Neuromodulators (L4-5) Flashcards
What technique associated with Human/Animal imaging can be used to study neuromodulators?
PET studies of receptor binding.
How can you study neuromodulators in whole animals?
- inject a drug and assess effect on behaviour
- inject a drug and record neuronal activity
- genetically modified animals e.g. lacking a receptor subtype
- lesion regions – effects on behaviour
How can you study neuromodulators in vitro?
LTP, single cell activity, network activity.
Neuromodulator transmitters should not be regarded as purely excitatory or inhibitory. Why?
- Their exact action depends on receptors, context, levels.
- On the same cell, they can be either excitatory or inhibitory.
With a few exceptions, what type of receptor do neuromodulators act upon? This being the main reason neuromodulators can both excite and inhibit.
Metabotropic.
What are pyramidal cells?
The principle excitatory cells of the cortex.
Name the 3 parts that make up a pyramidal cell.
- Soma
- Apical dendrites
- Basal dendrites
Define an Interneuron.
An interneuron is a neuron that forms a connection between other neurons. Interneurons are neither motor nor sensory.
Where are monoamines produced?
In the nuclei of the brainstem.
Dopamine neurons are present in which 2 regions of the brainstem?
- A10 = Ventral tegmental area
- A9 = Substantia nigra
True of false? Overall there are a large number of DA neurons in the brain.
False. Overall there are a small number of DA neurons in the brain, 1 million/10 billion.
Name the 3 main Dopamine pathways.
- Mesocortical pathway
- Mesolimbic pathway
- Nigrostriatal pathway
Describe the Mesocortical pathway.
Ventral tegmental area to prefrontal cortex. PFC important for higher cognitive functions such as motivation, planning, attention and working memory.
Describe the Mesolimbic pathway.
Ventral tegmental area to amygdala, hippocampus and frontal cortex. Thought to be involved in reward, euphoria induced by drugs.
Describe the Nigrostriatal pathway.
Neurons in substantia nigra mainly project to dorsal striatum. Part of the extrapyramidal motor system involved in the initiation and control of movement.
Ventral tegmental area neurons fire in two modes. What are they and what level of Dopamine do they release?
Tonic - Low levels
Phasic - High levels
What is tonic firing of DA?
Background level of dopamine release.
True or false? DA (and NA) exhibit an inverted “U”shaped function.
True.
Describe the synthesis of DA from precursor to DA.
Precursor = Tyrosine
Tyrosine + Tyrosine Hydroxylase = DOPA
DOPA + DOPA decarboxylase = DA
Which 2 enzymes breakdown DA?
Monoamine oxidase & COMT.
What does the Dopamine Transporter (DAT) do and where is it found?
It limits DA transmission and is only found on DA terminals.
How does the Dopamine transporter work?
Active transport by an Na/K ATPase pump which pushes through a DA molecule in every cycle.
Name the D1 like receptors.
- D1
- D5
Name the D2 like receptors.
- D2
- D3
- D4
True or false. Dopamine receptors are all metabotropic G-protein coupled receptors.
True.
D1-like receptors couple to Gs and do what?
Stimulate adenylate cyclase and therefore increase cAMP.
D2-like receptors couple to Gi and do what?
Inhibit adenylate cyclase and therefore decrease cAMP.
How many membrane alpha helices do Dopamine receptors have?
7.
Where on the neuron are DA receptors present?
Present on soma, dendrites, and nerve terminal.
Stimulation of DA receptors have different effects depending on the receptor location. Presynaptic autoreceptors regulate what?
Release of DA from terminals.
Which disease stems from the loss of dopamine neurons in the substantia nigra?
Parkinson’s disease.
How would you cause animals to display symptoms of Parkinson’s disease, what does this do to the animal and how would you reverse the process?
Inject 6-OHDA which causes loss of dopamine neurons in the substantia nigra and VTA.
Lesioned animals shows reduced learning deficits and LTP.
LTP and learning deficits reversed by L-DOPA treatment.
Define Long Term Potentiation (LTP).
Long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously.
True or false? Dopamine modulates the synaptic plasticity (LTP) thought to underlie learning and memory.
True.
Having Parkinson’s disease does what to the size of the hippocampus?
Reduces its size.
Coacaine and amphetamine work by blocking which transporters?
The monoamine transporters.
Which drug, cocaine or amphetamine also causes further dopamine to be released?
Amphetamine.
What is the overall effect of amphetamine and cocaine on the synaptic cleft?
Increased dopamine and noradrenaline concentration in the cleft.
Amphetamine causes weak inhibition of __________ _________ so prevents degradation of DA leaving free DA in terminals.
Monoamine oxidase.
List the roles of Serotonin (5-HT) in the body?
- Regulating food intake
- Learning and Memory
- Sleep-wake cycle
- Aggression
The 5-HT neurones arise from the _____ nucleus in the brainstem.
Raphe.
Describe the synthesis of 5-HT from precursor to 5-HT.
Precursor = L-Tryptophan
L-Tryptophan + Tryptophan Hydroxylase = 5-HTP
5-HTP + L-amino acid Decarboxylase = 5-HT
What type of vesicles is Serotonin stored in?
Large dense core vesicles.
Name the 5-HT re-uptake transporter.
The Serotonin Transporter (SERT)
What is 5-HT broken down by?
Monoamine oxidase.
How many subtypes of Serotonin are there?
14.
Which 5-HT receptor subtypes are G-protein linked receptors?
5-HT 1,2,4,5,6,7.
Which 5-HT receptor subtype is ionotropic?
5-HT 3.
Which 5-HT receptor subtypes are important in learning and memory?
5-HT1A, 5-HT4 and 5-HT6.
Name the diseases of Serotonin dysfunction.
- Depression
- Anxiety disorders
- Bipolar disorder
- Schizophrenia
- Obsessive compulsive disorder
Name some major symptoms of depression.
- depressed mood
- apathy
- weight changes
- sleep disturbances
- agitation
- fatigue
- worthlessness
- executive dyfunction
- suicidal ideation
What is the most widely used drug to treat depression and how does it work?
Prozac - Selective and potent inhibitor of SERT.
List the roles of noradrenaline (NA).
- Learning and memory
- Sensory processing
- Attention
Where do NA neurons arise from?
Locus Coeruleus.
Describe the firing of Locus Coeruleus neurons whilst awake and in different stages of sleep.
- Highest firing when awake.
- Lower during slow-wave sleep.
- Virtually silent during REM or paradoxical sleep.
Noradrenaline has the same synthesis pathway as DA apart from the last stage where DA becomes NA due to the activity of what enzyme?
Dopamine Hydroxylase.
True or false? NA transporter works in the same way as DA transporter.
True
Name the adrenergic receptor subtypes and what happens when each is activated.
a1 - adrenoceptors activate phosopholipase C, producing IP3 and DAG.
a2 - inhibit adenylate cyclase and decrease cAMP.
β1, β2, β3 - all stimulate adenylate cyclase and increase cAMP.
Name the transporter that transports vesicles containing monoamines to the presynaptic membranes.
VMAT.
What is ADHD characterised by?
- inattention
- hyperactivity
- impulsivity
What are the treatments for ADHD? And what simply do they do?
Psychostimulants (Ritalin) and guanfacine. Increase DA and NA levels.
ADHD is a genetic polymorphism of what?
Dopamine β Hydroxylase.
What effect of ADHD is used as a diagnostic tool?
Decreased NA synthesis.
What 2 chemicals react to form Acetlycholine? And what enzyme catalyses the reaction?
Acetyl CoA+Choline. Choline Acetyltransferase
ChAT
What process does Co-enzyme A arise from?
Glucose metabolism.
No re-uptake of Ach occurs in the synaptic cleft. Instead it is broken down into its constituent parts. Which enzyme catalyses the brekdown?
Acetylcholinesterase (AChE).
Name the 2 main receptor subtypes of Ach receptors. Are they ionotropic or metabotropic? Also name the subtypes of each.
Nicotinic - Ionotropic - a7 and a4β4
Muscarinic - Metabotropic - M1- M5
What is Alzheimers disease?
Form of dementia characterised by degeneration of the basal forebrain cholinergic neurons.
What are the symptoms of Alzheimers disease?
- Difficulty maintaining and sustaining attention
- Memory loss
- Mood changes - depression, irritability
- Psychosis - hallucinations, paranoid delusions
- Psychomotor - wandering, pacing
- Sleep-wake disturbances
