BB CAL Flashcards
Sodium ion concentrations
Axoplasm = 15
Interstitial fluid = 150
Potassium ion concentrations
Axoplasm = 150
Interstitial fluid = 5
Chloride ion concentrations
Axoplasm = 9
Interstitial fluid = 125
Anion concentrations
Axoplasm = high
Interstitial fluid = very low
Resting membrane potential
-65mV
Depolarised membrane potential
+40mV
Equilibrium potential for sodium
+58mV
Fast vs slow axonal transport
Fast = 400mm/day Slow = 2.5mm/day
Typical synaptic delay
0.5ms
Number of vesicles in a nerve terminal
10,000
Number of NT molecules stored in each vesicle
3000
How manyy vesicles fuse for each action potential?
1-10
What is the effect of autoreceptors?
Depends if they are excitatory or inhibitory
Control how much NT is released in subsequent APs
Examples of retrograde NTs
NO
Endocannabinoids
In a GCPR, which subunit is GTP attached to?
Alpha
What is the approximate threshold value/
-55mV
Structure of a ligand gated ion channel
Hetero-oligomeric proteins
4-5 subunits
Structure of a GCPR
Single polypeptide chain
Crosses the membrane 7 times
What can cause depolarisation?
Influx of Na+
Influx of Ca2+
Closing of K+ channels
Efflux of Cl-
What causes hyperpolarisation?
Opening of K+ channels
Influx of Cl-
Which amino acid is tyrosine synthesised from?
Phenylalanine
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
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
What is the molecule responsible for dopamine transport into vesicles?
VMAT2
Vesicular monoamine transporter 2
Requires ATP
Which type of calcium channels open in response to terminal bouton depolarisation?
N type
What happens when dopamine binds to D2 autoreceptors?
Inhibits dopamine synthesis
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
D1 receptor family
D1 and D5
GCPRs
Postsynaptic
Activate adenylate cyclase
D2 receptor family
D2, D3 and D4 GCPRs Mostly postsynaptic but some presynaptic Inhibit adenylate cyclase Activate K+ channels Decreased Ca2+ conductance
Where are D1 and D5 channels found?
D1 = basal ganglia D5 = hippocampus and hypothalamus
Where are D2, D3 and D4 channels found?
D2 = basal ganglia D3 = limbic areas D4 = frontal cortex, midbrain and medulla
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
Alpha methyl-p-tyrosine
Inhibits tyrosine hydroxylase
Blocks dopamine synthesis
Reserpine and tetrabenazine
Inhibits VMAT2
Inhibits vesicular storage of dopamine
Used in Huntingdon’s disease
Dopamine agonists
Pergolide Quinpirole Bromocriptine Apomorphine Used in PD
Dopamine receptor antagonists
Antipsychotics –> schizophrenia
Chlorprozamine, haloperidol, clozapine (D4 mainly)
Also have affinity for ACh , H1 and 5-HT2 receptors
Amantadine
Causes dopamine release
Blocks dopamine reuptake
Used in PD
Selegiline
MAOb inhibitor
+ rasagiline
Used in PD
Entacapone, tolcapone
COMT inhibitors
Used in pD
Used alongside L-Dopa
Antimuscarinics
Benzhexol, benztropine
Can be used in PD
Increase release and inhibit reuptake
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
What is needed for 5-HT storages
Vesicles
ATP
Na+
How is 5-HT inactivated?
Degraded by MAO initially
- -> 5-HIAA by aldehyde dehydrogenase (predominant) = oxidation
- -> 5-hydroxytryptophol by alcohol dehydrogenase = reduction
What type of receptors are 5-HT receptors?
All GCPRs
Except 5-HT3 which are ligand gated ion channels
5-HT1
Negatively coupled to adenylate cyclase Activate K+ channels A = anxiety + pain B = cranial blood vessels F = uterus
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
5-HT3
Ligand gated ion channels
Role in emesis
5-HT4
Positively coupled to adenylate cyclase
Relax oesophageal smooth muscle
Increase heart rate and force
5-HT6&7
Positively coupled to adenylate cyclase
Low peripheral expression
Which receptors affect serotonin release?
Inhibitory 5-HT1a receptors
Inhibition 5-HT1b/d autoreceptors
Buspirone, ipsapirone
5-HT1a partial agonists
Desensitise 5-HT1a receptors
Increase firing rate and 5-HT release
Used to treat anxiety
Sumatriptan
5-HT1b/d agonist
Used for migraine and cluster headache treatment
Induces cerebral blood vessel vasoconstriction and reduces release of neuropeptides
Ondansetron
5-HT3 antagonist
Anti-emetic
LSD
Agonist of 5-HT1 receptors
Irreversible MAOIs
Phenelzine, isocarboxazid Non-selective Cheese reaction (with tyramine ingestion)
Moclobemide
Reversible MOAIs
More selective for MAOa
Much less severe risk effects and Cheese reaction
Drugs that do not give rise to dependence
Cannabinoids
LSD
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
Drugs that only produce psychological withdrawal
Cocaine
Amphetamine
Nicotine
Caffeine
Physical dependence
Clear cut syndrome of physical symptoms
Relatively short lived –> 2 weeks
Opiate withdrawal
Diarrhoea Nausea/vomiting Abdominal discomfort Convulsions Sweating
Barbiturate withdrawal
Anxiety Insomnia Epileptic fits Sweating Tremors Delirium, delusions and hallucinations
Benzodiazepines withdrawal
Convulsions
Panic attacks
Anxiety
Alcohol withdrawal
Convulsions
Sweating
Tremors
Anxiety
Which drugs develop tolerance but not dependence?
LSD
GYN
Anticholinesterases
What is acute tolerance?
Tachyphylaxis –> densitisation
Occurs when a receptor becomes desensitisied after the first dose
Occurs with nicotine
Types of chronic tolerance
Cellular = pharmacodynamic Pharmacokinetic = metabolic
What is cellular tolerance?
Due to neuroadaptive changes that produce diminished responses to drugs
Follows chronic exposure
Major contributor to drug tolerance
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
Psychomotor stimulants
Nicotine
Amphetamine
Cocaine
Caffeine
CNS depressants
Alcohol
Opiates
Barbiturates
Benzodiazepines
Nicotine tolerance
All 3 types
Acute - to HR changes
Cellular - to nausea, dizziness
PK - only to a small degree
Where does nicotine act?
NA and VTA –> dependence and reward
Hippocampus –> increased attention
Reticular formation –> increased alertness
BZ tolerance
Cellular type
To antipsychotic effects more than anxiolytic effects
Where do BZs and barbiturates act?
Raphe nuclei –> increase 5-HT transmission
Reticular formation –> sedation
Barbiturate tolerance
PK –> p450 enzyme induction
Some cellular tolerance
Alcohol tolerance
Acute - in one session
Cellular = in regular drinking
PK = only in severe alcoholics –> p450
Opiate tolerance
Early = nausea and vomiting
Medium = euphoria, analgesia and respiratory depression
No tolerance = constipation, pupillary constriction
Opiate receptors
Mu –> euphoria, analgesia, resp depression, constipation
Kappa –> analgesia
Delta –> analgesia
Where do opiates act?
VTA and NA –> euphoria and dependence
PAG –> analgesia
Reticular formation –> sedation and respiratory depression
Area postrema = nausea and vomiting
Cocaine dependence
Psychological but not physical
Cocaine tolerance
Euphoria is lost
Cardiovascular effects do not show tolerance easily
Cocaine MoA
Inhibition dopamine reuptake
Where does cocaine act?
NA –> euphoria and dependence
Hypothalamus –> increased temperature and decreased food consumption
Reticular formation –> increased alterness
Caffeine tolerance
Fast = unpleasant effects
Little tolerance = psychostimulant effects
Caffeine MoA
Inhibits adenosine A1 receptors
Inhibits PDE which inactivates cAMP
Amphetamine tolerance
Cellular type
Means overdose is likely –> psychosis
Amphetamine MoA
Stimulate release of catecholamines (DA, NA, A)
Inhibit reuptake
Inhibit MAO
Where do amphetamines act?
NA –> euphoria and dependence
Hypothalamus –> increased temperature and decreased food consumption
Reticular formation –> increased alterness
