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202 theme 1 > How Drugs Control the Brain > Flashcards

How Drugs Control the Brain Flashcards

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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?

Study These Flashcards
A 
D1, D2 and D2 
coupled to Gi 
inhibit adenylyl cyclase
open K+ channels, close Ca2+ channels
postsynaptic and presynaptic (D3 autoreceptors)
25
what is the nigrostriatal system?
cells bodies in the substania nigra project to the striatum (caudate nucleus and putamen) important part of basal ganglia involved in movement
26
what can dysfunction of the nigrostriatal system cause?
Parkinson's disease | Huntington's disease
27
what is Parkinson's disease?
destruction of DA projections from SN to basal ganglia
28
what is Huntington's disease?
destruction of DA target neurons in striatum
29
which drugs act on the nigrostriatal system?
L-dopa, monoamine inhibitors (MAOi), dopamine receptor agonists = treatments for Parkinson's disease
30
what is the mesolimbic system?
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
psychomotor stimulants
cocaine | amphetamine
32
immediate effects of psychomotor stimulants on the mesolimbic system
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
long-term effects of psychomotor stimulants on the mesolimbic system
``` 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
what is the mesocortical system?
VTA projections to prefrontal cortex | roles in function such as working memory and planning
35
what can mesocortical system dysfunction cause?
schizophrenia
36
which drugs can affect the mesocortical system?
typical and atypical antipsychotics
37
how do typical antipsychotics work?
DA receptor antagonists increase DA turnover - lose autoreceptor inhibition blockage of postsynaptic receptors leads to upregulation e.g. chlorpromazine, haloperidol
38
side effects of typical antipsychotics
action on other dopaminergic systems extrapyramidal side effects (EPS) - tardive dyskinesia, etc system becomes supersensitive due to chronic blockade
39
how to atypical antipsychotics work?
specific to receptor subtype e.g. clozapine - antagonist of D4 receptors (only in cortex) reduce psychosis associated with schizophrenia without EPS
40
what does the serotonergic system have functions in?
mood, sleep, pain, emotion, appetite | many receptors - metabotropic and ionotropic
41
which drugs can affect the serotonergic system?
SSRIs MDMA LSD
42
how do SSRIs work?
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
how does MDMA work?
``` causes serotonin (+noradrenaline) receptors to run in reverse increased release of serotonin and blocked reuptake ```
44
how does LSD work?
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
what is the noradrenergic system?
``` 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
what is the adrenergic system?
primarily in lateral tegmenatal area projecting to thalamu and hypothalamus act on alpha and bet adrenergic receptors
47
what is the periphery cholinergic system?
acetylcholine at NMJ | synapses at autonomic ganglia
48
what is the central cholinergic system?
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
peripheral disorders of the cholinergic system
myasthenia gravis
50
what is myasthenia gravis?
auto-immune disease destroys cholinergic receptors in the muscle muscle weakness and eventual loss of muscle activity
51
central (brain) disorders of the cholinergic system
Alzheimer's disease addition (nicotine) epilepsy - mutations in nicotinic receptor genes other psychiatric disorders - comorbidity with smoking
52
what is Alzheimer's disease?
loss of cholinergic neurons in basal ganglia | possibly underlies deficits in memory associated with disease
53
what to acetylcholinesterase inhibitors do?
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
types of muscarinic receptors
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
what are muscarinic receptors?
metabotropic ACh receptors muscarine = agonist found in poisonous mushroom atropine = antagonist, belladonna alkaloid from deadly nightshade
56
what are nicotinic receptors?
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
nicotinic muscle receptors
2x alpha 1, beta, delta and gamma subunits at neuromuscular junction antagonist = curare - instant paralysis
58
nicotinic neuronal receptor
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
what is the histaminergic system involved in?
``` 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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