Neurotransmitters

Question 1

Dopamine synthetic mechanisms

Answer 1

1. Tyrosine hydroxylase converts tyrosine to DOPA
2. DOPA is decarboxylated to create Dopamine

Question 2

Dopamine metabolism

Answer 2

Dopamine is released from the nerve terminals.
It is taken back to the nerve terminals via DAT.
In the neurone it is metabolised by Monoamine oxidase B (MAOB) / Catechol-O-Methyl transfersase (COMT) creating DOPAC and HVA

Question 3

Key dopamine pathways

Answer 3

• Nigrostriatal. Substantia nigra pars compacta to striatum. Control of movement
• Mesolimbic. VTA to the nucleus accumbens. Reward pathway.
• Mesocortical. VTA to the prefrontal cortex. Cognitive control, motivation, mood.
• Tubularinfandibular. Ventral hypothalamus to medial eminence / pituitary. Dopamine release regulates prolactin secretion.

Question 4

Dopamine receptor subtypes

Answer 4

ALL metabotrophic

• *D1 like:** D1, D5. Both GPCRs linked to Gs. Increasing cAMP and stimulating the cell.
• *D2 like:** D2, D3, D4. GPCRs linked to Gi/o. Decreasing cAMP and inhibiting the cell.

Question 5

Acetylcholine synthetic mechanisms

Answer 5

ACh is synthesised from Choline and acetylcoA by the enzyme, choline acetyltransferase (CAT)

Question 6

Inactivation mechanisms of ACh

Answer 6

ACh is inactivated by enzymatic degradation. It is broken down in the synaptic cleft by Acetylcholinesterase (AChE) to acetate and choline. Choline is taken back to presynaptic cleft by choline carrier.

Question 7

Key neuronal pathways of ACh in the CNS

Answer 7

Striatum, cortex, hippocampus, thalamus

Question 8

AChR subtypes

Answer 8

Ionotrophic/nicotinic (nAChRs):
Can be heteromers or homomers of alpha and beta subunits e.g. α42β23 α75.
These are both ligand gated cation channels on the post-synpatic membrane that cause cellular depolarisation.

Metabotrophic/muscarinic (mAChRs):
m1, m3, m5: Postsynaptic excitatory Gq coupled GPCRs. Cleaves PIP2 into IP3 and DAG, increasing cytosolic Ca++.

m2, m4: Postsynaptic inhibitory Gi/o coupled GPCRs. Decrease cAMP.

Question 9

Enkephalin synthesis

Answer 9

Cleaved from precursor proteins e.g. pre-proenkephalin

Question 10

Enkephalin metabolism

Answer 10

Breakdown by aminopeptidase N (APN) and enkephalinase (extracellular) into inactive metabolites.

Question 11

Key enkephalin pathways in the CNS

Answer 11

Spinal cord: descending pathway consisting of nucleus raphe magnus and periaductal gray (pain pathway), dorsal horn

Bidirectional connections between the Central amygdala and Nucleus Accumbens modulate food intake.

Some modulation of sexual reinforcement via action in medial preoptic area of thalamus.

Question 12

Enkephalin receptor subtypes

Answer 12

All metabotrophic

Mu1/2. Presynaptic in the PAG and the dorsal horn. Gi/o. VDCC block. Inhibits adenylyl cyclase (decreasing cAMP) and opens K+ channels. membrane hyperpolarisation.

Delta + Kappa. Pre and post synaptic. Gi/o. VDCC block. Inhibits adenylyl cyclase (decreasing cAMP) and opens K+ channels. membrane hyperpolarisation.

Question 13

GABA Synthetic mechanisms

Answer 13

Glutamine is converted to glutamate, which is converted to GABA by glutamate decarboxylase.

Question 14

Glutamate synthetic mechanisms

Answer 14

Glutamine (from astrocyte) is transported into nerve terminal via Glutamine transporters. Once in a nerve terminal Glutaminase converts it to Glutamate.
It can also be synthesised from glucose.

Question 15

NA Synthetic mechanisms

Answer 15

1. Tyrosine converted to Dopa by tyrosine hydroxylase.
2. Dopa converted to dopamine by aromatic amino acid decarboxylase.
3. Dopamine converted to noradrenaline by dopamine- β-hydroxylase.

Question 16

Tachykinins/neurokinins synthetic mechanisms

Answer 16

These are peptides, thus synthesised from 2 main genes - different splice variants give rise to different peptide e.g. NK1, substance P.

The Bioactive peptides are cleaved from the large inactive peptide precursors encoded by these genes in the endoplasmic reticulum.

Question 17

Synthetic mechanisms of 5HT

Answer 17

Synthesised from L-tryptophan (dietary amino acid) in two steps by two enzymes.

Question 18

Storage of neuro/tachy kinins

Answer 18

Stored in large dense core vesicles in varicosities in PNS and synapses in CNS. These vesicles are located further from the synaptic membrane, therefore greater depolarisation is required to cause release of neuro/tachy kinins. For this reason, they are often co-released with other excitatory neurotransmitters such as glutamate.

Question 19

GABA metabolism

Answer 19

It is taken up both by pre-synaptic cells and glial cells, where it is broken down by GABA transaminase.

Question 20

Types of GABA receptors

Answer 20

1. Ionotrophic.
   GABA_{<strong>A</strong>} and GABA_C are both post-synaptic ion channels that cause inhibition by allowing Cl- entry.
2. Metabotrophic.
   GABA_B is coupled to Gi/o, causing inhibition by cAMP and opening K+ channels.

Question 21

metabolism of glutamate

Answer 21

80% of glumate is taken up by EAAT1 on astrocytes, where it is converted back to glutamine so that it can be transported back to pre-synpatic neurons.

Question 22

Types of glutamate receptors

Answer 22

1. Ionotrophic:
   * *AMPA:** Post-synaptic excitation via Na+ influx
   * *NMDA:** Post-synpaptic exitation via Ca++ and Na+ influx. Higher activation threshold, as it requires removal of Mg++ by depolarisaion.
   * *Kainate:** Pre/Post synaptic exciation via Na+ influx
2. Metabotrophic
   * *Group 1:** (mGlu1, 5). Coupled to Gq, activating PLC and thus increasing IP3 and DAG to cause postsynpatic excitation
   * *Group 2** (mGlu2, 3) & Group 3 (mGlu4, 6, 7 and 8): Cause presynaptic inhibition by coupling Gi/o to decrease adenlyate cyclase activity and open K+ channels.

Question 23

NA metabolism

Answer 23

Taken up by Noradrenaline reuptake transporter (NET), metabolised by COMT (glial cells) and Monoamine Oxidase B (Glia and neurons)

Question 24

Main NA pathways

Answer 24

Associated with mood and arousal

Locus Coeruleus (nuclei) project to thalamus, frontal cortex, hypothalamus and limbic system, as well as the cerebellum.

Raphe nuclei ascend to the amygdala and descend to the spinal cord (peripheral functions and pain perception).

Question 25

Types of NA receptor

Answer 25

ALL metabotrophic.

1. alpha-1. Gq, pre/post stimulation.
2. alpha-2. Gi/ Go, pre/post inhibition.
3. beta-1. Gs, post stimulation.
4. beta-2. Gs, post stimulation.

Question 26

Neuro/Tachykinin breakdown

Answer 26

Substance P and neuropeptides A, B and K are degraded by enkephalinase in extracellular spaces. Substance P is also hydrolysed by angiotensin converting enzyme (ACE).

Question 27

Neuro/tachkinin pathways

Answer 27

Substance P regulates affective behaviour and emesis in the brain.

Neurokinin A and substance P regulate nociception in the spinal cord.

Question 28

Neuro/tachykinin receptor types

Answer 28

ALL excitatory pre/post metabotrophic G_q coupled (PLC activation)

1. NK1. substance P > neurokinin A > neurokinin B
2. NK2. neurokinin neurokinin B > substance P
3. NK3. neurokinin B > neurokinin A > substance P
   (rank order of potency.)

Question 29

5HT metabolism

Answer 29

Reuptake of 5-HT into neurons with co transport of NA+ by SERT on the axons.

Broken down by Monoamine oxidase A and B

Question 30

5HT pathways

Answer 30

Serotonin is primarily found in the Raphe nuclei of brain stem with widespread projections to areas such as amygdala, hippcampus, spinal cord, neocortex

Question 31

5HT receptor subtypes

Answer 31

1. ionotrophic:
   * *5HT_3. **Non selective cation channel. Post-synpatic excitation.
2. Metabotrophic:
   * *5-HT₁ A;B;D;E;F:** Pre/post inhibition by Gi/Go
   * *5HT_2:** Pre/post synaptic stimulation
   * *5HT_4,6,7: Postsynaptic stimulation by G_s coupling
   * *5Ht₅: Post-synpatic inhibition by Gi/Go