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PH3501- Neuropharmacology > Lec 1-Synaptic transmission > Flashcards

Lec 1-Synaptic transmission Flashcards

1
Q

Classification of Neurotransmitters: AMINES

A
  • Catecholamines: Noradrenaline (NA); Dopamine (DA); Adrenaline
  • Indoleamines: 5-HT (5-Hydroxytryptamine) (Seretonin)
  • Acetylcholine (ACh)
  • Diamine: Histamine
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2
Q

Classification of neurotransmitters: Amino Acids

A
  • Glutamate
    • Excitatory
    • Depolarise neurone reduce the voltage of neurone so is closer to threshold, therefore, more likely to fire
  • GABA (Gamma Amino Butyric Acid)
    • Inhibitory
    • Hyperpolarise the cell because it increase the resting membrane potential meaning more stimulation is required to reach the threshold
  • Glycine
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3
Q

Classification of neurotransmitters: Peptides

A
  • Endorphins
  • Tachykinins
  • Various
  • Releasing factors
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4
Q

Classification of neurotransmitters: Purines

A

-Adenosine

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5
Q

Definition of terms: Neurone, Axon and Dendrite

A
  • Neurone: Classification (Function, location and transmitter)
  • AXON: Most neurones have a single action that carries signals to interconnected target cells and also provides a transport route to terminals
  • DENDRITES: Extend from the cell body to receive synaptic contacts from other neurones
    • Act as antenna
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6
Q

What are synapses

A
  • Synapses are sites for interneuronal communication: They are similar to the ‘junctions’ of the peripheral ANS but contain additional specific proteins essential for transmitter release
  • In the CNS, the amine transmitters are known to form classical synapses where the presynaptic membrane is closely apposed to the post-synaptic cell, it is also clear that in other locations no clear post-synaptic targets are present
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7
Q

What are the different types of synapse

A
  • Synapses are frequently names by the types of contact which they make
  • AXODENDRITIC
    • Axon terminal to dendrites of neighbouring cells (Serial)
  • Axosomatic:
    • Axon collateral synapse with soma of neighbouring cell
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8
Q

NA in the CNS (What does it control)

A

Noradrenergic transmission is important in the controls of:

  • Mood
  • Arousal
  • Reward system
  • Blood Pressure- clonidine and methyldopa- mostly used in HTN when pregnant
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9
Q

Important Noradrenergic pathways

A
  • NA releasing cells are packed into the Locus coeruleus (located in the brain stem known as the pons)
  • Axons project from the Locus ceoruleus down to the spinal cord
    • OR ascending to the Hypothalamus; the striatum; cortex and hippocampus
  • The fact that NA effects so many different parts of the brain indicates that it can affect many different aspects of our physiology
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10
Q

Synthesis of NA

A
  • In Parkinson’s disease, we use L-Dopa as the main treatment
  • A lack of dopamine in the body is the cause of symptoms so we try and externally apply the dopamine the body lacks
  • We cannot give regular dopamine due to the fact it doesn’t cross the BBB
  • L-dopa does and when give get converted into dopamine thus helping to relieve symptoms
  • Dopamine releasing neurones lack the enzyme Dopamine-B-hydroxylase this is because any dopamine present in the neurone would be converted to NA giving rise to a different response
  • Tyrosine hydroxylase is the rate-limiting step in this reaction
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11
Q

Control of NA synthesis; Short term

A
  • Both TH and AAAD are cytoplasmic enzymes
  • TH activity is inhibited by a-methyltyrosine
  • AAAD is as its name implies a non-specific decarboxylase
  • DbH is located, largely in a membrane-bound form with the synaptic vesicles of noradrenergic nerves; it is inhibited by disulphiram (given in cocaine and alcohol dependency) and copper chelators
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12
Q

Control of NA synthesis

A
  • The synthesis of NA is limited by the activity of the enzyme TH
  • The enzyme activity of TH is about 2 orders of magnitude lower than that of AAAD and DbH
  • NA inhibits the activity of TH (End product FEEDBACK INHIBITION) This allows the neuronal activity to control transmitter synthesis
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13
Q

Control of NA synthesis (LONG TERM)- the 2 mechanisms involved

A
  • Increased synthesis of the enzymes TH and DbH as a consequence of long-term stimulation (mRNAs for these proteins are increased after about 20 minutes of such stimulation)
  • Increased release of growth factors from cells, which are noradrenergic fibres innervate are taken into the terminals and transported back to the cell body where it increases the synthesis of both TH and DbH
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14
Q

Storage of NA

A
  • NA is stored within the dense-cored vesicles (70-200nm diameter)
  • There are also more numerous small synaptic vesicles which contain high concentrations of ATP but little soluble proteins
  • RESERPINE blocks the proton gradient dependent pump responsible for transport of the amines into these vesicles
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15
Q

Noradrenergic Synapse

A
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16
Q

Organisation of NA synapse

A
  • Axon terminates in pre-synaptic terminal
  • Lots of mitochondria= increased energy production
  • Pre-synaptic receptors bind NA (alpha-2) modulates the further release of NA
  • The uptake-1 mechanism is a site of action for drugs that we can target
    • SSRI’s- block re-uptake of 5-HT
    • For NA this amphetamine and cocaine (enhanced NA concentrations)
    • Tri-cyclic antidepressants= amitriptyline
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17
Q

Characteristics of NA release

A
  • Morphological, electrophysiological and chemical evidence has shown that transmitter is released in packets or Quanta
  • Quanta is a unit of neurotransmitter released from vesicles
  • The release occurs by a process of Exocytosis in which the synaptic vesicles fuse with the pre-synaptic membrane and release their contents into the extracellular space
  • The number of quanta released determines the size of an EPSP and IPSP (Excitatory and Inhibitory Post Synaptic Potentials)
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18
Q

Fusion of synaptic vesicles with cell membrane

A
  • Synaptic vesicle in the act of fusing shown in a freeze-fracture electron micrograph of a frog nerve terminal
  • A: The active zone can be seen as a ridge of 10nm membrane particles
  • B: Holes (box) are sites of vesicles fusion while shallow depression mark where vesicles have collapsed flat after fusion
19
Q

Inactivation of noradrenaline

A
  • NA is inactive, subsequent to its release by reuptake:
    • Uptake 1 involves reuptake into neurones
    • Uptake 2 involves reuptake into non-neuronal elements (Glial cells)
  • Both uptake mechanisms are saturable active transport systems capable of concentrating the amine against a large concentration gradient
    • Active transport
20
Q

Characteristics of uptake mechanisms

A

Uptake 1

  • Is low capacity, high affinity
  • Other substrates dopamine and 5-HT
  • Inhibited by cocaine, amphetamine and tricyclic antidepressants (Amitriptyline)

Uptake 2

  • Is high capacity, low affinity (25%)
  • Inhibited by norepinephrine, steroid hormones
21
Q

Catabolism of NA

A
  • Mandelic acids are excreted in the urine
    • We can test for excessive NA transmission which may happen in tumour of chromaffin cells= build up of mandelic acids
22
Q

Actions of NA in the CNS

A
  • The actions of NA in the CNS are mainly inhibitory (Alpha2 and Beta2 receptors) but some excitation is seen (Alpha1 and Beta1 receptors)
23
Q

NA receptor subtypes in the CNS

A
  • Alpha-1
    • Excitatory receptors by increasing PL-C
    • Decrease K+ conductance (High inside the cell)
    • Blocking K conductance increases excitatory effect
  • Alpha-2-
    • We decrease Ca conductance we decrease NA
    • inhibit cAMP
  • Beta-1
    • Same as Alpha-1
  • Beta-2
    • Works via NO pathway
24
Q

The role of pre-synaptic receptors: The pre-synaptic receptors are classified as

A
  • Autoreceptors- Where the receptors recognise the transmitter that is released from that terminal
  • Heteroreceptors- Which recognise other transmitters which are different from that released by that terminal
25
Q

The role of pre-synaptic receptors: II

A
  • Ca-dependent exocytosis of NA into the synaptic cleft via the vesicles fusion
  • NA then binds to post-synaptic receptors to initiate its action
  • NA in the synaptic cleft will diffuse and bind to a pre-synaptic Alpha-2-adrenoreceptor which is linked to cAMP
  • This will then inhibit adenylate cyclase and reduce the concentration of cAMP
  • Less cAMP means less phosphorylation of Ca channels
  • Therefore less Ca in the cell => reducing exocytosis and so release of NA
  • Even with an AP down the neurone without the phosphorylation the Ca channels will not open
26
Q

Pre-synaptic receptors and NA release

A
  • Inhibitory autoreceptors- Alpha2 receptors- binds NA and then blocks the subsequent release of NA
  • Inhibitory heteroreceptor: Opiate, H3 (Histamine), M2 (Muscarinic), D2 (Dopamine)
  • Facilitatory heteroreceptor: Angiotensin II, Nicotinic ACh
27
Q

Consequences of DA (Dopamine) release: 3 functional consequences in the brian

A
  • DA has 3 functional consequences
    • Motor control (Nigrostriatal System-neurones which project to the striatum from the nigra)
    • Behavioural effects (Mesolimbic and mesocortical systems)- roles in reward; drug dependence and schizophrenia (to much DA)
      • We can give dopamine antagonist to reduce DA but can result in Parkinsonian symptoms
    • Endocrine control (Tuberoinfundibular system)- control of hormonal effects from prolactin and growth hormone
28
Q

Important dopaminergic pathways

A
  • DA cell bodies sit in 2 major areas:
  • Substania nigra
    • This gives rise to a pathway that extends to the striatum; olfactory tubercle (smell) as well as anterior limbic cortex and frontal cortex
    • Gives rise to Parkinsonian pathways
  • Nucleus accumbens (also known as ventral tegmental area)
    • These pathways give rise to behavioural pathways; reward and drug dependency effects
      *
29
Q

Synthesis of DA

A
  • DA is a precursor for NA and its synthesis follows the same route
  • Dopaminergic neurones are distinct from noradrenergic neurones in that they don’t contain DbH and thus are unable to synthesis NA
30
Q

Storage of DA

A
  • The storage of DA is vesicular, similar to that for NA
31
Q

Catabolism of DA

A
  • DOPAC and HVA are both excreted out of the urine
  • Both can be measured as a function of dopaminergic transmission
32
Q

Characteristics of DA release

A

The characteristics of DA release are similar to those for NA it is

  • Quantal
  • Exocytotic

The inactivation of DA is by active reuptake

33
Q

DA in the CNS

A
  • Parkinson’s disease is associated with a deficiency of nigrostriatal dopaminergic neurones
    • 6-hydroxyDA legion model- if we inject this into the brain near the nigrostriatal area, this will kill the DA neurones- they become paralysed- can be reversed by L-dopa
    • Knock out DA neurones on one side of the brain, the animal can only move one side of the body
  • Behavioural effects of excess DA are characterised by stereotyped behaviour patterns and can be produced by DA releasing agents (Amphetamine) or DA agonist (Apomorphine)
  • Hormone release from the anterior pituitary is regulated by DA which inhibits prolactin release and increases growth hormone release
34
Q

5-Hydroxytryptamine (5-HT, serotonin) in the CNS: Actions of 5-HT

A
  • Hallucinatory behaviour
  • Feeding behaviour
  • Control of mood and emotion
  • Control of sleep/wakefulness
  • Control of sensory pathways including nociception
  • Control of body temperature
  • Vomiting

LSD is a partial agonist at 5-HT2 receptor

35
Q

Important 5-HT pathways

A
  • Rostral Raphe Nuclei- projects to
    • cerebellum
    • Hypothalamus
    • Thalamus
    • Caudate Nucleus
    • Cortex
    • Hippocampus
  • Caudal Raphe Nuclei- projects to the spinal cord
36
Q

Synthesis of 5-HT

A
37
Q

Control of 5-HT synthesis

A
  • The enzyme tryptophan hydroxylase is not saturated with substrate and this the synthesis of 5-HT is dependent on the concentrations of tryptophan available
  • Tryptophan hydroxylase is not controlled by endo product feedback inhibition
  • AAAD, the enzyme that decarboxylates 5-hydroxytryptophan is the same enzyme which decarboxylates DOPA
38
Q

Metabolism of 5-HT

A
  • The only significant metabolite of 5-HT in the CNS is 5-hydrocyindole acetic acid (5-HIAA)
  • The formation of this metabolite from the CNS is inhibited by probenecid and this has been used to estimate the turnover of the transmitter by measuring the increase of 5-HIAA levels in the brain after probenecid treatment
39
Q

Characteristics of 5-HT release

A

As for the other amines

  • Quantal
  • Exocytotic

5-HT is inactivated by uptake mechanism as is the case for NA and DA

40
Q

5-HT receptors

A
  • 5-HT (1-7) receptors with (Many with A-D subtypes) have been identified in the brain
  • Only one of these, the 5-HT3 receptor is a ligand-gated ion channel
  • The remainder of the receptors are coupled to G-proteins (Coupled to cAMP or IP3 second messengers)
  • Their pharmacology, in many cases is difficult to elucidate because of the lack of specific antagonists
41
Q

5-HT receptor: 1A, 1D, 2A, 3

A
  • 5-HT1A- Increases K+ conductance (K+ leaving the cell)= net negative charge= hyperpolarisation= reduced activity
  • 5-HT1D- Decrease adenylate cyclase= pre-synaptic effect
  • 5-HT3- agonists are used in chemotherapy induced nausea
42
Q

5-HT receptors: III

A
  • The 5-HT1D receptors on the pre-synaptic terminal decrease release of the transmitter when activated by 5-HT
  • It also has an axon collateral that releases 5-HT onto the cell body
  • The 5-HT1A receptors in the cell body, when activated by 5-HT decrease cell firing i.e. reduce 5-HT release ( BUT these receptors also down-regulate when chronically activated i.e. lose effectiveness)
  • Look at again on BB
43
Q
A

PH3501- Neuropharmacology (28 decks)

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