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MPharm Y3S2 > Pharmacology CNS > Flashcards

Pharmacology CNS Flashcards

1
Q

What is the CNS composed of?

A

The brain and the spinal cord

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2
Q

What are the different regions of the brain?

A

Brain stem
Cerebellum
Forebrain

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3
Q

What are the cavities in the brain?

A

Called ventricles, contains the cerebrospinal fluid

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4
Q

What are the functions of the brain stem?

A

Relay centre- all info from spinal cord
Reticular formation- important in consciousness and wakefulness
Reflexes involved in balance and posture
Site of exit for most cranial nerves

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5
Q

What is the function of the relay centre in the brain stem?

A

All info from spinal cord
Information between higher brain and spinal cord
Initial processing (neural integration)- synapses, not a passive process

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6
Q

What is the function of reticular formation in the brain stem?

A

Important in consciousness and wakefulness
Network of neurones throughout the brain stem
Receives and integrates sensory input from periphery- ‘filters’ unnecessary information
Consciousness- unconscious when sleeping-only allows very important info, arousal (wakefulness)= reticular activating system

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7
Q

Name the different areas of the brain stem:

A

Midbrain (top)
Pons (middle)
Medulla oblongata (bottom)

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8
Q

Describe the functions of the medulla oblongata:

A

Involuntary functions
-vital reflex centre (control of breathing, circulation, digestion e.g the respiratory control centre)
-non vital relex centre (e.g coughing, vomiting (chemoreceptor trigger zone-CTZ, when stimulated, triggers vomiting))

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9
Q

Describe the function of the midbrain:

A

Contains the substantia nigra
Important in Parkinsons disease

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10
Q

What are the functions of the cerebellum?

A

Attached to the brainstem
involved in co-ordinated voluntary movement (fine control)
Integration of information:
-position of the body
-sensory info from muscles, joints, skin, eyes, ears, viscera, inputs from motor areas of the cerebrum
-involved in planning and initiation of movement, inputs from motor areas
-Procedural memory, co-ordination of subconscious motor tasks
Balance
Eye movement

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11
Q

Name the two areas of the forebrain:

A

Cerebrum
Diencephalon

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12
Q

Name the two subparts of the diencephalon:

A

Thalamus
Hypothalamus

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13
Q

What is the function of the thalamus?

A

Relay centre
Sensory input (all via thalamus, preliminary processing, filtering, directing of signals)- directing attention
Motor control

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14
Q

What is the function of the hypothalamus?

A

Major homeostatic control centre
Integrates homeostatic input e.g BP, HR
Regulation of autonomic NS and endocrine system
e.g control of body temp
Controls secretion of hormones by the pituitary gland
Forms part of the limbic system (emotion, behavioural patterns and memory)
Role in sleep wake cycle

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15
Q

What is the limbic system?

A

Interconnecting group of structures in the forebrain
Basic emotions
Neural centres controlling basic behaviour
Olfaction (smell)- olfactory bulb
Hippocampus (memory)

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16
Q

Describe the basic emotions due to the limbic system:

A

Fear, anxiety, anger- stimulate amygdala
Pleasure, satisfaction- septal nuclei

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17
Q

Describe the neural centres controlling basic behaviours in the limbic system:

A

Preparing for attack/ defence, laughing, crying
Survival- eating, drinking, sexual behaviour- reward pathways- drug stimulating these pathways can cause addiction
Punishment pathways

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18
Q

Describe the composition of the cerebrum:

A

Consists of the cerebral cortex and the basal nuclei (aka basal ganglia)
Collections of neuronal cell bodies (nuclei or ganglia) includes stratum (caudate nucleus, putamen and separating structure), globus plaids
Also the substantia nigra and the subthalamic nuclei in the brainstem

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19
Q

What is the function of the cerebrum?

A

Involved in control of movement (extrapyramidal motor system)
Modulation of motor activity- generally an inhibitory role
Inhibit muscle tone (stop muscle being contracted)
Purposeful vs unwanted movements
Posture/support (co-ordination of sustained contractions)

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20
Q

Describe the structure and function of the cerebral cortex:

A

Two hemispheres, left and right
80% of weight of human brain
Consists of a shell of grey and an inner mass of white matter
Highly convoluted to increase surface area
Control collateral side of body e.g left hemisphere will control movement of right side of body
Hemispheres aren’t completely symmetrical in structure nor equivalent in function

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21
Q

What does the grey matter consist of?

A

Cell bodies
Dendrites
Glia

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22
Q

What does white matter consist of?

A

Myelinated axonal tracts

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23
Q

Describe why the cerebral cortex is highly convoluted (folded):

A

Gyri (gyrus)= peaks
Sulci (sulcus)= troughs
Increases SA of grey area so increased processing, amount of convolution is proportional to the complexity of the organism

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24
Q

What is the function of the cerebral cortex?

A

Concerned with ‘higher functions’ including sensory analysis and perception, conscious though, language, motor initiation (voluntary) and co-oridination, intullect

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25
Q

Name the different lobes of the brain:

A

Frontal lobe
Parietal lobe
Occipital lobe
Temporal lobe

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26
Q

Describe the features of the frontal lobe:

A

1º motor cortex
Premotor area
Prefrontal area
Separated by the lateral and central sulcus
Has the Broca’s area

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27
Q

Describe the features of the parietal lobe:

A

1º somatosensory cortex
Somatic sensory association area
Has the Wernicke’s area

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28
Q

Describe the features of the occipital lobe:

A

1º visual cortex
2º association area

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29
Q

Describe the features of the temporal lobe:

A

1º auditory cortex
2º association area

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30
Q

Describe the somatosensory cortex:

A

Analyses inputs from mechanoreceptors (touch, stretch), thermo receptors and nociceptors (pain) in the skin, muscles, joints and internal organs
All the information goes via brain stem to the thalamus to the somatosensory cortex which receives info from receptors on the opposite side of the body

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31
Q

Where is the somatosensory cortex located?

A

Parietal lobe of the cerebral cortex

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32
Q

What is somatotrophic organisation?

A

Increase size of brain where the brain area is devoted to a particular part of the body means increased pain e.g hands/ lips occupy greater area of brain so more pain
The area of cortex devoted to each area is proportional to the amount of info received from that area

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33
Q

What is ‘plasticity’ in somatotrophic organisation?

A

There is ‘plasticity’ within the neurons of the somatosensory cortex (if one area received extra stimulation or decreased stim the size of the devoted area will change accordingly)

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34
Q

Where does information go once it reaches the somatosensory cortex?

A

Information passes to its ‘association areas’ where further processing occurs, before combining with other sensory input and then information form past experiences
-analysis, integration, perception

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35
Q

What is the motor homunculus?

A

Use dependency for cortical space
Plasticity- more an area is used, the more cortex will be devoted to it

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36
Q

Describe the motor control in the motor cortex:

A

Responsible for voluntary movements
Motor cortex sends signals to the a-motor neurons
Motor cortex has input from the supplementary motor area, premotor cortex, posterior parietal cortex, basal ganglia, thalamus and cerebellum
-planning, programming, co-ordination of complex movement

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37
Q

What are the areas involved in motor control?

A

Pre-motor cortex
Supplemental motor area

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38
Q

Describe the cortical areas involved in language:

A

In 90% of people, the left hemisphere is used in relation to language
Distinct areas are specialised for the production and understanding of language
Aphasias (language deficits resulting from brain damage) have enabled the language centres to be identified
Broca’s area
Wernicke’s area

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39
Q

What is the function of Broca’s area?

A

Involves the articulation of speech (controls muscles via motor cortex for speaking)
Damage= understand language but can’t speak

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40
Q

What is the function of Wernicke’s area?

A

Involves comprehension and planning/coherence of language
Damage= struggle to understand what has been said and words coming out the wrong way- even hearing and reading words
Somatosensory for braile

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41
Q

Name the 4 different glial cell types:

A

Astrocytes
Microglia
Oligodendrocyte
Ependymal cells

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42
Q

What are the role of the astrocytes?

A

The most abundant glial cells in the CNS- even more than neurons
Dynamic role
Structural support
BBB
Repair- scar tissue (glial scar)
*Maintance of the extracellular environment
Modulation of synapse function

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43
Q

How does the astrocyte have a dynamic role?

A

Communicate with each other (gap junctions and chemical signals-neurotransmitters) and with neurones

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44
Q

How is the astrocyte involved in structural support?

A

Including scaffold development- guide developing axons to the right place

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45
Q

How is the astrocyte involved in the BBB?

A

Foot processes, contract BVs of CNS

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46
Q

How is the astrocyte involved in the maintenance of the extracellular environment?

A

Needs to be kept constant for neurone function
Neurotransmitters (astrocytes remove neurotransmitter (NT) from EC fluid to presynaptic terminal)
Keeps K+ conc low- if K+ increases, neurons will depolarise ands stop them from working properly
Astrocytes have transporters on membrane so can take NTs into cell, breakdown NT and store precursor, return precursor back to neuronal cell

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47
Q

How is the astrocyte involved in the modulation of synapse function?

A

Formation
Maintenance
Modification of NT release

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48
Q

What is the function of the microglia?

A

Immune cells of the CNS
Macrophages of the CNS
-scavengers
-release of cytokines
Role in neurodegenerative disease

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49
Q

Name and describe the different forms of microglia:

A

Resting or activated - structural differences
Resting (look thin/sparse), homeostatic
Activated (thicker- retract- less ramified- amoeboid):
-mobile- can move to damage in CNS tissue
-pro inflammatory if cytokine response not well controlled

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50
Q

What is the function of the oligodendrocytes?

A

Form the myelin sheath around neuronal axons
White matter

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51
Q

What is the function of ependymal cells?

A

Epithelial cells
-lines the fluid filled cavities of the CNS (ventricles)
Secrete cerebrospinal fluid (CSF)
Ciliated- important in moving the CSF with the ventricles
BBB

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52
Q

Name the 9 neurotransmitters:

A

Acetylcholine, Noradrenaline, Adrenaline, Dopamine, Serotonin (5-HT), Histamine, Glutamate, GABA, Glycine

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53
Q

Which neurotransmitters are catecholamine neurotransmitters?

A

Noradrenaline, adrenaline and dopamine

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54
Q

Which neurotransmitters are amino acid neurotransmitters?

A

GABA, glutamate and glycine

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55
Q

How is glutamate synthesised?

A

Can be synthesised in the presynaptic terminal
From glucose (via TCA cycle) GABA-T enzyme
From glutamine by action of glutaminase enzyme

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56
Q

What is glutamate?

A

A universal cellular constituent and a non-essential a.a

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57
Q

What are the 2 major cellular sources of glutamate?

A

Metabolic glutamate
Transmittable glutamate

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58
Q

Name the two types of glutamate receptors:

A

Metabotropic glutamate receptors (mGluRs)
Ionotropic glutamate receptors

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59
Q

Describe the ionotropic glutamate receptors and their different classes?

A

Ligand gated ion channels
NMDAr
AMPAr
Kainate r

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60
Q

What are the differences and similarities between the 3 classes of ionotrophic glutamate receptors?

A

They 3 classes are separated on responsiveness to synthetic analogues
NMDAr only responds to NMDA
All activated by L-glutamate
Different pharmacological properties
Different biophysical properties and functional effects on neurones
All have similar structures, tetramers- 4 subunits

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61
Q

Describe the NMDA receptors:

A

Assembles from 7 potential subunits encoded by 7 different genes
GluN1, GluN2A, GluN2C, GluN2D, GluN3A, GluN3D
The receptor is a tetrameric complex- hetero tetramer (mixture of subunits)
Typically 2 GluN1 and 2 GluN2 subunits come together
Alternative splicing can affect the GluN1 gene (8 variants identified)

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62
Q

Describe the structure of the NMDAr:

A

Each subunit of the tetramer has:
-extracellular N-terminal domain labelled ATD (amino terminal domain
-an extracellular ligand-binding domain (LBD)- binds the agonist
-three transmembrane spanning a-helical domains (M1,M3,M4)- hold ion channel in plasma membrane
One re-enterent P-loop called M2
An intracellular C-terminus

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63
Q

What properties can the NMDAr composition affect?

A

Agonist and co-agonist potency
Deactivation rate- how long the ion channels stay open for
Mg
Ion permeation (e.g pH)
Channel conductance- how ions move through channel
GluN2 subunits affects pharmacology of NMDAr

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64
Q

What are the ion channel responses for AMPAr and kainite receptors?

A

Desensitisation occurs rapidly- rapid activation and deactivation

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65
Q

What are the ion channel responses for NMDAr?

A

The extent and time- course of destination of the NMDAr depends on the subunit
Cation selective ion channel, Na+, K+, Ca2+
Noted for its high permeability for Ca2+ ions
GluN2A/B deactivating rapidly
GluN2C/D deactivating slowly

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66
Q

Name the binding sites for the NMDAr:

A

Glutamate (agonist site) or receptor site
Glycine site
Polyamine binding site
Mg2+ site
Channel blocking site

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67
Q

Describe the agonist activation of the NMDAr:

A

Each tetramer binds two molecules of glutamate
EC50 value for glutamate is 0.5-3µm (dictated by GluN2 subunit)
NMDA is a synthetic agonist- works the same way as glutamate

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68
Q

Describe the co-agonist activation of the NMDAr:

A

2 molecules of glycine are required for full activation
EC50 value 1µm
D-sereine, D-alanine can also act as a co-agonist
GluN1 is the glycine binding site

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69
Q

Describe competitive antagonists at the glutamate binding site:

A

D-AP5- prevents glutamate from binding preventing activation
Limited drug development due to conservation of glutamate binding site between different NMDAr, AMPAr, Kainate r

70
Q

Describe antagonists at the glycine binding site of NMDAr:

A

Kynurenic acid and CGP 61594

71
Q

Describe the Mg2+ binding site on NMDAr:

A

Channel is blocked by Mg2+ at resting neuronal membrane potentials
This feature gives NMDAr voltage dependent channel block
With no extracellular Mg2+ at resting potential, channel is open more and for longer

72
Q

Describe the polyamine site on NMDAr:

A

Located in the amino terminal domain (ATD)
Polyamines act as +ve allosteric modulators
Can be intracellular or extracellular
Can increase affinity for glycine and increase NMDAr response

73
Q

Name examples of +ve allosteric modulators on the polyamine site:

A

Spermine
Spermidine (long chain aliphatic amine)

74
Q

Name an example of -ve allosteric modulators and what is its effect?

A

Ifenprodil (experimental)
Binds to a site close to the polyamine site
It inhibits NMADr activity

75
Q

Describe the channel blocking site on NMDAr and examples of these:

A

Inside the ion channel pore- can only act when the pore is open
Ketamine- a dissociative anaesthetic and analgesic
Phencyclidine- a psychometric
MK-801 (dizocilpine)- epilepsy
Memantine- binds to M2 domain deep inside channel pore- Alzheimers

76
Q

Describe neurosteroids used at the NMDAr:

A

Can alter the activity of the NMDAr
Can be +ve or -ve allosteric modulators
e.g pregnenolone, +ve allosteric modulator at GluN2Ar

77
Q

Describe the features of the AMPAr:

A

4 genes encode different subunits:
GluA1, GluA2, GluA3, GluA4
Can be homotetramer or heterotetramer
Can change properties depending on different genes similar to NMDA
All structurally similar to NMDAr

78
Q

Describe the features of the kainate r:

A

5 genes encode different subunits:
GluK1, GluK2, GluK3, GluK4, GluK5
All structurally similar to NMDAr

79
Q

What is the difference between the AMPAr and the NMDAr?

A

AMPA- impermeable to Ca2+, only allow K+ and Na+ to move through pore
NMDAr- highly permeable to Ca2+

80
Q

What is the reason for the difference in Ca2+ permeability between the AMPAr and the NMDAr?

A

Due to the single a.a different in the M2 domain
RNA editing of GluA2 gene in the M2 domain- not encoded in the gene, just changes in mRNA
Q= glutamine, neutral a.a
R= arginine, +ve charged a.a, decreased permeability to Ca2+

81
Q

What is the outcome for the difference in the Ca2+ permeability between the AMPAr and the NMDAr?

A

Shown to be critical for electrical activity in the brain
If have the GluA2 subunit with glutamine a.a shown for mice to have seizures- likely due to Ca2+ overload in neurones

82
Q

What is the distribution of AMPAr and kainate receptors in the brain?

A

Important ion channels in the brain
AMPAr mediate fast excitatory transmission
Typicaly AMARr are co-expressed with NMDAr
Kainate r are more limited in expression/ distribution

83
Q

Name and describe drugs that work at AMPAr:

A

Perampanel- AMPAr antagonist:
-anti-epileptic- non- competitive antagonist (-ve allosteric modulator)
Ampakines e.g cyclothiazide, piracetam
(+ve allosteric modulator), acts at the AMPAr, boosts the effects of glutamate

84
Q

Describe metabrotropic glutamate receptors:

A

GPCRs- 7 transmembrane domain belonging to class C family
Different to other glutamate r as ligand normally binds to the TMD
Large extracellular N-terminal domain where glutamate binds
8 subtypes- mGluR1-mGluR8

85
Q

Describe group 1 metabrotropic glutamate receptors:

A

Includes mGluR1 and mGluR5
Post synaptic (excitatory)
Gaq/ 1 linked- increase Ca2+ via IP3/DAG

86
Q

Describe group 2 and 3 metabrotropic glutamate receptors:

A

Group 2- mGluR2 and mGluR3
Group 3- mGluR4, mGluR6, mGluR7, mGluR8
Pre-synapatic location- neuromodulaiton (inhibitory)
Gai linked- decrease cAMP

87
Q

What would be the effect of antagonists for group 1 metabrotropic glutamate receptors?

A

Hold potential for epilepsy, pain, Parkinson’s, neuroprotection

88
Q

What would be the effect of antagonists for group 2 metabrotropic glutamate receptors?

A

Potential as cognition enhancers

89
Q

What would be the effect of -ve allosteric modulators for group 3 metabrotropic glutamate receptors?

A

Potential for Parkinson’s and anxiety

90
Q

What is the end plate potential (EPP) on glutamate r neurotransmission?

A

EPP on muscle cells is a type of EPSP excitatory post synaptic potential
EPP is very large (70mV) and activates an action potential in the muscle cell which then propagates
In the CNS presynaptic neurons generate small EPSP, less than 1mV
Input from many pre-synaptic neurons is required to generate an AP
Depolarisation eventually reaches the threshold (10mV)

91
Q

What are the different types of synapses?

A

Type I
Type II

92
Q

Describe type I synapses:

A

Glutamatergic- spine neurone
Excitatory
Round synaptic vesicles
Large post synaptic density
Large synaptic cleft/large active zone

93
Q

Describe type II synapses:

A

GABA- axomatic/ shaft neurone
Inhibitory
Flattened (oval) synaptic vesicle
Less post synaptic density
Narrow synaptic cleft/small active zone

94
Q

What is post synaptic density (PSD)?

A

Receptors are clustered by lots of reg proteins into areas called a ‘post synaptic density’
A typical PSD (protein) is 350nm in diameter and can contain 20 NMDAr and 10-50 AMPAr

95
Q

Name and describe a predominant protein in PSD and its binding:

A

PSD-95, contains PDZ domains involved in protein protein interactions and 3D scaffold organisation
PSD-95 binds to NMADr terminal region localising them at post synaptic sites
PSD-95 does not bind directly to AMPAr, instead PSD-95 binds to TARP proteins which regulate AMPAr e.g stargazing

96
Q

What does TARP stand for?

A

Transmembrane AMPAr regulatory protein

97
Q

What and where does mGluR interact?

A

Interact with a PDZ protein called Homer
Located on the edges of the post synaptic density and not in the centre

98
Q

Describe the excitatory post synaptic current (EPSC):

A

Post synaptic membranes contain both AMPAr and NMDAr
AMPAr= fast
NMDAr= sow
NMDAr also thought to be a ‘coincidence detector’- detects glutamate and change in membrane potential
Each type of glutamate r contributes to different gases of the EPSC

99
Q

What is synaptic plasticity in glutamate receptors?

A

It is long term changes in connectivity between neurons
Long term potentiation (LTP) is a form of synaptic plasticity
Enhancement of synaptic transmission following high freq stim (a conditioning burst)
LTP is involved in learning and memory
Increase in synaptic strength
Activity is required in both presynaptic and post synaptic neurons

100
Q

Describe the normal transmission of glutamate receptors:

A

Glutamate normally activates AMPAr
NMDAr blocked by Mg2+
Brief depolarisation= short lived excitation

101
Q

What is the conditioning train in glutamate receptors?

A

Mimics frequent synaptic activity/ repetitive firing of neurons
Conditions them to high levels of synaptic activity

102
Q

Describe the synaptic transmission of glutamate receptors after conditioning train?

A

More glutamate released, so more receptor activated
Sufficient depolarisation post synaptic membrane- mediated by AMPAr which allows unlocking of NMDAr to occur
Depolarisation is sustained to increase Ca2+ influx in post synaptic cell which activates various signalling pathway, increase expression of AMPAr, increase expression of kinases, which phosphorylates AMPAr and facilitates activation via glutamate
Ca2+ to NO synthase to NO to retrograde messenger, action on pre-synaptic cell enhances NT release
Long term altered gene expression

103
Q

Describe LTP in glutamte receptors:

A

Post synaptic AMPAr or activated NMDAr requires sustained depolarisation (mediated by AMPAr) to release Mg2+ block- allows channel opening and Ca2+ entry
Ca2+ entry can activate other enzymes including kinases (PCK,CaMKII) which phosphorylate AMPAr increases responses
Phosphorylation increases AMPAr conductance and can increase expression

104
Q

Describe excitotoxicity in glutamate receptors:

A

High Ca2+ permeability of NMDAr can cause problems
High glutamate conc-> Ca2+-> toxicity
Glutamate excititoxicity can cause neuronal cell death
Attempts to block NMDAr to decrease toxicity in situations such as ischemic stroke- major factor

105
Q

What does GABA stand for?

A

Gamma amino butyric acid

106
Q

What is GABA?

A

Main inhibitory neurotransmitter in the brain
20% of CNS neurons are GABA-ergic
Most GABA neurons are short interneurons- link between other neurons
Widespread distribution of GABA in brain
Key role in regulating neuronal transmission

107
Q

Describe GABA synthesis and metabolism:

A

Precursor is glucose
GABA is formed from glutamate by the action of GAD (glutamic acid decarboxylase)- GAD is only found in GABA-ergic neurons, neurones which don’t have this can’t carry out this function
Metabolised by GABA-T (GABA a-oxoglutarate transamidase)
GABA shunt- preserves GABA

108
Q

Describe GABA storage, release and uptake:

A

Synthesis in GABAergic nerve terminals
Packed into vesicles by ventricular transporter
Released GABA can be recycled via GABA transporters (GAT) on presynaptic terminal
GABA can also be taken up by astrocytes GAT3

109
Q

Name the different types of GABA transporters and where are they found?

A

GAT1 expressed on neurones
GAT3 expressed on astrocytes

110
Q

Name drugs that target the GABA transporter and their effect:

A

Guvacine
Tiagabine
Reputake inhibtor so increases the conc of GABA in synapse

111
Q

Name a drug that targets the GABA transaminase and its effect:

A

Vigabtrin
Inhibitor so preserves the conc of GABA in neurones and synapses

112
Q

Name and describe the two types of receptors GABA can act on:

A

GABAa- ionotropic, member of Cys loop family (ligand gated ion channel)
GABAb- metabotropic, member of class C GPCRs

113
Q

Where are GABAa receptors located?

A

Post synaptically
Synaptic and extra synaptic sites- found in both regions but side synapse makes it harder for neuron to reach depolarisation state to AP

114
Q

Describe the signalling for GABAa r:

A

Mediate fast and tonic post synaptic inhibition
Ion channel is selective for anions, Cl-
Typically the equilibrium potential for Cl- is more -ve than the resting membrane potential at -70mV
Cl- influx causes hyperpolarisation thus reducing excitability

115
Q

Describe the structure of the GABAa r:

A

Similar structure to the nicotinic acetyl choline receptor
Pentameric- 5 subunits come together to form an ion channel complex
Heteromeric- made of different subunits
Made of multiple subunits

116
Q

Describe the different subunits of the GABAa r:

A

19 have been identified
6 a, 3 B, 3 g, plus delta, theta, sigma etc

117
Q

What does each pentamer of the GABAa r contain?

A

2a, 2B and one game
Most combinations are:
a1B2g2 (60% of all)
a2B3g2
a3B3g2

118
Q

Describe the individual GABAa subunit structure:

A

Long extracellular N terminus
4 full transmembrane domains (3 full TMD in glutamate)
Short extraceullar C terminus (longer intracellular C terminus in glutamate)
Long intracellular loop between TM2 and TM4
TM2 lines the ion channel

119
Q

What are the binding sites in GABAa receptor?

A

Receptor site (GABA site)
Benzodiazepine site
Modulatory site (barbituate)
Steroid site
Picrotoxin site (channel blocking)
Ethanol is also thought to bind and increase activity

120
Q

Describe the GABAa receptor site where a GABA (agonist) binds:

A

Located between an a and B subunit interface
There are 2 sites per pentamer
Muscimol (GABA analogue from psychoactive mushrooms) binds here as a potent agonist

121
Q

Describe antagonists at the receptor site of GABAa r:

A

Bicucilline (natural product) competes with GABA and blocks the site (antagonist)
Bicucilline blocks IPSPs in CNS synapses and causes convulsions

122
Q

Describe the different outcomes of positive allosteric modulators:

A

+ve affinity= increased sensitivity to agonist
+ve efficacy= increases sensitivity and response to agonist

123
Q

Describe the different outcomes of negative allosteric modulators:

A

-ve affinity= harder for agonist to open ion channel, need to increase conc
-ve efficacy= less of a response to the agonist

124
Q

Describe the benzodiazepine site of the GABAa r:

A

+ve allosteric modulators
Drugs that selectively enhance the effect of GABA
Bind with high affinity to the BDZ site located between a and g subunit interface
Alters the receptor affinity for GABA, increased
Certain a subunits aren’t modulated a4,a6

125
Q

Name examples of benzodiazepines and their use:

A

Diazepam, valium
Used clinically- anxiety, epilepsy, anaesthesia, sleep
Benzodiazepine antagonists also exist e.g flumazenil

126
Q

Describe the barbiturate site of the GABAa r:

A

Drugs binding here increases ligand binding to BDZ and GABA sites
Single channel recordings suggest mean channel open time is increased by barbiturates

127
Q

Name and describe an example of barbiturates:

A

Phenobarbital
CNS depressants used in anaesthesia and epilepsy

128
Q

Describe the neurosteroid site of the GABAa r:

A

Endogenous modulators that enhance the effects of GABA
Thought to act on transmembrane regions of the a subunit (M1 and M2)

129
Q

Name and describe examples of neurosteroids:

A

Metabolites of progesterone (allopregnanolone), cortisone (THDOC) and androgens
Synthetic steroid alphaxalone also binds here
Ganaxolone in clinical trials

130
Q

Describe the channel blocking site in GABAa r:

A

Inside the channel pore
Picrotoxin (natural product) binds here
Requires channel opening to gain access to TMD
Inhibitors such as picrotoxin cause convulsions so no clinical use

131
Q

Describe the function of GABAb r:

A

Couple through Gai/0
Signalling inhibits CaV channels and decreases nT release from presynaptic terminals
Open K+ channels to increase hyperpolarisation

132
Q

Describe the structure of GABAb r:

A

GPCRs
Dimeric structure- 2 GPCRs B1 and B2 linked through C terminals

133
Q

Name and describe a competitive agonist and antagonists at the GABAb receptor:

A

Baclofen is an agonist at GABAb r
Competitive antagonist e.g 2-hydroxyl-saclofen

134
Q

Describe the glycine receptor:

A

Is similar to the GABAa r (cys-loop family)
Ligand gated ion channel, chloride selective
5 glycine receptor subunits clones

135
Q

Name and describe glycine receptor antagonists:

A

Strychnine (plant alkaloid) acts as a convulsant- due to decrease in inhibitory effect
Tetanus toxin prevents glycine release from inhibitory neurons- causes jaw lock due to reflex hyperexitability

136
Q

Name and describe glycine transporters:

A

GlyT1 and GlyT2
They remove glycine from extracellular fluid
Expressed on astrocytes and neurones

137
Q

What does 5-HT stand for?

A

5-hydroxytriptamine

138
Q

What is 5-HT?

A

Aka serotonin
Monoamine NT
5HT found in gut, platelets and CNS

139
Q

Describe the synthesis of 5HT:

A

Tryptophan (diet) is the precursor for 5HT
Tryptophan hydroxylase generates 5-hydroxytryptophan
Converted to 5-hydroxytriptamine by dopa decarboxylase

140
Q

How is 5HT metabolised?

A

By MonoAmine Oxidase (MAO) and aldehyde dehydrogenase
Degraded to 5-hydroxyindoleacetic acid (5-HIAA) and this form is excreted

141
Q

Describe the release of 5HT:

A

VMAT (vesicular monoamine transporter) loads 5HT into vesicles
MOA control degradation
SERT permits reuptake of 5HT

142
Q

Describe 5HT as a neurotransmitter:

A

An important CNS NT
Stored and released from serotonergic neurons (neurons that use 5HT as a NT)
Cell bodies lie in Raphe nucleus and project to many areas
Simular distribution in noradrengeric neurones

143
Q

What is 5HT involved in physiologically?

A

Sleep, appetite, pain, thermoregulation, mood

144
Q

Describe serotonin receptors:

A

14 known 5HT r, all but one are GPCRs
5HT3 is a ligand gated ion channel
All are thought to be expressed in the CNS and PNS

145
Q

Name the 7 different classes of 5HT receptors:

A

5HT3
5HT1r (1A,1B,1D,1E,1F) couple to Gai/o
5HT2 (2A, 2B, 2C) couple to Gaq/11
5HT4, 5HT5A, 5HT6, 5HT7 receptors couple to Gas

146
Q

Name and describe examples of 5HT2 antagonists:

A

Antagonists used for migraine prophylaxis
Block excitatory actions
Ketaserin, methysergide, pizotifen
Ergotamine (fungus derived)

147
Q

What is the function of 5HT2 receptors?

A

Cause SM contraction, vasoconstriction
Activation of PLC, increase in intracellular Ca2+

148
Q

Name an example of a 5HT3 receptor antagonist:

A

Ondansertron- antiemetic

149
Q

What is the function of the 5HT3 receptors?

A

Ligand gates ion channels found on neurons involved in vomiting reflex in CNS/PNS

150
Q

What are the 4 areas of the brain that are involved in protection and nourishment of the brain?

A

Skull and vertebral column
The meninges - protective membranes
Cerebrospinal fluid (CSF)
BBB-highly selective of what enters and leaves the brain

151
Q

What is the meninges?

A

Membranes that surround the brain
Not the BBB
Protect the brain
Have the spinal and cranial meninges
3 membranes (layers)

152
Q

Name the 3 layers of the meninges:

A

Dura mater (outer)-underneath cranium- strong
Arachnoid mater- highly vascularised (spidery) layer
Pia mater (inner)- Fine, thin membrane adhering to brain tissue, gentle

153
Q

What is the function of the spinal meninges?

A

Between the Pia and arachnoid mater have subarachnoid space of spinal cord

154
Q

What is the function of the cranial meninges?

A

Outside of this have dural sinus- filled with blood

155
Q

What is the function of the fluid compartment of the brain?

A

Keeping the neurones in the brain in a highly controlled environment- also a.a and NTs
Is critical for function e.g changing K+ cause depolarisation of neurons-> A/Ps

156
Q

Name and describe the 2 main extracellular fluid compartments:

A

CSF compartment- in the ventricles and central canal of the spinal cord
The interstitial compartment0 the space containing the interstitial fluid surrounding the cells of the CNS

157
Q

Describe the barriers of the fluid compartments in the brain:

A

Fluid compartments are continuous
Blood-CSF barrier- made up of choroid epithelium which make CSF
BBB-epithelial cells into interstitial fluid

158
Q

Describe the function of the ventricles in the brain:

A

Fluid filled cavities within the brain
Contain the CSF
4 ventricles continuous with the central canal of the spinal cord
Lined with ependymal cells (are ciliated)- beating of cilia which allows the flow of CSF

159
Q

Name the 4 ventricles in the brain:

A

Left and right lateral ventricles- underneath each cerebral hemisphere
Third ventricle (central)
Fourth ventricle (within the brain stem)

160
Q

Describe the CSF:

A

125-150ml of CSF
-constant turnover (balance between constantly produced/drained)
-so constant pressure
Density same as brain tissue- so brain can float in CSF- acts as a shock absorber
Exchange with interstitial fluid

161
Q

Describe the composition of the CSF:

A

Composition highly regulated
Different to blood
Decreased K+, more Na+, no protein

162
Q

Where is the CSF secreted from?

A

Secreted by the specialised epithelial cells of the choroid plexuses in the ventricles
Selective transport mechanisms

163
Q

Where does the CSF drain to?

A

Drains into the subarachnoid space via the arachnoid vili into the dural sinus, then into the venous system

164
Q

Describe the BBB:

A

Barrier between the blood and the interstitial fluid of the brain
Cerebral microvascular endothelial cells are associated cells/ structures
Over 400 miles of BVs within the brain to increase the SA of BBB

165
Q

How is the BBB highly regulated?

A

K+ can change in the blood but will not change in the interstitial fluid
Attempts to keep out unwanted substances:
-circulating NTs (e.g glutamate, glycine, hormones)
-xenobiotics

166
Q

Describe the structure of a general capillary not in the brain:

A

Allows substances to move in and out of the blood easily
Aqueous pathway (pores) between endothelial cells (4nm)-paracellular pathway
May have fenestrations through endothelial cells (20-100nm)
Vesicular transport (pinocytosis, endocytosis)

167
Q

Describe the structure of a brain capillary:

A

Endothelial cells of cerebral microvasculature have tight junctions (no pores)- holds cells tightly together
Pericytes- help control movement
Astrocyte (glial cells) foot process also surround the capillary- maintenance of tight junctions
No intercellular clefts, no fenestra

168
Q

What is true about substances moving from the blood into the brain?

A

Any substance moving from blood into the brain interstitial fluid must pass through the endothelial cell

169
Q

Name and describe how some parts of the brain are outside the BBB:

A

The circumventricular organs:
-posterior pituraitary
-the area postrema
Isolated from the rest of the brain by tanycytes (the tanycytic membrane)- surrounds circumventricular organs

170
Q

Why is the posterior pituitary outside the BBB?

A

Substances has to get in and out of the brain which can’t cross the BBB
Secretes protein hormones

171
Q

Why is the area postrema outside the BBB?

A

AKA chemoreceptor trigger zone
Causes vomiting

MPharm Y3S2 (22 decks)

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