How Drugs Control the Brain Flashcards
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)
- 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)
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)
- 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)
Too much GABA = loss of … and …
- Too much GABA = loss of consciousness and coma
- (Too little GABA = leads to convulsions and seizures)
Too little GABA = leads to … and …
- Too little GABA = leads to convulsions and seizures
- (Too much GABA = loss of consciousness and coma)
Many epilepsy treatments aim to enhance … transmission
GABA
Main Neuronal Types - GABA vs GLU
- … neurons - use GLUTAMATE (excitatory)
- … interneurons - use GABA (inhibitory)
- Projection neurons - use GLUTAMATE (excitatory)
- Local interneurons - use GABA (inhibitory)

Inhibitory control of cortical pyramidal neurons

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
- 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

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
- 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

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
- 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

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
- B… - binding increases the receptor affinity for GABA
- 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
-
Benzodiazepine - binding increases the receptor affinity for GABA
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
- Benzodiazepine - binding increases the receptor affinity for GABA
- 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
- Benzodiazepine - binding increases the receptor affinity for GABA
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 …
- 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
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
- …
- 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
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, …
- 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
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
- 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
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. …)
- 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)
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. …)
-
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)
Baclofen is a GABA-… agonist that has been used for muscle spasms and spasticity, and neuropathic pain. - in what disease?
Baclofen is a GABA-B agonist that has been used for muscle spasms and spasticity, and neuropathic pain. - huntington’s disease
GABA… receptor agonists: Alcohol (ethanol), barbiturates, and benzodiazepine.
GABAa receptor agonists: Alcohol (ethanol), barbiturates, and benzodiazepine.
GABA… receptor agonists: Baclofen
GABAb receptor agonists: Baclofen
- Which of these does not bind to a GABA(A)R?
- A.Benzodiazepine
- B.Ethanol
- C.PCP (phencyclidine)
- D.Barbiturate
- E.GABA
- 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
GABA is always an inhibitory neurotransmitter - T OR F
- It depends on the elechtrochemical gradient of Cl- ions. It is excitatory during development.
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
- 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
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
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)
*

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)
*

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
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
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
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
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
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
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)
- Typical antipsychotics (e.g. chlorpromazine and …)
- 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
- Specific to receptor subtype
- 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)
- Typical antipsychotics (e.g. chlorpromazine and haloperidol)
- 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
- Specific to receptor subtype
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)
- Side effects - action on other dopaminergic systems
- Typical antipsychotics (e.g. chlorpromazine and haloperidol)
- Atypical antipsychotics (E.g. …)
- Specific to receptor subtype
- E.g … - antagonist of D4 receptors (cortex only)
- Reduce psychosis associated with schizophrenia
- Antipsychotic effects without …
- Specific to receptor subtype
- 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)
- Typical antipsychotics (e.g. chlorpromazine and haloperidol)
- 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
- Specific to receptor subtype
DA acts through ionotropic receptors T OR F
F - metabotropic only
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

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

The Serotonergic system
- function in:-
- M…
- S…
- P…
- E…
- A…
- function in:-
- mood
- sleep
- pain
- emotion
- Appetite
Serotonin receptors - metabotropic / ionotropic?
both (not assessed in detail)

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
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
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
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
- Alpha adrenergic receptors
- 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
-
Alpha adrenergic receptors
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
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
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
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
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
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
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
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
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
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
- … receptor 2x a1, b, d and g subunits
- 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
-
Muscle receptor 2x a1, b, d and g subunits
- Vary in their pharmacology, selectivity and kinetics and conductance
- Located pre and postsynaptically
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
- Muscle receptor 2x a1, b, d and g subunits
- 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
- Muscle receptor 2x a1, b, d and g subunits
- Vary in their pharmacology, selectivity and kinetics and conductance
- Located pre and postsynaptically
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

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

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