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Year 2 - Theme 1 > How drugs control the brain - L13 > Flashcards

How drugs control the brain - L13 Flashcards

1
Q

What happens when there is too much GABA?

A
  • Loss of consciousness and coma
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2
Q

What happens when there is too little GABA?

A
  • Leads to convulsions and seizures
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3
Q

How do epilepsy treatments act on GABA

A
  • Many epilepsy treatments act to enhance GABA transmission
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4
Q

Main types of neurons

A
  • Projection neurons - GLU(exception is purkinje cell in cerebellum which is GABAergic)
  • Local interneurons - GABA
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5
Q

Types of influential interneurons affecting cortical pyramidal neurons?

A
  • Basket cells
  • Axo-axonic acells
  • Dendrite-targeting interneurons
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6
Q

How do interneurons influence cortical pyramidal neurons?

A
  • Information is transferred from excitatory glutamatergic synapses to the pyramidal neuron dendrite
  • Excitation travels along the dendritic tree to the soma and axon initial segment, where it could generate an action potential
  • Along this dendro-somatic-axonal axis, information can be differently filtered by GABAergic synapses possessing specific basic and plasticity properties
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7
Q

What are the two main families of GABA receptor families

A

GABA(a) ionotropic receptors and GABA(b) metabotropic receptors

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8
Q

Describe GABA(a) ionotropic receptors

A
  • Ligand gated Cl- channel
  • Fast IPSPs
  • Mainly GABAergic interneurons
  • Post synaptic
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9
Q

Describe GABA(b) metabotropic receptors

A
  • G protein coupled 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

What is the more recently discovered GABA receptor?

A

GABAc is a more recently discovered third class which is similar to GABAa in structure and functions, but are made of different type

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11
Q

What are the subunits that make up GABA(a) receptors

A
  • Heteropentameric structure - 2 alpha + 3 more subunits
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12
Q

What is picrotoxin?

A
  • Is a non-competitive GABAa antagonist that can cause convulsions
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13
Q

What is a direct agonist of GABA(a) receptor?

A
  • Muscimol
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14
Q

What is a direct antagonist of GABA(a) receptor(experimental tool)?

A
  • Bicuculline
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15
Q

What are indirect agonists of GABA(a) receptors

A
  • Benzodiazepine - binding increases the receptor affinity for GABA
  • Increase frequency of channel opening
  • Anxiolytic(drugs used to reduce anxiety) 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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16
Q

What is the action of benzodiazepine action eg diazepam(valium)

A
  • Benzodiazepine binding site on the alpha subunit of GABA(a) receptor
  • Indirect agonist - benzodiazpine binds to alpha subunit, changes conformation of the receptor so GABA activation of receptor is more effective
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17
Q

What are the effects of benzodiazepine

A
  • Reduce anxiety
  • Cause sedation
  • Reduce convulsions
  • Relax muscles
  • Cause amnesia
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18
Q

What is the effect of inverse agonists?

A
  • Inverse agonists bind to benzodiazepine site and have opposite effects
  • Produce anxiety and predisposition to convulsions
19
Q

How do barbiturates and alcohol affect GABA(A)Rs

A
  • Bind at different sites on the receptor
  • Both have same effect, to enhance GABA(A) activity and effects are additive
  • Alcohol also interacts with NMDA, glycine, nicotinic and serotonin receptors
  • Low doses of alcohol - mild euphoria and anxiolytic effects
  • Higher doses - incoordination, amnesia
20
Q

What is baclofen?

A
  • GABA(b) receptor agonist

- Used as a muscle relaxant to reduce spasticity eg in huntington’s disease

21
Q

What is the effect of Gi coupled receptor

A
  • Inhibits adenylyl cyclase
  • Gby gated k+ channels
  • Increases K+ conductance
  • Decreases Ca2+ conductance(presynaptically)
  • Slow hyperpolarizing current(late inhibitory postsynaptic potential)
22
Q

Does inhibition of GABA(b) transmission have the same effect as inhibiting GABA(a) receptors

A

No. eg seizure

23
Q

What are diffuse modulatory systems

A
  • Specific populations of neurons that project diffusely and modulate the activity of glutamate and GABA neurons in their areas
24
Q

What are patterns of communication in the neurotransmitter systems -

A
  • Point-point-point systems
  • Hormones released by the hypothalamus
  • ANS neurons activating body tissues
  • Diffuse modulatory system with divergent axonal projections(not classical synapse)
25
Q

What are the systems that are part of the dopaminergic system

A
  • Nigrostriatal system(75% of brain DA) - motor control
  • Mesolimbic system
  • Mesocortical system(behavioural effects)
  • Tuberohypophyseal system(endocrine control)

Cell bodies in the midbrain that project into the forebrain

26
Q

Is dopamine excitatory or inhibitory

A
  • Dopamine produces both EPSPs and IPSPs depending on the receptor subtype and coupled G proteins
27
Q

What are the metabotropic dopamine receptors?

A
  • D1-5
28
Q

How do D1-like receptors function?

A
  • D1-like(1 and 5)
  • Gs stimulates adenylyl cyclase
  • Stimulates phospholipase C
  • Postsynaptic
29
Q

How do D2-like receptors function?

A
  • D2-like(2,3 and 4)
  • Gi - inhibit adenylyl cyclase
  • open K+ channels
  • Close Ca2+ channels
  • Postsynaptic
  • presynaptic autoreceptors(D3)
30
Q

What is the nigrostriatal system?

A
  • Cell bodies in the substantia nigra project to the striatum(caudate nucleus and putamen)
  • Important part of the basal ganglia involved in movement
31
Q

What can dysfunction of the nigrostriatal system cause?

A
  • Parkinson’s disease - destruction of DA projections from SN to basal ganglia
  • Huntington’s disease - destruction of DA target neurons in striatum
32
Q

What drugs are used to treat parkinson’s

A
  • L-DOPA, monoamine oxidase inhibitors, dopamine receptor agonists-treatments for parkinson’s disease
33
Q

Why is substantia nigra a ‘black substance’

A
  • Due to high levels of melanin in dopaminergic neurons
34
Q

What is the mesolimbic system

A
  • 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
35
Q

What happens when there is dysfunction of the mesolimbic system

A
  • Addiction - most drugs of abuse lead to enhanced DA release in the NAcc
  • eg. cocaine and amphetamine - psychomotor stimulants
36
Q

What are the immediate effects of psychomotor stimulants when there is dysfunction of the mesolimbic system

A
  • Give the feeling of increased alertness and self confidence, a sense of exhilaration and euphoria and a decreased appetite
  • Large doses can cause stereotypy(persistent repetition of an act) 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
37
Q

What are the long-term effects of psychomotor stimulants where there is dysfunction of the mesolimbic system

A
  • Natural rwards, eg 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
38
Q

What is the mesocortical system?

A
  • VTA projections to prefrontal cortex

- Role in functions such as working memory and planning

39
Q

What drugs are typical antipsychotics that have an effect on the mesocortical system

A
  • Chlorpromazine and haloperidol
40
Q

Effect of chlorpromazine and haloperidol on the mesocortical system

A
  • DA receptors anatagonists(pre and postsynaptic)
  • Increase DA turnover - lose autoreceptor inhibition
  • Blockade of postsynaptic receptors - upregulation
41
Q

What are the side effects of antipsychotics on other dopaminergic systems?

A
  • Action on other dopaminergic systems

- Extrapyramidal side effects - tardive dyskinesia etc (chronic blockade causes system to become supersensitive)

42
Q

What is an atypical antipsychotic

A
  • Specific to receptor subtype

- eg clozapine - antagonist of D4 receptors(cortex only)

43
Q

Effects of clozapine

A
  • Reduce psychosis associated with schizophrenia

- Antipsychotic effects without EPS

Year 2 - Theme 1 (30 decks)

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