Chemicals in the brain part 2 Flashcards
What are the monoamines
- Catecholamines - dopamine, epinephrine(adrenaline) and norephinephrine
- Indolamines - serotonin(5-Hydroxytryptamine, 5-HT)
What are the two steps of dopamine synthesis
1) Tyrosine –> L-dopa reaction carried out by Tyrosine hydroxylase
2) L-dopa –> dopamine reaction carried out by dopa decarboxylase
What is administered for treating parkinson’s disease
- Levodopa
How is epinephrine synthesised
- Dopamine –> Norepinephrine carried out by dopamine beta-hydroxylase(DBH)
- Norepinephrine –> epinephrine carried out by phentolamine N-methyltransferase(PNMT)
Location of DBH
- DBH located in synaptic vesicles only, and NE is the only neurotransmitter synthesised within vesicles
How does catecholamine release occur
- Released by Ca2+ dependent exocytosis
- Binds and activates receptor
- Signal terminated by reuptake into the axon terminal by transporters powered by electrochemical gradient(dopamine transporters DATs), norepinephrine transporters(NETs) etc
How does catecholamine reuptake occur
- Signal terminated by reuptake into the axon terminal by transporters powered by electrochemical gradient (Dopamine transporters DATs), Norepinephrine transporters (NETs) etc
• In the cytoplasm, the catecholamines are- Reloaded back into vesicles
- Enzymatically degraded by monoamine oxidases(MAOs)
Or - Inactivated by Catechol-O-methyl-transferase (COMT)
Effect of amphetamine on catecholamine transporter
- Amphetamine reverses transporter so pumps out transmitter and blocks reuptake(DA and NE)
Effect of cocaine and methylphenidate on DA uptake
- Cocaine and methylphenidate(ritalin) block DA reuptake into terminals
- More DA in synaptic cleft - extended action on postynaptic neuron
Effect of selegiline on dopaminergic nerve terminals
- MAO inhibitor found in dopaminergic nerve terminals thus preventing the degradation of DA allowing more to be released on subsequent activations(treatment of early-stage PD, depression and dementia)
Effect of entacapone on catecholamine release and reuptake
- Catechol-O-methyl-transferase(COMT) inhibitor
- Treatment of PD
Stages of serotonin synthesis
- Tryptophan –> 5-HTP carried out by tryptophan hydroxylase
- 5-HTP –> 5-Hydroxytryptamine(Serotonin, 5-HT) carried out by 5-HTP decarboxylase
How does serotonin storage, release and reputake occur
- Stored in vesicles
- Signal terminated by reuptake by serotonin transporters(SERTs) on presynapticmembrane
- Destroyed by MAOs in the cytoplasm
Effect of fluoxetine(prozac) on serotonin release and reuptake
- Fluoxetine(prozac) blocks reuptake of serotonin(SSRI - selective serotonin reuptake inhibitor) (treatment of depression, OCD)
Effect of fenfluramine on serotonin release and reuptake
- Fenfluramine stimulates the release of serotonin and inhibits its reuptake(has been used as an appetite suppressant in the treatment of obesity)
Effect of MDMA(methylenedioxymethamphetamine)(ecstasy) on NE and serotonin transporters
- Causes NE and serotonin transporters to run backwards releasing neurotransmitter into synapse/extracellular space/extracellular space(assessed for therapeutic potential in PTSD)
What does choline acetyltransferase cause
- Conversion of choline + acetyl CoA into acetylcholine
What is acetylcholine packed by
- Is packaged into vesicles by vesicular acetylcholine transporter(VAChT)
What is Ach degraded by
- Rapidly degraded in synaptic cleft by acetylcholinesterase(AChE)
- Acetylcholine –> acetate + choline
What happens to choline that is produced from Ach degradation
- Choline is transported back into the presynaptic terminal and converted to acetylcholine
What is the rate limiting step in acetylcholine production
- Amount of choline is rate limiting step
Effect of AChE inhibitors
- Block the breakdown of Ach, prolonging its actions in the synaptic cleft
Effect of neostigmine on Ach
- Is an acetylcholinesterase inhibitor which prolongs the action of Ach in the synaptic cleft
Effect of black widow spider venom on Ach release
- Stimulates its release
Effect of tetanus toxin on the release of glycine and GABA at inhibitory neurons
- Inhibits release of glycine and gABA at inhibitory neurons, resulting in dis-inhibition of cholinergic neurons(release of Ach), which causes permanent muscle contraction
What are some examples of neuropeptide transmitters
- Endorphins, neuropeptide y, substance p, endogenous opioids, vasopressin
How are neuropeptide transmitters released
- Follow the secretory pathway but NOT released in the same way as small molecule transmitters
- Dense core vesicle fusion and exocytosis occurs as a result of global elevations of Ca2+(sustained or repeated depolarization or release of Ca2+ from intracellular stores)
- Neuropeptide vesicle membrane recycled but not refilled
How are neuropeptide signals terminated
- Bind to and activate receptor
- Neurpeptides signalling is terminated by diffusion from site of release and degradation by proteases in the extracellular environment
- Release is slower than small molecule release and signals may be maintained for longer
How does retrograde signalling work with soluble gases such as nitric oxide and carbon monoxide
1) Nitric oxide made in postsynaptic neuron by nitric oxide synthase(activated by the binding of Ca2+ and calmodulin)
2) The gas is not stored but rapidly diffuses from its site of synthesis. Diffuses between cells(into presynaptic cell - retrograde transmitter)
3) Activates guanylyl cyclase which makes the second messenger cGMP
4) Within a few secs of being produced, NO is converted to biologically inactive compound(switching off the signal)
5) Useful for coordinating activities of multiple cells in a small region(tens of micrometers)
What are some other examples of transmitters/retrograde signalling
- Endocannabinoids - small lipids which cause reduced GABA release at certain inhibitory terminals
- A cannabinoid is also the active component of the active compoent of marijuana(cannabis sativa)
