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Flashcards in BB CAL Deck (89):
1

Sodium ion concentrations

Axoplasm = 15
Interstitial fluid = 150

2

Potassium ion concentrations

Axoplasm = 150
Interstitial fluid = 5

3

Chloride ion concentrations

Axoplasm = 9
Interstitial fluid = 125

4

Anion concentrations

Axoplasm = high
Interstitial fluid = very low

5

Resting membrane potential

-65mV

6

Depolarised membrane potential

+40mV

7

Equilibrium potential for sodium

+58mV

8

Fast vs slow axonal transport

Fast = 400mm/day
Slow = 2.5mm/day

9

Typical synaptic delay

0.5ms

10

Number of vesicles in a nerve terminal

10,000

11

Number of NT molecules stored in each vesicle

3000

12

How manyy vesicles fuse for each action potential?

1-10

13

What is the effect of autoreceptors?

Depends if they are excitatory or inhibitory
Control how much NT is released in subsequent APs

14

Examples of retrograde NTs

NO
Endocannabinoids

15

In a GCPR, which subunit is GTP attached to?

Alpha

16

What is the approximate threshold value/

-55mV

17

Structure of a ligand gated ion channel

Hetero-oligomeric proteins
4-5 subunits

18

Structure of a GCPR

Single polypeptide chain
Crosses the membrane 7 times

19

What can cause depolarisation?

Influx of Na+
Influx of Ca2+
Closing of K+ channels
Efflux of Cl-

20

What causes hyperpolarisation?

Opening of K+ channels
Influx of Cl-

21

Which amino acid is tyrosine synthesised from?

Phenylalanine

22

What is the first step of dopamine synthesis from tyrosine?

Tyrosine --> L-Dopa
By tyrosine hydroxylase
This is the rate limiting step
Requires THB as a cofactor

23

What is the second step of dopamine synthesis from L-Dopa?

L-Dopa --> dopamine
By dopamine decarboxylase
Uses vitamin B6 as a cofactor
Also catalyses the final synthetic steps of 5-HT, histamine, tyramine and tryptamine synthesis

24

What is the molecule responsible for dopamine transport into vesicles?

VMAT2
Vesicular monoamine transporter 2
Requires ATP

25

Which type of calcium channels open in response to terminal bouton depolarisation?

N type

26

What happens when dopamine binds to D2 autoreceptors?

Inhibits dopamine synthesis

27

Two fates of dopamine

--> homovanilic acid by COMT then MAO
- this is the major pathway
- can be used to monitor dopamine turnover

--> 3,4-dihydrophenylacetic acid (DOPAC) by MAO and aldehyde dehydrogenase

28

D1 receptor family

D1 and D5
GCPRs
Postsynaptic
Activate adenylate cyclase

29

D2 receptor family

D2, D3 and D4
GCPRs
Mostly postsynaptic but some presynaptic
Inhibit adenylate cyclase
Activate K+ channels
Decreased Ca2+ conductance

30

Where are D1 and D5 channels found?

D1 = basal ganglia
D5 = hippocampus and hypothalamus

31

Where are D2, D3 and D4 channels found?

D2 = basal ganglia
D3 = limbic areas
D4 = frontal cortex, midbrain and medulla

32

What are the 3 dopamine pathways in the brain?

Nigrostriatal
- 75% of brains dopamine
- cell bodies in SNPC
- axons terminate in corpus striatum
- involved in motor control
- death leads to PD

Mesolimbic
- cell bodes in VTA of midbrain
- axons terminate in the NA and olfactory tubercle
- involved in Schizophrenia

Mesocortical
- cell bodies in the VTA of midbrain
- axons project to the frontal and cingulate cortices
- involved in memory, motivation, reward, addiction

33

Alpha methyl-p-tyrosine

Inhibits tyrosine hydroxylase
Blocks dopamine synthesis

34

Reserpine and tetrabenazine

Inhibits VMAT2
Inhibits vesicular storage of dopamine
Used in Huntingdon's disease

35

Dopamine agonists

Pergolide
Quinpirole
Bromocriptine
Apomorphine
Used in PD

36

Dopamine receptor antagonists

Antipsychotics --> schizophrenia
Chlorprozamine, haloperidol, clozapine (D4 mainly)
Also have affinity for ACh , H1 and 5-HT2 receptors

37

Amantadine

Causes dopamine release
Blocks dopamine reuptake
Used in PD

38

Selegiline

MAOb inhibitor
+ rasagiline
Used in PD

39

Entacapone, tolcapone

COMT inhibitors
Used in pD
Used alongside L-Dopa

40

Antimuscarinics

Benzhexol, benztropine
Can be used in PD
Increase release and inhibit reuptake

41

How is 5-HT synthesised?

Tryptophan taken up into nerve terminal

Tryptophan --> 5-hydroxytyptophan 5-HTP b
- by tryptophan hydroxylase
- required tetrahydrobiopterin
- rate limiting step

5-HTP --> 5-HT
- by DOPA decarboxylase

42

What is needed for 5-HT storages

Vesicles
ATP
Na+

43

How is 5-HT inactivated?

Degraded by MAO initially

--> 5-HIAA by aldehyde dehydrogenase (predominant) = oxidation
--> 5-hydroxytryptophol by alcohol dehydrogenase = reduction

44

What type of receptors are 5-HT receptors?

All GCPRs
Except 5-HT3 which are ligand gated ion channels

45

5-HT1

Negatively coupled to adenylate cyclase
Activate K+ channels
A = anxiety + pain
B = cranial blood vessels
F = uterus

46

5-HT2

Coupled to inositol phosphate
A = anxiety, depression, pain, vascular, tracheal and bronchial smooth muscle contraction
B = rat fundic strip contraction
C = spinal distribution --> CSF formation rate

47

5-HT3

Ligand gated ion channels
Role in emesis

48

5-HT4

Positively coupled to adenylate cyclase
Relax oesophageal smooth muscle
Increase heart rate and force

49

5-HT6&7

Positively coupled to adenylate cyclase
Low peripheral expression

50

Which receptors affect serotonin release?

Inhibitory 5-HT1a receptors
Inhibition 5-HT1b/d autoreceptors

51

Buspirone, ipsapirone

5-HT1a partial agonists
Desensitise 5-HT1a receptors
Increase firing rate and 5-HT release
Used to treat anxiety

52

Sumatriptan

5-HT1b/d agonist
Used for migraine and cluster headache treatment
Induces cerebral blood vessel vasoconstriction and reduces release of neuropeptides

53

Ondansetron

5-HT3 antagonist
Anti-emetic

54

LSD

Agonist of 5-HT1 receptors

55

Irreversible MAOIs

Phenelzine, isocarboxazid
Non-selective
Cheese reaction (with tyramine ingestion)

56

Moclobemide

Reversible MOAIs
More selective for MAOa
Much less severe risk effects and Cheese reaction

57

Drugs that do not give rise to dependence

Cannabinoids
LSD

58

Psychological effects of withdrawal

Produced by all drugs of dependence
Due to effects on the limbic system
Mood changes
Anxiety
Agitation
Feeling unable to cope

59

Drugs that only produce psychological withdrawal

Cocaine
Amphetamine
Nicotine
Caffeine

60

Physical dependence

Clear cut syndrome of physical symptoms
Relatively short lived --> 2 weeks

61

Opiate withdrawal

Diarrhoea
Nausea/vomiting
Abdominal discomfort
Convulsions
Sweating

62

Barbiturate withdrawal

Anxiety
Insomnia
Epileptic fits
Sweating
Tremors
Delirium, delusions and hallucinations

63

Benzodiazepines withdrawal

Convulsions
Panic attacks
Anxiety

64

Alcohol withdrawal

Convulsions
Sweating
Tremors
Anxiety

65

Which drugs develop tolerance but not dependence?

LSD
GYN
Anticholinesterases

66

What is acute tolerance?

Tachyphylaxis --> densitisation
Occurs when a receptor becomes desensitisied after the first dose
Occurs with nicotine

67

Types of chronic tolerance

Cellular = pharmacodynamic
Pharmacokinetic = metabolic

68

What is cellular tolerance?

Due to neuroadaptive changes that produce diminished responses to drugs
Follows chronic exposure
Major contributor to drug tolerance

69

What is pharmacokinetic tolerance?

Due to an increase in metabolism of a drug
Caused by induction of liver enzymes
Overcome by taking a larger dose

70

Psychomotor stimulants

Nicotine
Amphetamine
Cocaine
Caffeine

71

CNS depressants

Alcohol
Opiates
Barbiturates
Benzodiazepines

72

Nicotine tolerance

All 3 types
Acute - to HR changes
Cellular - to nausea, dizziness
PK - only to a small degree

73

Where does nicotine act?

NA and VTA --> dependence and reward
Hippocampus --> increased attention
Reticular formation --> increased alertness

74

BZ tolerance

Cellular type
To antipsychotic effects more than anxiolytic effects

75

Where do BZs and barbiturates act?

Raphe nuclei --> increase 5-HT transmission
Reticular formation --> sedation

76

Barbiturate tolerance

PK --> p450 enzyme induction
Some cellular tolerance

77

Alcohol tolerance

Acute - in one session
Cellular = in regular drinking
PK = only in severe alcoholics --> p450

78

Opiate tolerance

Early = nausea and vomiting
Medium = euphoria, analgesia and respiratory depression
No tolerance = constipation, pupillary constriction

79

Opiate receptors

Mu --> euphoria, analgesia, resp depression, constipation
Kappa --> analgesia
Delta --> analgesia

80

Where do opiates act?

VTA and NA --> euphoria and dependence
PAG --> analgesia
Reticular formation --> sedation and respiratory depression
Area postrema = nausea and vomiting

81

Cocaine dependence

Psychological but not physical

82

Cocaine tolerance

Euphoria is lost
Cardiovascular effects do not show tolerance easily

83

Cocaine MoA

Inhibition dopamine reuptake

84

Where does cocaine act?

NA --> euphoria and dependence
Hypothalamus --> increased temperature and decreased food consumption
Reticular formation --> increased alterness

85

Caffeine tolerance

Fast = unpleasant effects
Little tolerance = psychostimulant effects

86

Caffeine MoA

Inhibits adenosine A1 receptors
Inhibits PDE which inactivates cAMP

87

Amphetamine tolerance

Cellular type
Means overdose is likely --> psychosis

88

Amphetamine MoA

Stimulate release of catecholamines (DA, NA, A)
Inhibit reuptake
Inhibit MAO

89

Where do amphetamines act?

NA --> euphoria and dependence
Hypothalamus --> increased temperature and decreased food consumption
Reticular formation --> increased alterness