • Too much GABA = loss of consciousness and coma
  • (Too little GABA = leads to convulsions and seizures)
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4
Q

Too little GABA = leads to … and …

A
  • Too little GABA = leads to convulsions and seizures
  • (Too much GABA = loss of consciousness and coma)
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5
Q

Many epilepsy treatments aim to enhance … transmission

A

GABA

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6
Q

Main Neuronal Types - GABA vs GLU

  • … neurons - use GLUTAMATE (excitatory)
  • … interneurons - use GABA (inhibitory)
A
  • Projection neurons - use GLUTAMATE (excitatory)
  • Local interneurons - use GABA (inhibitory)
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7
Q

Inhibitory control of cortical pyramidal neurons

A
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8
Q

Two main families of GABA receptor:

  • GABA(A) … receptors
    • Ligand gated Cl- channel
    • … iPSPs (inhibitory post synaptic potentials)
    • Mostly GABAergic internuerons
  • GABA(B) … receptors
    • G protein couples receptors
    • Indirectly coupled to K+ or Ca2+ channel through 2nd messengers (opens K+ channel, closes Ca2+ channel)
    • … IPSPs
    • Both pre- and post- synaptic
A
  • GABA(A) Ionotropic receptors
    • Ligand gated Cl- channel
    • Fast iPSPs (inhibitory post synaptic potentials)
    • Mostly GABAergic internuerons
  • GABA(B) Metabotropic receptors
    • G protein couples receptors
    • Indirectly coupled to K+ or Ca2+ channel through 2nd messengers (opens K+ channel, closes Ca2+ channel)
    • Slow IPSPs
    • Both pre- and post- synaptic
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9
Q

Two main families of GABA receptor:

  • GABA(A) Ionotropic receptors
    • … gated …- channel
    • Fast iPSPs (inhibitory post synaptic potentials)
    • Mostly GABAergic internuerons
  • GABA(B) Metabotropic receptors
    • … … couples receptors
    • Indirectly coupled to K+ or Ca2+ channel through 2nd messengers (opens K+ channel, closes Ca2+ channel)
    • Slow IPSPs
    • Both pre- and post- synaptic
A
  • GABA(A) Ionotropic receptors
    • Ligand gated Cl- channel
    • Fast iPSPs (inhibitory post synaptic potentials)
    • Mostly GABAergic internuerons
  • GABA(B) Metabotropic receptors
    • G protein couples receptors
    • Indirectly coupled to K+ or Ca2+ channel through 2nd messengers (opens K+ channel, closes Ca2+ channel)
    • Slow IPSPs
    • Both pre- and post- synaptic
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10
Q

GABA(A) receptors

  • Heteropentameric structure - 2 a + 3 more subunits
  • Cl- channel gated by the binding of two agonist molecules
  • Cl- potential is near … potential increasing chloride permeability
  • … the neuron decreasing the … effects of an excitatory input
A
  • Heteropentameric structure - 2 a + 3 more subunits
  • Cl- channel gated by the binding of two agonist molecules
  • Cl- potential is near resting potential increasing chloride permeability
  • Hyperpolarizes the neuron decreasing the depolarizing effects of an excitatory input
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11
Q

GABA(A) receptors and drugs

  • Complex receptor with multiple binding sites
  • Direct agonists and antagonists (bind at GABA binding site)
    • M… - agonist
    • B… - antagonist (Experimental tool)
  • Indirect agonists
    • B… - binding increases the receptor affinity for GABA
      • Increase frequency of channel opening
      • Anxiolytic and hypnotic drugs with rapid onset, but less satisfactory in the long term
    • B… - increase the duration of channel openings (anaesthesia, epilepsy treatment)
    • A… - agonist
A
  • Complex receptor with multiple binding sites
  • Direct agonists and antagonists (bind at GABA binding site)
    • Muscimol - agonist
    • Bicuculline - antagonist (Experimental tool)
  • Indirect agonists
    • Benzodiazepine - binding increases the receptor affinity for GABA
      • Increase frequency of channel opening
      • Anxiolytic and hypnotic drugs with rapid onset, but less satisfactory in the long term
    • Barbiturates - increase the duration of channel openings (anaesthesia, epilepsy treatment)
    • Alcohol - agonist
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12
Q

GABA(A) receptors and drugs

  • Complex receptor with multiple binding sites
  • Direct agonists and antagonists (bind at GABA binding site)
    • Muscimol - …
    • Bicuculline - … (Experimental tool)
  • Indirect agonists
    • Benzodiazepine - binding increases the receptor affinity for GABA
      • Increase … of channel opening
      • … and hypnotic drugs with rapid onset, but less satisfactory in the long term
    • Barbiturates - increase the … of channel openings (anaesthesia, epilepsy treatment)
    • Alcohol - agonist
A
  • Complex receptor with multiple binding sites
  • Direct agonists and antagonists (bind at GABA binding site)
    • Muscimol - agonist
    • Bicuculline - antagonist (Experimental tool)
  • Indirect agonists
    • Benzodiazepine - binding increases the receptor affinity for GABA
      • Increase frequency of channel opening
      • Anxiolytic and hypnotic drugs with rapid onset, but less satisfactory in the long term
    • Barbiturates - increase the duration of channel openings (anaesthesia, epilepsy treatment)
    • Alcohol - agonist
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13
Q

GABA(A) Receptor - benzodiazepine action - E.g diazepam (Valium)

  • Benzodiazepine binding site on the a subunit of GABA(A) receptor
  • Indirect agonist - benzodiazepine binds to alpha subunit, changes conformation of the receptor so GABA activation of receptor is more effective
  • Effects of benzodiazepine are to:
    • Reduce …
    • Cause …
    • Reduce …
    • Relax …
    • Cause …
  • Inverse agonists bind to benzodiazepine site and have opposite effects
    • produce … and predisposition to …
A
  • Benzodiazepine binding site on the a subunit of GABA(A) receptor
  • Indirect agonist - benzodiazepine binds to alpha subunit, changes conformation of the receptor so GABA activation of receptor is more effective
  • Effects of benzodiazepine are to:
    • Reduce anxiety
    • Cause sedation
    • Reduce convulsions
    • Relax muscles
    • Cause amnesia
  • Inverse agonists bind to benzodiazepine site and have opposite effects
    • produce anxiety and predisposition to convulsions
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14
Q

GABA(A) Receptor - benzodiazepine action - E.g diazepam (Valium)

  • Benzodiazepine binding site on the a subunit of GABA(A) receptor
  • Indirect agonist - benzodiazepine binds to alpha subunit, changes … of the receptor so GABA activation of receptor is more effective
  • Effects of benzodiazepine are to:
    • Reduce anxiety
    • Cause sedation
    • Reduce convulsions
    • Relax muscles
    • Cause amnesia
  • Inverse agonists bind to benzodiazepine site and have … effects
    • …
A
  • Benzodiazepine binding site on the a subunit of GABA(A) receptor
  • Indirect agonist - benzodiazepine binds to alpha subunit, changes conformation of the receptor so GABA activation of receptor is more effective
  • Effects of benzodiazepine are to:
    • Reduce anxiety
    • Cause sedation
    • Reduce convulsions
    • Relax muscles
    • Cause amnesia
  • Inverse agonists bind to benzodiazepine site and have opposite effects
    • produce anxiety and predisposition to convulsions
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15
Q

GABA(A) Rs - barbiturates and alcohol

  • Bind at different sites on the receptor
  • Both have same effect: to enhance GABA(A) activity and effects are additive - combining the two can be …
  • Alcohol also interacts with ,,,, glycine, N.. and serotonin receptors
  • Low doses of alcohol: Mild … and anxiolytic effects
    • Higher doses - incoordination, …
A
  • Bind at different sites on the receptor
  • Both have same effect: to enhance GABA(A) activity and effects are additive - combining the two can be fatal
  • Alcohol also interacts with NMDA, glycine, nicotinic and serotonin receptors
  • Low doses of alcohol: Mild euphoria and anxiolytic effects
    • Higher doses - incoordination, amnesia
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16
Q

GABA(A) Rs - barbiturates and alcohol

  • Bind at … sites on the receptor
  • Both have same effect: to enhance GABA(A) activity and effects are additive - combining the two can be fatal
  • Alcohol also interacts with NMDA, G…, nicotinic and S… receptors
  • Low doses of alcohol: Mild euphoria and … effects
    • Higher doses - …, amnesia
A
  • Bind at different sites on the receptor
  • Both have same effect: to enhance GABA(A) activity and effects are additive - combining the two can be fatal
  • Alcohol also interacts with NMDA, glycine, nicotinic and serotonin receptors
  • Low doses of alcohol:
    • Mild euphoria and anxiolytic effects
    • Higher doses - incoordination, amnesia
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17
Q

GABA(B) receptor - metabotropic

  • Agonist - Baclofen (used as a muscle relaxant to reduce spasticity e.g. in Huntington’s disease)
    • G… coupled - inhibits adenylyl cyclase
    • GBY gated …+ channels - Increases …+ conductance
  • Slow hyperpolarizing current (… inhibitory postsynaptic potential)
  • Inhibition of GABA(B) transmission does not have same behavioural outcome as inhibition of GABA(A) receptors (e.g. …)
A
  • Agonist - Baclofen (used as a muscle relaxant to reduce spasticity e.g. in Huntington’s disease)
    • Gi coupled - inhibits adenylyl cyclase
    • GBY gated K+ channels - Increases K+ conductance
  • Slow hyperpolarizing current (late inhibitory postsynaptic potential)
  • Inhibition of GABA(B) transmission does not have same behavioural outcome as inhibition of GABA(A) receptors (e.g. seizure)
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18
Q

GABA(B) receptor - metabotropic

  • Agonist - … (used as a muscle relaxant to reduce spasticity e.g. in Huntington’s disease)
    • Gi coupled - inhibits … …
    • GBY gated K+ channels - Increases K+ conductance
  • Slow hyperpolarizing current (late inhibitory postsynaptic potential)
  • Inhibition of GABA(B) transmission does not have same behavioural outcome as inhibition of GABA(A) receptors (e.g. …)
A
  • Agonist - Baclofen (used as a muscle relaxant to reduce spasticity e.g. in Huntington’s disease)
    • Gi coupled - inhibits adenylyl cyclase
    • GBY gated K+ channels - Increases K+ conductance
  • Slow hyperpolarizing current (late inhibitory postsynaptic potential)
  • Inhibition of GABA(B) transmission does not have same behavioural outcome as inhibition of GABA(A) receptors (e.g. seizure)
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19
Q

Baclofen is a GABA-… agonist that has been used for muscle spasms and spasticity, and neuropathic pain. - in what disease?

A

Baclofen is a GABA-B agonist that has been used for muscle spasms and spasticity, and neuropathic pain. - huntington’s disease

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20
Q

GABA… receptor agonists: Alcohol (ethanol), barbiturates, and benzodiazepine.

A

GABAa receptor agonists: Alcohol (ethanol), barbiturates, and benzodiazepine.

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21
Q

GABA… receptor agonists: Baclofen

A

GABAb receptor agonists: Baclofen

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22
Q
  • Which of these does not bind to a GABA(A)R?
  • A.Benzodiazepine
  • B.Ethanol
  • C.PCP (phencyclidine)
  • D.Barbiturate
  • E.GABA
A
  • Which of these does not bind to a GABA(A)R?
  • A.Benzodiazepine
  • B.Ethanol
  • C.PCP (phencyclidine) - blocks the NMDA receptor
  • D.Barbiturate
  • E.GABA
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23
Q

GABA is always an inhibitory neurotransmitter - T OR F

A
  • It depends on the elechtrochemical gradient of Cl- ions. It is excitatory during development.
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24
Q

Neurotransmitter systems

  • Glutamate and GABA the main workhouse of the brain
  • … neurons - primary route of sensory and motor information and relay neurons between brain areas
  • … neurons - interneurons, maintain balance between excitation and inhibition
A
  • Glutamate and GABA the main workhouse of the brain
  • Glutamate neurons - primary route of sensory and motor information and relay neurons between brain areas
  • GABA neurons - interneurons, maintain balance between excitation and inhibition
25
Q

The Diffuse Modulatory Systems

  • Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas.
    • … (DA)
    • … (5-HT)
    • … (NA/NE)
    • Adrenergic
    • … (Ach)
    • Histaminergic
A
  • Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas.
    • Dopaminergic (DA)
    • Serotonergic (5-HT)
    • Noradrenergic (NA/NE)
    • Adrenergic
    • Cholinergic (Ach)
    • Histaminergic
26
Q

The Dopaminergic System

  • Dopamine neurons
    • Cell bodies in the …
    • Project into the …
  • Nigrostriatal system (75% of brain D - A) motor control
  • … system (limbic parts of brain)
  • … system (behavioural effects)
  • (also Tuberohypophyseal system for endocrine control)
A
  • Dopamine neurons
    • Cell bodies in the midbrain
    • Project into the forebrain
  • Nigrostriatal system (75% of brain D - A) motor control
  • Mesolimbic system (limbic parts of brain)
  • Mesocortical system (behavioural effects)
  • (also Tuberohypophyseal system for endocrine control)
    *
27
Q

The Dopaminergic System

  • Dopamine neurons
    • Cell bodies in the midbrain
    • Project into the forebrain
  • … system (75% of brain D - A) motor control
  • Mesolimbic system (limbic parts of brain)
  • Mesocortical system (behavioural effects)
  • (also Tuberohypophyseal system for … control)
A
  • Dopamine neurons
    • Cell bodies in the midbrain
    • Project into the forebrain
  • Nigrostriatal system (75% of brain D - A) motor control
  • Mesolimbic system (limbic parts of brain)
  • Mesocortical system (behavioural effects)
  • (also Tuberohypophyseal system for endocrine control)
    *
28
Q

Dopamine (DA) receptors

  • Only works through … receptors - … receptors D1-5
  • Dopamine produces both EPSPs and IPSPs depending on the receptor subtype and coupled G proteins
  • D1- like (1 and 5) Gs :
    • stimulate … …
    • Stimulate … C
    • POSTSYNAPTIC
  • D2- like (2, 3 and 4) Gi :
    • Inhibit adenylyl cyclase
    • Open K+ channels
    • Close Ca2+ channels
    • POSTSYNAPTIC and PRESYNAPTIC AUTORECEPTORS (D3)
  • Need a balance of these systems - maintains dopaminergic …
A
  • Only works through metabotropic receptors Metabotropic receptors D1-5
  • Dopamine produces both EPSPs and IPSPs depending on the receptor subtype and coupled G proteins
  • D1- like (1 and 5) Gs :
    • stimulate adenylyl cyclase
    • Stimulate phospholipase C
    • POSTSYNAPTIC
  • D2- like (2, 3 and 4) Gi :
    • Inhibit adenylyl cyclase
    • Open K+ channels
    • Close Ca2+ channels
    • POSTSYNAPTIC and PRESYNAPTIC AUTORECEPTORS (D3)
  • Need a balance of these systems - maintains dopaminergic tone
29
Q

Dopamine (DA) receptors

  • Only works through metabotropic receptors Metabotropic receptors D1-5
  • Dopamine produces both EPSPs and IPSPs depending on the receptor subtype and coupled G proteins
  • …- like (1 and 5) Gs :
    • stimulate adenylyl cyclase
    • Stimulate phospholipase C
    • …SYNAPTIC
  • …- like (2, 3 and 4) Gi :
    • Inhibit adenylyl cyclase
    • Open …+ channels
    • Close …+ channels
    • POSTSYNAPTIC and PRESYNAPTIC … (D3)
  • Need a balance of these systems - maintains dopaminergic tone
A
  • Only works through metabotropic receptors Metabotropic receptors D1-5
  • Dopamine produces both EPSPs and IPSPs depending on the receptor subtype and coupled G proteins
  • D1- like (1 and 5) Gs :
    • stimulate adenylyl cyclase
    • Stimulate phospholipase C
    • POSTSYNAPTIC
  • D2- like (2, 3 and 4) Gi :
    • Inhibit adenylyl cyclase
    • Open K+ channels
    • Close Ca2+ channels
    • POSTSYNAPTIC and PRESYNAPTIC AUTORECEPTORS (D3)
  • Need a balance of these systems - maintains dopaminergic tone
30
Q

The Dopaminergic system continued

  • Nigrostriatal system:
    • cell bodies in the substantia nigra project to the striatum (Caudate nucleus and putamen)
    • Important part of the basal ganglia involved in movement
  • Dysfunction:
    • … disease - destruction of DA projections from SN to basal ganglia
    • … disease - destruction of DA target neurons in striatum
  • Drugs:
    • L-…, Monoamine oxidase (MAO) inhibitors, Dopamine receptor agonists - treatments for …
A
  • Nigrostriatal system:
    • cell bodies in the substantia nigra project to the striatum (Caudate nucleus and putamen)
    • Important part of the basal ganglia involved in movement
  • Dysfunction:
    • Parkinson’s disease - destruction of DA projections from SN to basal ganglia
    • Huntington’s disease - destruction of DA target neurons in striatum
  • Drugs:
    • L-DOPA, Monoamine oxidase (MAO) inhibitors, Dopamine receptor agonists - treatments for Parkinson’s
31
Q

The Dopaminergic system continued

  • … system:
    • cell bodies in the substantia nigra project to the striatum (… nucleus and …)
    • Important part of the basal … involved in movement
  • Dysfunction:
    • Parkinson’s disease - destruction of DA … from SN to basal ganglia
    • Huntington’s disease - destruction of DA target neurons in striatum
  • Drugs:
    • L-DOPA, … oxidase (MAO) inhibitors, Dopamine receptor agonists - treatments for Parkinson’s
A
  • Nigrostriatal system:
    • cell bodies in the substantia nigra project to the striatum (Caudate nucleus and putamen)
    • Important part of the basal ganglia involved in movement
  • Dysfunction:
    • Parkinson’s disease - destruction of DA projections from SN to basal ganglia
    • Huntington’s disease - destruction of DA target neurons in striatum
  • Drugs:
    • L-DOPA, Monoamine oxidase (MAO) inhibitors, Dopamine receptor agonists - treatments for Parkinson’s
32
Q

Doapminergic system - Mesolimbic system:

  • Mesolimbic system - Cell bodies in ventral tegmental area (VTA) project to the limbic system, nucleus accumbens (Nacc)
  • Role in … (…) of several categories of stimuli, including drugs of abuse
  • Dysfunction:
    • … - most drugs of abuse lead to enhanced DA release in the Nacc - E.g. cocaine and amphetamine - psychomotor stimulants
  • Immediate effects:
    • Give the feeling of increased alertness and self confidence, a sense of exhilaration and euphoria and a decreased appetite
    • Large doses can cause stereotrypy and …
    • Cause peripheral effects that mimic activation of the sympathetic division of the ANS, increased heart rate and blood pressure, dilation of pupils etc.
  • Long term effects:
    • Natural …, e.g. water, food, sex increase DA transmission and leads to … of associated behaviours
    • Increased … by cocaine etc. short circuits pathway, drug taking behaviours become reinforced
    • Downregulation of endogenous DA system - c…
A
  • Mesolimbic system - Cell bodies in ventral tegmental area (VTA) project to the limbic system, nucleus accumbens (Nacc)
  • Role in reinforcement (Reward) of several categories of stimuli, including drugs of abuse
  • Dysfunction:
    • Addiction - most drugs of abuse lead to enhanced DA release in the Nacc - E.g. cocaine and amphetamine - psychomotor stimulants
  • Immediate effects:
    • Give the feeling of increased alertness and self confidence, a sense of exhilaration and euphoria and a decreased appetite
    • Large doses can cause stereotrypy and psychosis
    • Cause peripheral effects that mimic activation of the sympathetic division of the ANS, increased heart rate and blood pressure, dilation of pupils etc.
  • Long term effects:
    • Natural rewards, e.g. water, food, sex increase DA transmission and leads to reinforcement of associated behaviours
    • Increased DA by cocaine etc. short circuits pathway, drug taking behaviours become reinforced
    • Downregulation of endogenous DA system - craving
33
Q

Doapminergic system - Mesolimbic system:

  • Mesolimbic system - Cell bodies in … … area (VTA) project to the limbic system, … … (Nacc)
  • Role in reinforcement (Reward) of several categories of stimuli, including drugs of …
  • Dysfunction:
    • Addiction - most drugs of abuse lead to … DA release in the Nacc - E.g. … and … - psychomotor stimulants
  • Immediate effects:
    • Give the feeling of increased alertness and self confidence, a sense of exhilaration and euphoria and a decreased appetite
    • Large doses can cause stereotrypy and psychosis
    • Cause peripheral effects that mimic activation of the sympathetic division of the ANS, increased heart rate and blood pressure, dilation of pupils etc.
  • Long term effects:
    • Natural rewards, e.g. water, food, sex increase … transmission and leads to reinforcement of associated behaviours
    • Increased DA by cocaine etc. short circuits pathway, drug taking behaviours become reinforced
    • Downregulation of endogenous DA system - craving
A
  • Mesolimbic system - Cell bodies in ventral tegmental area (VTA) project to the limbic system, nucleus accumbens (Nacc)
  • Role in reinforcement (Reward) of several categories of stimuli, including drugs of abuse
  • Dysfunction:
    • Addiction - most drugs of abuse lead to enhanced DA release in the Nacc - E.g. cocaine and amphetamine - psychomotor stimulants
  • Immediate effects:
    • Give the feeling of increased alertness and self confidence, a sense of exhilaration and euphoria and a decreased appetite
    • Large doses can cause stereotrypy and psychosis
    • Cause peripheral effects that mimic activation of the sympathetic division of the ANS, increased heart rate and blood pressure, dilation of pupils etc.
  • Long term effects:
    • Natural rewards, e.g. water, food, sex increase DA transmission and leads to reinforcement of associated behaviours
    • Increased DA by cocaine etc. short circuits pathway, drug taking behaviours become reinforced
    • Downregulation of endogenous DA system - craving
34
Q

Mesocortical system: - Dopaminergic System

  • Mesocortical system: … projections to prefrontal cortex
  • Role in functions such as working memory and planning
  • Dysfunction:
    • S…
  • Drugs:
    • Typical antipsychotics (e.g. chlorpromazine and …)
      • DA receptors antagonists (pre and postsynaptic)
      • Increase DA turnover - lose autoreceptor inhibition
      • Blockade of postsynaptic receptors - upregulation
    • Antipsychotic effects - action in mesocortical systems
    • Side effects - action on other dopaminergic systems
      • … side effects (EPS) - tardive dyskinesia etc. (chronic blockade causes system to become supersensitive)
  • Atypical antipsychotics (E.g. clozapine)
    • Specific to receptor subtype
      • E.g clozapine - antagonist of D4 receptors (cortex only)
    • Reduce psychosis associated with schizophrenia
    • Antipsychotic effects without EPS
A
  • Mesocortical system: VTA projections to prefrontal cortex
  • Role in functions such as working memory and planning
  • Dysfunction:
    • Schizophrenia
  • Drugs:
    • Typical antipsychotics (e.g. chlorpromazine and haloperidol)
      • DA receptors antagonists (pre and postsynaptic)
      • Increase DA turnover - lose autoreceptor inhibition
      • Blockade of postsynaptic receptors - upregulation
    • Antipsychotic effects - action in mesocortical systems
    • Side effects - action on other dopaminergic systems
      • Extrapyramidal side effects (EPS) - tardive dyskinesia etc. (chronic blockade causes system to become supersensitive)
  • Atypical antipsychotics (E.g. clozapine)
    • Specific to receptor subtype
      • E.g clozapine - antagonist of D4 receptors (cortex only)
    • Reduce psychosis associated with schizophrenia
    • Antipsychotic effects without EPS
35
Q

Mesocortical system: - Dopaminergic System

  • Mesocortical system: VTA projections to … cortex
  • Role in functions such as working memory and planning
  • Dysfunction:
    • Schizophrenia
  • Drugs:
    • Typical antipsychotics (e.g. chlorpromazine and haloperidol)
      • DA receptors antagonists (pre and postsynaptic)
      • Increase DA turnover - lose autoreceptor inhibition
      • Blockade of postsynaptic receptors - upregulation
    • Antipsychotic effects - action in mesocortical systems
      • Side effects - action on other dopaminergic systems
        • Extrapyramidal side effects (EPS) - tardive dyskinesia etc. (chronic blockade causes system to become supersensitive)
  • Atypical antipsychotics (E.g. …)
    • Specific to receptor subtype
      • E.g … - antagonist of D4 receptors (cortex only)
    • Reduce psychosis associated with schizophrenia
    • Antipsychotic effects without …
A
  • Mesocortical system: VTA projections to prefrontal cortex
  • Role in functions such as working memory and planning
  • Dysfunction:
    • Schizophrenia
  • Drugs:
    • Typical antipsychotics (e.g. chlorpromazine and haloperidol)
      • DA receptors antagonists (pre and postsynaptic)
      • Increase DA turnover - lose autoreceptor inhibition
      • Blockade of postsynaptic receptors - upregulation
    • Antipsychotic effects - action in mesocortical systems
    • Side effects - action on other dopaminergic systems
      • Extrapyramidal side effects (EPS) - tardive dyskinesia etc. (chronic blockade causes system to become supersensitive)
  • Atypical antipsychotics (E.g. clozapine)
    • Specific to receptor subtype
      • E.g clozapine - antagonist of D4 receptors (cortex only)
    • Reduce psychosis associated with schizophrenia
    • Antipsychotic effects without EPS
36
Q

DA acts through ionotropic receptors T OR F

A

F - metabotropic only

37
Q

The Serotonergic system

  • Nine raphe nuclei in reticular formation with diffuse projections
    • each projects to a different part of the brain
  • … projections to cerebellum and spinal cord (pain)
  • ,,, reticular activating system (with LC)
  • Dorsal and medial raphe project throughout the cerebral cortex
  • Raphe neurons fire tonically during …, quiet during …
A
  • Nine raphe nuclei in reticular formation with diffuse projections
    • each projects to a different part of the brain
  • Descending projections to cerebellum and spinal cord (pain)
  • Ascending reticular activating system (with LC)
  • Dorsal and medial raphe project throughout the cerebral cortex
  • Raphe neurons fire tonically during wakefulness, quiet during sleep
38
Q

The Serotonergic system

  • Nine raphe nuclei in reticular formation with .. projections
    • each projects to a different part of the brain
  • Descending projections to cerebellum and spinal cord (…)
  • Ascending reticular activating system (with …)
  • Dorsal and medial raphe project throughout the … cortex
  • Raphe neurons fire tonically during wakefulness, quiet during sleep
A
  • Nine raphe nuclei in reticular formation with diffuse projections
    • each projects to a different part of the brain
  • Descending projections to cerebellum and spinal cord (pain)
  • Ascending reticular activating system (with LC)
  • Dorsal and medial raphe project throughout the cerebral cortex
  • Raphe neurons fire tonically during wakefulness, quiet during sleep
39
Q

The Serotonergic system

  • function in:-
    • M…
    • S…
    • P…
    • E…
    • A…
A
  • function in:-
    • mood
    • sleep
    • pain
    • emotion
    • Appetite
40
Q

Serotonin receptors - metabotropic / ionotropic?

A

both (not assessed in detail)

41
Q

Drugs with general effects on serotonergic system

  • Selective Serotonin Reuptake Inhibitors e.g…. (…)
    • increase serotonin function by preventing its uptake
    • treatment for depression and anxiety disorders
    • but depression not a simple case of low serotonergic tone (effects not seen for 2-3 weeks)
    • increased availability of serotonin triggering downstream pathways
        • long term modulatory effects
        • second messenger cascades, gene transcription etc.
  • … (…) - …
    • causes serotonin (and norepinephrine) transporters to run in reverse
    • increased release of serotonin and blocked reuptake
A
  • Selective Serotonin Reuptake Inhibitors e.g.fluoxetine (Prozac)
    • increase serotonin function by preventing its uptake
    • treatment for depression and anxiety disorders
    • but depression not a simple case of low serotonergic tone (effects not seen for 2-3 weeks)
    • increased availability of serotonin triggering downstream pathways
        • long term modulatory effects
        • second messenger cascades, gene transcription etc.
  • Methylenedioxymethamphetamine (MDMA) - ecstasy
    • causes serotonin (and norepinephrine) transporters to run in reverse
    • increased release of serotonin and blocked reuptake
42
Q

Drugs with general effects on serotonergic system

  • Selective Serotonin Reuptake Inhibitors e.g.fluoxetine (Prozac)
    • increase serotonin function by preventing its …
    • treatment for … and … disorders
    • but depression not a simple case of low serotonergic tone (effects not seen for …-… weeks)
    • increased availability of serotonin triggering downstream pathways
        • long term modulatory effects
        • second messenger cascades, gene transcription etc.
  • Methylenedioxymethamphetamine (MDMA) - ecstasy
    • causes serotonin (and norepinephrine) transporters to run in reverse
    • increased release of serotonin and blocked …
A
  • Selective Serotonin Reuptake Inhibitors e.g.fluoxetine (Prozac)
    • increase serotonin function by preventing its uptake
    • treatment for depression and anxiety disorders
    • but depression not a simple case of low serotonergic tone (effects not seen for 2-3 weeks)
    • increased availability of serotonin triggering downstream pathways
        • long term modulatory effects
        • second messenger cascades, gene transcription etc.
  • Methylenedioxymethamphetamine (MDMA) - ecstasy
    • causes serotonin (and norepinephrine) transporters to run in reverse
    • increased release of serotonin and blocked reuptake
43
Q

Drugs with effects on serotonergic receptors (2)

  • … – (Lysergic acid diethylamide) hallucinogen
    • Causes a dreamlike state with altered sensory perceptions
    • … potent agonist at 5HT1A receptors in raphe nucleus
    • Hallucinogenic properties at 5HT2A receptors in prefrontal cortex
A
  • LSD – (Lysergic acid diethylamide) hallucinogen
    • Causes a dreamlike state with altered sensory perceptions
    • LSD potent agonist at 5HT1A receptors in raphe nucleus
    • Hallucinogenic properties at 5HT2A receptors in prefrontal cortex
44
Q

The Noradrenergic System

  • Projections form the … … throughout the brain
  • Role in arousal and attention
  • … receptors
    • Alpha adrenergic receptors
      • a1 Gq
      • a2 Gi
    • Beta … receptors
      • b1, 2 and 3 Gs
A
  • Projections form the Locus Coeruleus throughout the brain
  • Role in arousal and attention
  • Metabotropic receptors
    • Alpha adrenergic receptors
      • a1 Gq
      • a2 Gi
    • Beta adrenergic receptors
      • b1, 2 and 3 Gs
45
Q

The Noradrenergic System

  • Projections form the Locus Coeruleus throughout the brain
  • Role in … and …
  • Metabotropic receptors
  • Alpha adrenergic receptors
    • a1 G…
    • a2 G…
  • Beta adrenergic receptors
    • b1, 2 and 3 G…
A
  • Projections form the Locus Coeruleus throughout the brain
  • Role in arousal and attention
  • Metabotropic receptors
  • Alpha adrenergic receptors
    • a1 Gq
    • a2 Gi
  • Beta adrenergic receptors
    • b1, 2 and 3 Gs
46
Q

The Adrenergic System

  • Primarily in lateral tegmental area, projecting to … and ….
  • Acts on a- and β- … receptors
A
  • Primarily in lateral tegmental area, projecting to thalamus and hypothalamus.
  • Acts on a- and β- adrenergic receptors
47
Q

The Cholinergic System

  • In the periphery
    • … at NMJ and synapses in the autonomic ganglia
  • In the brain
    • Basal forebrain complex
    • … innervation of the Hippocampus and the neocortex
  • Brain stem complex
    • innervates the dorsal … and telencephalon
    • control … of sensory relay neurons and provide a cholinergic link between the brain stem and basal forebrain complex
A
  • In the periphery
    • Acetylcholine at NMJ and synapses in the autonomic ganglia
  • In the brain
    • Basal forebrain complex
    • Cholinergic innervation of the Hippocampus and the neocortex
  • Brain stem complex
    • innervates the dorsal thalamus and telencephalon
    • control excitability of sensory relay neurons and provide a cholinergic link between the brain stem and basal forebrain complex
48
Q

The Cholinergic System

  • In the periphery
    • Acetylcholine at … and synapses in the … ganglia
  • In the brain
    • Basal … complex
    • Cholinergic innervation of the Hippocampus and the neocortex
  • Brain … complex
    • innervates the dorsal thalamus and telencephalon
    • control excitability of sensory relay neurons and provide a cholinergic link between the brain stem and basal forebrain complex
A
  • In the periphery
    • Acetylcholine at NMJ and synapses in the autonomic ganglia
  • In the brain
    • Basal forebrain complex
    • Cholinergic innervation of the Hippocampus and the neocortex
  • Brain stem complex
    • innervates the dorsal thalamus and telencephalon
    • control excitability of sensory relay neurons and provide a cholinergic link between the brain stem and basal forebrain complex
49
Q

Disorders of the cholinergic system

  • Peripheral
    • … … - Autoimmune disease - destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity
  • Brain
    • … disease - Loss of cholinergic neurons in the basal ganglia - possibly underlies deficits in memory associated with the disease.
    • Addiction: … addiction
    • … - Autosomal dominant nocturnal frontal lobe … (ADNFLE) associated with mutations in nicotinic receptor genes.
    • Other psychiatric disorders - Comorbidity with …
A
  • Peripheral
    • Myasthenia gravis - Autoimmune disease - destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity
  • Brain
    • Alzheimer’s disease - Loss of cholinergic neurons in the basal ganglia - possibly underlies deficits in memory associated with the disease.
    • Addiction: nicotine addiction
    • Epilepsy - Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with mutations in nicotinic receptor genes.
    • Other psychiatric disorders - Comorbidity with smoking
50
Q

Disorders of the cholinergic system

  • Peripheral
    • Myasthenia gravis - Autoimmune disease - destroys … receptors in the muscle - muscle … and eventual loss of muscle …
  • Brain
    • Alzheimer’s disease - … of cholinergic neurons in the basal ganglia - possibly underlies deficits in memory associated with the disease.
    • Addiction: nicotine addiction
    • Epilepsy - Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with … in nicotinic receptor genes.
    • Other psychiatric disorders - Comorbidity with smoking
A
  • Peripheral
    • Myasthenia gravis - Autoimmune disease - destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity
  • Brain
    • Alzheimer’s disease - Loss of cholinergic neurons in the basal ganglia - possibly underlies deficits in memory associated with the disease.
    • Addiction: nicotine addiction
    • Epilepsy - Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with mutations in nicotinic receptor genes.
    • Other psychiatric disorders - Comorbidity with smoking
51
Q

Acetylcholinesterase Inhibitors

  • Prolong action of acetylcholine at the synapse
    • Treatment for Alzheimer’s disease (e.g. physostigmine)
    • Treatment for Myasthenia gravis (neostigmine)
    • Insecticides & Chemical warfare agents, e.g. “Sarin”
  • NMJ:
    • B… - prevents release of ACh at NMJ
    • L… - permanent release - depletes ACh at NMJ
  • Two types of acetylcholine receptor
    • … - metabotropic
    • …. – ionotropic - Visceral motor system / sympathetic & parasympathetic preganglionic neurons
A
  • Prolong action of acetylcholine at the synapse
    • Treatment for Alzheimer’s disease (e.g. physostigmine)
    • Treatment for Myasthenia gravis (neostigmine)
    • Insecticides & Chemical warfare agents, e.g. “Sarin”
  • NMJ:
    • Botox - prevents release of ACh at NMJ
    • Latrotoxin - permanent release - depletes ACh at NMJ
  • Two types of acetylcholine receptor
    • Muscarinic - metabotropic
    • Nicotinic – ionotropic - Visceral motor system / sympathetic & parasympathetic preganglionic neurons
52
Q

Acetylcholinesterase Inhibitors

  • Prolong action of acetylcholine at the synapse
    • Treatment for … disease (e.g. physostigmine)
    • Treatment for … … (neostigmine)
    • Insecticides & Chemical warfare agents, e.g. “Sarin”
  • NMJ:
    • Botox - prevents release of ACh at NMJ
    • Latrotoxin - permanent release - depletes ACh at NMJ
  • Two types of acetylcholine receptor
    • Muscarinic - …
    • Nicotinic – … - Visceral motor system / sympathetic & parasympathetic preganglionic neurons
A
  • Prolong action of acetylcholine at the synapse
    • Treatment for Alzheimer’s disease (e.g. physostigmine)
    • Treatment for Myasthenia gravis (neostigmine)
    • Insecticides & Chemical warfare agents, e.g. “Sarin”
  • NMJ:
    • Botox - prevents release of ACh at NMJ
    • Latrotoxin - permanent release - depletes ACh at NMJ
  • Two types of acetylcholine receptor
    • Muscarinic - metabotropic
    • Nicotinic – ionotropic - Visceral motor system / sympathetic & parasympathetic preganglionic neurons
53
Q

Muscarinic receptors – metabotropic

  • … (agonist) found in poisonous mushroom Amanita muscaria
  • … (antagonist) belladonna alkaloid extracted from deadly nightshade
    • M1
    • M3 via Gq to phospatidylinositol hydrolysis
    • M5 (smooth muscles and glands)
    • M2
    • M4 via Gi to inhibit cAMP (smooth and cardiac muscle)
  • Lead to opening or closing of …+, …+ or …- channels - hyperpolarization or depolarization (cell type/receptor type dependent)
  • Pre and postsynaptic receptors
  • Presynaptic autoreceptors - negative feedback - stop ACh release
A
  • Muscarine (agonist) found in poisonous mushroom Amanita muscaria
  • Atropine (antagonist) belladonna alkaloid extracted from deadly nightshade
    • M1
    • M3 via Gq to phospatidylinositol hydrolysis
    • M5 (smooth muscles and glands)
    • M2
    • M4 via Gi to inhibit cAMP (smooth and cardiac muscle)
  • Lead to opening or closing of K+, Ca2+ or Cl- channels - hyperpolarization or depolarization (cell type/receptor type dependent)
  • Pre and postsynaptic receptors
  • Presynaptic autoreceptors - negative feedback - stop ACh release
54
Q

Nicotinic receptors - ionotropic

  • Nicotine (agonist) found in … - 5 subunits surrounding a central pore
    • … receptor 2x a1, b, d and g subunits
      • (neuromuscular junction NMJ)
      • (Antagonist - curare (poison darts) - instant paralysis)
    • … receptors
      • Heteromeric combination of a3,4,5 and b2,3,4 or 6
      • Homomeric receptors a7, 8 or 9
      • a3b4 on autonomic ganglia
      • a4b2 and a7 most common brain receptors
  • Vary in their pharmacology, selectivity and kinetics and conductance
  • Located pre and …
A
  • Nicotine (agonist) found in tobacco - 5 subunits surrounding a central pore
    • Muscle receptor 2x a1, b, d and g subunits
      • (neuromuscular junction NMJ)
      • (Antagonist - curare (poison darts) - instant paralysis)
    • Neuronal receptors
      • Heteromeric combination of a3,4,5 and b2,3,4 or 6
      • Homomeric receptors a7, 8 or 9
      • a3b4 on autonomic ganglia
      • a4b2 and a7 most common brain receptors
  • Vary in their pharmacology, selectivity and kinetics and conductance
  • Located pre and postsynaptically
55
Q

Nicotinic receptors - ionotropic

  • Nicotine (agonist) found in tobacco - 5 subunits surrounding a central pore
    • Muscle receptor 2x a1, b, d and g subunits
      • (neuromuscular junction NMJ)
      • (Antagonist - curare (poison darts) - instant paralysis)
    • Neuronal receptors
      • Heteromeric combination of a3,4,5 and b2,3,4 or 6
      • Homomeric receptors a7, 8 or 9
      • a3b4 on autonomic ganglia
      • a4b2 and a7 most common brain receptors
  • Vary in their pharmacology, selectivity and kinetics and conductance
  • Located pre and postsynaptically
A
  • Nicotine (agonist) found in tobacco - 5 subunits surrounding a central pore
    • Muscle receptor 2x a1, b, d and g subunits
      • (neuromuscular junction NMJ)
      • (Antagonist - curare (poison darts) - instant paralysis)
    • Neuronal receptors
      • Heteromeric combination of a3,4,5 and b2,3,4 or 6
      • Homomeric receptors a7, 8 or 9
      • a3b4 on autonomic ganglia
      • a4b2 and a7 most common brain receptors
  • Vary in their pharmacology, selectivity and kinetics and conductance
  • Located pre and postsynaptically
56
Q

The Histaminergic System

  • … & attention
  • Reactivity of … system
  • Mediation of … responses
  • Influence of brain blood flow
  • 3 …-protein-coupled Rs
A
  • Arousal & attention
  • Reactivity of vestibular system
  • Mediation of allergic responses
  • Influence of brain blood flow
  • 3 G-protein-coupled Rs
57
Q

The Histaminergic System

  • Arousal & …
  • Reactivity of vestibular system
  • Mediation of allergic responses
  • Influence of … … flow
  • 3 G-protein-… Rs
A
  • Arousal & attention
  • Reactivity of vestibular system
  • Mediation of allergic responses
  • Influence of brain blood flow
  • 3 G-protein-coupled Rs
58
Q

Summary - How drugs control the brain

  • Modulation of brain activity and function by GABA and the diffuse neurotransmitter systems
  • Many receptors for each …
  • Diverse receptor properties and differential distribution throughout the brain allows single neurotransmitters to modulate multiple …
  • DA - only …
  • S - both …and …
A
  • Modulation of brain activity and function by GABA and the diffuse neurotransmitter systems
  • Many receptors for each neurotransmitter
  • Diverse receptor properties and differential distribution throughout the brain allows single neurotransmitters to modulate multiple behaviours
  • DA - only metaboptropic
  • S - both m and I

Year 2 Medicine (162 decks)

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