Serotonin Flashcards
Where is 5HT in the brain?
Midline of brainstem: raphe nuclei
Dorsal and medial raphe nuclei (B7 and 8) make up most of the projections to the forebrain.
5HT innervation of forebrain is greater than dopamine, but same as NE.
5HT is also in the gut/bloodstream
How is 5HT synthesized?
5HT is a monoamine but its a INDOLAMINE (not a catecholamine)
Precursor is tryptophan (I’m calling it T) (amino acid that its synthesized from)
1. Tryptophan hydroxylase converts T into 5-HTP (5 hydroxyl-tryptophan) which is the rate limiting step.
2. AADC (dompaine decarboxylase or aromatic aminoacid decarboxylase) converts 5HTP into 5HT.
Trypo hydroxylaze only found in 5ht neurons: great marker for antibodies or mrna.
Pharmacology: PCPA which blocks 5HT synthesis by inhibiting tryptophan hydroxylase.
What is PCPA?
Para-chlorophenylalanine: blocks 5HT synthesis by irreversible inhibiting tryptophan hydroxalaze. This means that body has to make more enzymes in order to make 5HT.
Describe tryptophan or 5HT in the blood in regards to diet, crossing the BBB, and what happens when you reduce it.
In the blood, T competes with other amino acids for transport across BBB. Ratio of these determines 5HT synthesis.
Higher carb diet: higher insulin, stimulates protein synthesis (takes amino acids out of the bloodstream) but tryptophan is not effected by insulin, so higher carb diets make T getting into brain more likely.
Decrease T in the blood (or reduce it compared to other amino acids) causes less T to get into the brain.
If you give a cocktail of amino acids without 5HT, you see a reduction in the ratio of T to other amino acids and the liver is activated which uses any T to synthesize other proteins, further reducing 5HT in the brain.
If you reduce 5HT (shown in CSF or microdialysis)
- Ppl in remission from depression have short relapse of some symptoms (but not healthy people)
- In healthy people you see impulsivity.
How is 5HT packaged, released, where are receptors, reuptaken and breakdown?
Vesicular transport: VMAT2 (like DA and NE)
- sensitive to reserpine like all other monoamines
Normal synaptic transmission
Autoreceptors
- Presynaptic terminal to hyperpolarize and reduce calcium
- Somatodendritic on raphe neural cell bodies to slow firing
Reuptake: SERT removes 5HT from the synapse
Breakdown/degradation: uses MAO to create 5-HIAA (MAO inhibitors block this process and prevent it being chewed up)
- Levels of 5-HIAA in CSF indicate activity (more metabolite, more 5ht released)
What are some drugs that effect release of 5HT?
Amphetamine like mechanisms (reverse transporter)
- Fenfluramine (for appetite suppression, but caused people to die of heart problems)
- MDMA/Ecstasy/Molly: recreational drug that hits all monamine transporters, but higher affinity for SERT than D or meth-amphetamine.
- SERT blockers (rather than reverse)
- SSRIs like Fluoxetine or prozac. Works like cocaine but selective for 5HT.
What are the 5HT receptor subtypes?
14 5HT receptors; metabotropic
7 main families
Non selective (espeically nonselective within families, so understanding is limited, but genetic knockouts are helping )
1 family: 5 subtypes (no C)
2 family: 3 subtypes
Describe the 5HT 1A receptor subtype
Postsynaptic: hippocampus, septum, amygdala
Somatodendritic autoreceptors: raphe nucleus
- Inhibit CAMP and or open K+ channels (membrane hyperpolarization)
Agonists: 8-OHDPAT (full agonist) Buspirone (partial agonist)
- stimulates postsynaptic receptors but also reduces 5HT release.
Antagonist: WAY- 100635
Describe the 5HT 1B and 1D receptors
Presynaptic autoreceptors
Postsynaptic: striatum and nucleus accumbens
Different selective drugs hit these as opposed to 1A.
When you stimulate these, you hyperpolarize.
Describe the 5HT 2A receptor subtpes.
Postsynaptic
In Cortex, striatum, nucleus accumbens
- Activate phosphoinostitide 2nd messenger pathway.
- Increases Ca+ in postsynaptic cells and activates PKC (like alpha 1 adrenergic receptors)
Agonists: DOI
- hallucinogeneic to humans, LSD stems from its ability to stimulate 2A receptors (regulating sensory functions and disrupting them)
Antagonists: Ketanserin, could block the hallucinations
2C is also postsynaptic and can have antagonistic effects with 2A.
Briefly describe how we test behavioral functions with 5HT?
Oldest NT, if you take it away animal still survives (unlike with DA you’d die)
-5HT suppresses behaviors usually
Human investigations
- Compare CSF levels of 5-HIAA or postmortem with certain conditions
- Assess responses to SSRIs or receptors antagonists/agonists
- Identify genetic polymorphisms or SERT or 5-HT receptors in disorders (different copies of a gene might be better or worse for a certain receptor or transporter)
Animal Investigations
- Neurotoxins: 5-7 DHT
- KO mice that lack receptors or delete enzyme that makes 5HT
- Psychopharmacological studies.
What are some behavioral functions of 5HT?
Sensory filtering
Temp regulation (overdose issues with this)
Sleep Wake cycles (inhibit wakefulness and REM)
Pain modulation
Learning and Memory
Cognitive flexibility
Describe 5HT and hunger/satiety.
SSRis or 5HT releasers (1B or 2C receptor agonists) cause hypophagia
- eat less per meal, get fuller faster , but same amount of meals.
- eat less fatty foods
- causes more inactivity/resting
5HT is a short term satiety signal.
Disinhibits PARAVENTRICULAR HYPOTHALAMUS to promote satiety.
If you reduce 5HT (1A receptor agnoist which stimulates somatodendritic autoreceptors in raphe) you get hyperphagia.
Describe 5HT and modulation of anxiety.
5HT manage anxiety in opposing manners.
Anxiety is NOT fear. Fear is known threat. Anxiety is apprehension.
Assay: elevated plus/zero maze. Time spend in open/closed areas = anxiety levels. There is a drive toe xplore and a drive to stay away from heights.
A1 agnoists (reduce 5HT release via autoreceptors)
- reduce anxiety, animal will explore more
- drugs that target here (buspirone partial agonist) treat anxiety in humans
A1 knockout (increase 5HT release) increase anxiety -KO early on, increase anxiety, but later KO no effect. Its likely a developmental effect.
2A/2C agonists increase anxiety (postsynaptic)
2A/2C knockouts reduce anxiety. (postsynaptic)
In general: reduce 5HT, reduce anxiety.
Describe 5HT and aggression.
Aggression: cause harm.
Low 5HT: increased aggressive behavior (depends on genetics, drug regimne, type of agression)
1A/1B agonists reduce aggression in mice.
- due to stimulation of post synaptic receptors (rather than the autoreceptors which reduce 5HT release)
TEST THIS IDEA: resident intrudor mice. If given a 1a or 1b agonist, they reduce their attacks. Less 5HT, more aggression.
However, if you overexpress 1A receptors in raphe (autoreceptors) that causes hyper aggression cause its reducing 5HT release.
MEANING
Tryptophan depletion in humans causes aggressive behaviors in lab tests.
- Game for points, if you have T depletion (less 5HT in brain) you are more likely to attack your opponent. (could be related to 5HT regulation of impulsivity)
