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Year 2 Medicine > How Drugs Control the Brain > Flashcards

How Drugs Control the Brain Flashcards

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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
Study These Flashcards
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
_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
* 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
_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)
* 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
_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)
* 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
_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 ...
* 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
_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
* 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
_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 ...
* 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
_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
* **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
_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...
* 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
_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
* 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
_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
* 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
_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 ...
* 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
DA acts through ionotropic receptors T OR F
F - metabotropic only
37
_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 ...
* 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
_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
* **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
_The Serotonergic system_ * function in:- * M... * S... * P... * E... * A...
* function in:- * **mood** * **sleep** * **pain** * **emotion** * **Appetite**
40
Serotonin receptors - metabotropic / ionotropic?
both (not assessed in detail)
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_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
* 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
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_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 ...
* 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
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_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
* **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**
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_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
* **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**
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_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...
* **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**
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_The Adrenergic System_ * Primarily in lateral tegmental area, projecting to ... and .... * Acts on a- and β- ... receptors
* **Primarily in lateral tegmental area, projecting to thalamus and hypothalamus.** * **Acts on a- and β- adrenergic receptors**
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_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
* 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
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_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
* **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**
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_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 ...
* 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**
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_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
* 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
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_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
* 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
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_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
* 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
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_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
* **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
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_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 ...
* **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**
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_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
* 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
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_The Histaminergic System_ * ... & attention * Reactivity of ... system * Mediation of ... responses * Influence of brain blood flow * 3 ...-protein-coupled Rs
* **Arousal** & attention * Reactivity of **vestibular** system * Mediation of **allergic** responses * Influence of brain blood flow * 3 **G**-protein-coupled Rs
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_The Histaminergic System_ * Arousal & ... * Reactivity of vestibular system * Mediation of allergic responses * Influence of ... ... flow * 3 G-protein-... Rs
* **Arousal & attention** * **Reactivity of vestibular system** * **Mediation of allergic responses** * **Influence of brain blood flow** * **3 G-protein-coupled Rs**
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_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 ...
* 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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