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202 theme 1 > How Drugs Control the Brain > Flashcards

How Drugs Control the Brain Flashcards

1
Q

what is the GABAergic system?

A

widespread distribution throughout the brain
inhibitory interneurons - keep excitation in check
many epilepsy treatments act to enhance GABA transmission

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2
Q

what happens if there is too much/too little GABA?

A

too much: loss consciousness and coma

too little: leads to convulsions and seizures

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3
Q

what are the main neuronal types?

A

projection neurons: glutamate

local interneurons: GABA

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4
Q

how is inhibition of cortical pyramidal neurons controlled?

A

information is transferred from excitatory glutamergic synapses to pyramidal neuron dendrite
excitation (information) travels along dendritic tree to soma and axon initial segment (could initiate action potential)
along dendro-somatic-axonal axis, information can be differently filtered by GABAergic synapses processing specific, basic and plastic properties

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5
Q

main families of GABA receptor

A

GABA(A) ionotropic receptors - fast IPSPs, mostly GABAergic interneurons
GABA(B) metabotropic receptors - slow IPSPs, both pre and postsynaptic
GABA (C) = recently discovered 3rd class - similar to GABA(A)

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6
Q

GABA (A) ionotropic receptors

A

heteropentameric structures - 2 alpha + 3 more subunits
Cl- channel gates by binding of 2 agonist molecules (GABA)
Cl- potential is near resting potential, increasing Cl- permeability
hyperpolarises the neuron
decreases depolarising effect of excitatory input

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7
Q

what is picrotoxin?

A

non-competitive antagonist of GABA(A) receptor
can cause convulsions
comes from fishberry, no clinical uses

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8
Q

direct agonists and antagonists of GABA(A) receptors

A

muscimol (agonist)

bicuculline (antagonist)

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9
Q

indirect agonists of GABA(A) receptors

A

benzodiazepines - increases receptor affinity for GABA
barbituates - incerase duration of channel opening
alcohol

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10
Q

how do benzodiazepines work?

A

binding site is on alpha subunit of GABA(A) receptor

changes conformation of receptor, so GABA activation of receptor is more effective - channel opens more frequently

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11
Q

effects of benzodiazepines

A

anxiolytic and hypnotic drugs with rapid onset

cause sedation, reduce convulsions, relax muscles, cause amnesia

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12
Q

how do barbituates work?

A

bind at different sites on receptor
enhance GABA (A) activity
effects are additive -

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13
Q

how does alcohol work?

A

interacts with NMDA, glycine, nicotinic and serotonin receptors
low doses: mile euphoria, anxiolytic
high doses: incoordination, amnesia

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14
Q

GABA (B) metabotropic receptors

A

Gi coupled - inhibits adenylyl cyclase
G beta-gamma gated K+ channels - K+ conductance increases, Ca2+ conductance presynaptically decreases
slow hyperpolarising current (late IPSP)
inhibition does not have same behavioural outcome as inhibition of GABA (A) receptors

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15
Q

what is baclofen?

A

GABA (B) receptor agonist
used as muscle relaxant to reduce spasticity
e.g. in Huntington’s disease

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16
Q

what do glutamate neurons do?

A

primary route of sensory and motor information and relay neurons between brain areas

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17
Q

what do GABA neurons do?

A

interneurons: maintain balance between excitation and inhibition

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18
Q

what are diffuse modulatory systems?

A

specific populations of neurons that project diffusely and modulate activity of glutamate and GABA neurons in target areas

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19
Q

examples of diffuse modulatory systems

A 
dopaminergic (DA)
serotonergic (5-HT)
noradrenergic (NA)
adrenergic 
cholinergic (ACh)
histaminergic
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20
Q

patterns of communication in the nervous system

A

point-to-point
hormones released by hypothalamus
ANS neurons activating body tissues
diffuse modulatory system with divergent axonal projections

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21
Q

what is the dopaminergic system?

A 
dopamine neurons : cell bodies in midbrain which project to forebrain
involves 3 systems:
nigrostriatal 
mesolimbic 
mesocortical
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22
Q

types of dopamine receptors

A

metabotropic receptors
D1-D5
can produce both EPSPs and IPSPs (depends on subtype and coupled G proteins)
D1-like, D2-like

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23
Q

what are D1-like dopamine receptors?

A 
D1 and D5
coupled to Gs
stimulate adenylyl cyclase 
stimulate phospholipase C 
postsynaptic
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24
Q

what are D2-like dopamine receptors?

A 
D1, D2 and D2 
coupled to Gi 
inhibit adenylyl cyclase
open K+ channels, close Ca2+ channels
postsynaptic and presynaptic (D3 autoreceptors)
25
Q

what is the nigrostriatal system?

A

cells bodies in the substania nigra project to the striatum (caudate nucleus and putamen)
important part of basal ganglia involved in movement

26
Q

what can dysfunction of the nigrostriatal system cause?

A

Parkinson’s disease

Huntington’s disease

27
Q

what is Parkinson’s disease?

A

destruction of DA projections from SN to basal ganglia

28
Q

what is Huntington’s disease?

A

destruction of DA target neurons in striatum

29
Q

which drugs act on the nigrostriatal system?

A

L-dopa, monoamine inhibitors (MAOi), dopamine receptor agonists
= treatments for Parkinson’s disease

30
Q

what is the mesolimbic system?

A

cell bodies in ventral tegmental are (VTA) project to the limbic system - nucleus accumbens
role in reinforecement (reward) in several categories of stimuli eg. drugs of abuse

31
Q

psychomotor stimulants

A

cocaine

amphetamine

32
Q

immediate effects of psychomotor stimulants on the mesolimbic system

A

feeling of increased alertness and self confidence
sense of exhilaration and euphoria
decreased appetite
in large doses: stereotypy and psychosis
peripheral effects that mimic activation of ANS (increased HR and BP, pupil dilation)

33
Q

long-term effects of psychomotor stimulants on the mesolimbic system

A 
natural rewards (water, food, sex) increase DA transmission, leading to reinforcement of associated behaviours 
increase DA by cocaine short-circuits the pathway: drug taking behaviours are reinforced 
downregulation of endogenous DA system (craving)
34
Q

what is the mesocortical system?

A

VTA projections to prefrontal cortex

roles in function such as working memory and planning

35
Q

what can mesocortical system dysfunction cause?

A

schizophrenia

36
Q

which drugs can affect the mesocortical system?

A

typical and atypical antipsychotics

37
Q

how do typical antipsychotics work?

A

DA receptor antagonists
increase DA turnover - lose autoreceptor inhibition
blockage of postsynaptic receptors leads to upregulation
e.g. chlorpromazine, haloperidol

38
Q

side effects of typical antipsychotics

A

action on other dopaminergic systems
extrapyramidal side effects (EPS) - tardive dyskinesia, etc
system becomes supersensitive due to chronic blockade

39
Q

how to atypical antipsychotics work?

A

specific to receptor subtype
e.g. clozapine - antagonist of D4 receptors (only in cortex)
reduce psychosis associated with schizophrenia without EPS

40
Q

what does the serotonergic system have functions in?

A

mood, sleep, pain, emotion, appetite

many receptors - metabotropic and ionotropic

41
Q

which drugs can affect the serotonergic system?

A

SSRIs
MDMA
LSD

42
Q

how do SSRIs work?

A

increase serotonin function by preventing reuptake
treatment for anxiety and depression
effects not seen for 2-3 weeks
increased availability of serotonin triggers downstream pathways
long term modulatory effects (second messenger cascades, gene transcription)

43
Q

how does MDMA work?

A 
causes serotonin (+noradrenaline) receptors to run in reverse 
increased release of serotonin and blocked reuptake
44
Q

how does LSD work?

A

hallucinogen
causes dreamlike state with altered sensory perception
potent agonist at 5-HT1 A receptors in raphe nucleus
hallucinogenic properties at 5-HT2 A receptors in prefrontal cortex

45
Q

what is the noradrenergic system?

A 
projections from locus coeruleus throughout brain 
role in arousal and attention
metabotropic receptors 
alpha adrenergic:
alpha 1 = Gq, 
alpha 2 = Gi
beta adrenergic - Gs
best activated by novel non painful stimuli
46
Q

what is the adrenergic system?

A

primarily in lateral tegmenatal area projecting to thalamu and hypothalamus
act on alpha and bet adrenergic receptors

47
Q

what is the periphery cholinergic system?

A

acetylcholine at NMJ

synapses at autonomic ganglia

48
Q

what is the central cholinergic system?

A

basal forebrain complex: cholinergic innervation of hippocampus and neocortex
brainstem complex: innervates dorsal thalamus and telencephalon
controls excitability of sensory relay neurons
provide cholinergic link between brain stem and basal forebrain complex

49
Q

peripheral disorders of the cholinergic system

A

myasthenia gravis

50
Q

what is myasthenia gravis?

A

auto-immune disease
destroys cholinergic receptors in the muscle
muscle weakness and eventual loss of muscle activity

51
Q

central (brain) disorders of the cholinergic system

A

Alzheimer’s disease
addition (nicotine)
epilepsy - mutations in nicotinic receptor genes
other psychiatric disorders - comorbidity with smoking

52
Q

what is Alzheimer’s disease?

A

loss of cholinergic neurons in basal ganglia

possibly underlies deficits in memory associated with disease

53
Q

what to acetylcholinesterase inhibitors do?

A

prolong acetylcholine action at the synapse
treatment for Alzheimer’s: physotigmine
treatmetn for Myasthenia gravis: neostigmine
botox - prevents release of ACh at NMJ
latrotoxin - depletes ACh at NMJ

54
Q

types of muscarinic receptors

A

M1, M3, M5: via Gq to phophatidylinositol hydrolysis (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
post and presynaptic receptors
prsynaptic autoreceptors provide negative feedback to stop ACh release

55
Q

what are muscarinic receptors?

A

metabotropic ACh receptors
muscarine = agonist found in poisonous mushroom
atropine = antagonist, belladonna alkaloid from deadly nightshade

56
Q

what are nicotinic receptors?

A

ionotopic ACh receptors
vary in pharmacology, selectivity, kinetics and conductance
located pre and post synaptically
5 sububits surrounding a central pore
nicotine = agonist
Na+ and Ca2+ depolarisation and direct transmitter release

57
Q

nicotinic muscle receptors

A

2x alpha 1, beta, delta and gamma subunits
at neuromuscular junction
antagonist = curare - instant paralysis

58
Q

nicotinic neuronal receptor

A

heteromeric combination of alpha 3, 4, 5 and beta 2, 3, 4
homomeric receptros of alpha 7, 8, 9
alpha-3 beta-4 on autonomic ganglia
alpha-4 beta-2 and alpha-7 are most common brain receptors

59
Q

what is the histaminergic system involved in?

A 
arousal and attention
reactivity of vestibular system 
mediation of allergic responses 
influence brain blood flow 
3 g-protein coupled receptors

202 theme 1 (13 decks)

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