Lecture 12 Flashcards
How does diffusion enable modulation systems of the brain?
Have effects over large areas of the brain
Many of the body’s sensory, motor and cognitive functions are carried out by fast, specific, spatially organized neural connections
Perform regulatory functions rather than specific tasks
e.g. Falling asleep/waking up/becoming attentive
Changing mood
Other functions involve more general alterations in the function of the brain
What are common features of neurotransmitters?
Core of each system has a small set of neurons
Neurons arise from the central core of the brain
(often in the brain stem)
Each neuron may contact more than 100 000 postsynaptic neurons spread widely across the brain
Neurons release neurotransmitters into the extracellular fluid to allow diffusion to many neurons
Where are ACh located?
ANS
What are examples of catecholamines?
dopamine, noradrenaline
What is a good marker for cholinergic neurons and why?
ChAT; every neuron that releases ACh must have ChAT
How is Acetyl CoA produced by and where?
Cellular respiration, mitochondria
What does ACh degrade into and what enzyme catalyses the reaction?
Acetic acid and choline
AChE
What happens to the choline?
Taken up from the extracellular solution then recycled
What prevents release of ACh?
Botulinum toxin
- produced by bacteria in Black Widow Spider
- venom (latrotoxin) first increases ACh release at the neuromuscular junction then eliminates it
- seems to work by allowing a big Ca influx
What act as AChE inhibitors?
nerve gas insecticide Alzheimer's treatments - organophosphates - Alzheimer's disease shows reduced ACh
What block ACh receptors?
Nicotinic
curare
- neuromuscular blocks in blowpipes prevent prey from moving
alpha-Bungarotoxin
- from snake venom
- binds to nAChRs and takes days to unbind
- (Bungarus multicinctus)
Muscarinic atropine - found in Belladonna - causes pupils to dilate - women in the past used atropine to make eyes look bigger - can be fatal
What are the two cholinergic complexes of ACh?
Basal forebrain complex Pontomesencephalotegmental complex (brain stem)
What forms the Basal forebrain complex?
Medial septal nuclei
Basal nucleus of Meynert
How are the neurons distributed in the basal forebrain complex?
Neurons are scattered among several nuclei so the function of these nuclei are largely unknown
(Among the first to die in Alzheimer’s disease)
What does the Basal forebrain complex do?
Regulate brain excitability during arousal and sleep/wake cycles
What possible role does the Basal forebrain complex have?
Learning and memory
Where is the pontomesencephalotegmental complex located?
Pons and midbrain tegmentation
What is the precursor used in the synthesis of catecholamines?
tyrosine (an amino acid)
Where is tyrosine hydroxylase located?
All catecholaminergic neurons
rate limiting factor
Where is dopamine beta-hydroxylase located?
Synaptic vesicles
Where is PNMT located?
Bound in cytosol of presynaptic terminal
How are catecholamines removed and/or degraded?
Majority undergoes reuptake into presynaptic terminals Metabolized by: - catechol-O-methyltransferase (COMT) (mainly in cytoplasm) - Monoamine oxidase (MAO) (on outer mitochondrial membrane) - MAO-A: breaks down noradrenaline and serotonin - MAO-B: breaks down dopamine
What are the two catecholamine systems?
Dopaminergic and noradrenergic
What is the nigrostriatal pathway?
Neurons found in the substantia nigra of the midbrain
Axons project to the striatum
Pathway facilitates the initiation of voluntary movements
Degeneration of this pathway leads to Parkinson’s disease
- characterized by motor dysfunction
e.g. tremor, rigidity, lack of coordination, not very smooth muscle
How is Parkinson’s disease treated?
Aims to increase dopamine
How are dopamine levels increased?
Addition of L-Dopa removes the rate limiting step of tyroxine hydroxylase
MAO-B inhibitors reduce the breakdown of dopamine, increasing levels
What is the Mesocorticolimbic pathway?
Neurons found in the ventral tegmental area of the midbrain
Axons project to the frontal cortex and limbic system
Assigned many functions
Involved in a “reward” system i.e. pleasure
We are motivated to perform behaviors that stimulate dopamine release
Behaviors associated with the delivery of drugs which result in dopamine release are reinforced = addiction
Where does the noradrenergic system arise from?
Locus coeruleus
Does the noradrenergic system have many neurons?
No; about 25 000
Where does the noradrenergic system innervate?
Nearly all of the brain
- one neuron can project to both the cerebral and cerebellar cortex
How many synapses can one neuron make in the noradrenergic system?
250 000
What is the noradrenergic system involved in?
Regulating attention, arousal, sleep-wake cycles, learning and memory, anxiety and pain, mood
How is the noradrenergic system most strongly activated by?
New, unexpected, non-painful sensory stimuli
What does the serotonergic system arise from?
Raphe nuclei
(each nucleus projects to a different area)
(similar diffuse innervation of brain to noradrenergic system)
What does the serotonergic system modulate?
Pain-related sensory signals, sleep-wake cycles, mood and emotional behavior
When is the serotonergic system most strongly activated?
Wakefulness
e.g. caudal nuclei innervate spinal cord
Where is tryptophan obtained from?
Our diet
e.g. grains, meat, dairy, chocolate
How does tryptophan move in the body?
Moves from gut to blood to extracellular fluid
What is the rate limiting factor in serotonin synthesis?
tryptophan
How many subtypes are there in 5-HT receptors?
7
Are 5-HT receptors ionotropic or GPCRs?
All but one are GPCRs
One is ionotropic
Are 5-HT receptors excitatory or inhibitory?
Both
What terminates the synthesis of serotonin?
Removed from synaptic cleft by a specific transporter
Reloaded into vesicles or degraded by MAO-A
What are treatments for anxiety?
Antidepressants
Affects each person differently
Can be more effective for one person than the other
What do tricyclic compounds do?
Block uptake of 5-HT and noradrenaline
What do serotonin-selective reuptake inhibitors (SSRIs)
Selectively prevent 5-HT uptake
e.g. fluoxetine (prozac)
What are MAO-A inhibitors?
Reduce enzymatic degradation of 5-HT and noradrenaline
What is the mechanism for anxiety treatment?
unknown
Increase in noradrenaline and 5-HT levels is immediate but therapeutic effects take weeks to develop. Why?
Action of these drugs take hours to days but the therapeutic effects take about two weeks at least
- cannot just be an increase in neurotransmitters in the synaptic cleft for an effect (?)
What is the cheese effect?
Cheese = high in tyramine
Tyramine is an amine found in high quantaties
It has sympathomimetic effects by increasing noradrenaline release
MAO normally breaks down tyramine
MAO-A inhibitors lead to a hypertensive crisis
How is ATP often packed in?
Vesicles as a co-transmitter
What effects does ATP have?
A lot
What receptors do ATP bind to as a neurotransmitter?
Purinergic receptors
- P2X = ligand gated ion channels
- P2Y = GPCRs
What effects do endocannabinoids have?
Effects on sensation
What are endocannabinoids?
ENDOgenous forms of CANNABIS
Small lipid molecules that do not require synaptic vesicles
How are endocannabinoids released?
Released from one cell to another
What do endocannabinoids bind to?
Cannabinoid receptors
G-protein coupled
What is nitric oxide?
Gasotransmitter that is small and membrane permeable
Where is Nitric oxide located in?
Present in lots of different cells
How do nitric oxide travel in the synaptic cleft?
go backwards and forwards
How fast do nitric oxide break down?
Rapidly broken down
