Serotonergic Neurotransmission and Serotonergic Drugs Flashcards
most important location of 5-HT in the brain (+ others)
raphe nuclei
dorsal raphe nuclei project to cortex, hippocampus, amygdala, striatum and hypothalamus
ventral raphe nuclei project to cerebellum, medulla and spinal cord
Synthesis, storage, release, termination and metabolism of 5-HT
- tryptophan is taken into neuron via carrier mediated transport
- tryptophan is converted to 5-HT in 2 steps catalysed by tryptophan hydroxylase and aromatic AA (DOPA) decarboxylase
- 5-HT is actively packaged into vesicles by an amine transporter
- release is via classical Ca2+-mediated exocytosis
- termination is via uptake by a serotonin transporter
- Degradation is via monoamine oxidase and aldehyde dehydrogenase
receptor targets of 5-HT
physiological response - 1A
Gi
Presynaptic (inhibitory autoreceptors) on raphe neurons
physiological response - 1B
Gi
Presynaptic (inhibitory) on basal ganglia neurons
physiological response - 1D
Gi
Presynaptic (inhibitory) on basal ganglia neurons
physiological response - 2A
Gq
pre and postsynaptic - excitatory or inhibitory
physiological response - 2B
Gq
pre and postsynaptic - excitatory or inhibitory
physiological response - 2C
Gq
pre and postsynaptic - excitatory or inhibitory
physiological response - 3
ion channel
pre and post synaptic
excitatory on cortical and area postrema neurons
physiological response - 4
Gs
pre and postsynaptic
excitatory (including as facilitatory autoreceptors)
physiological response - 5 and 6
unknown
physiological response - 7
Gs
not known
function of 5-HT
sleep
wakefulness
mood
feeding and appetite - overall effect of serotonin is to reduce appetite
MOA of some anti-emetics
serotonin antagonist
pathophysiology of depression
deficiency in monamine (NA and 5-HT) transmission is thought to underlie depression
SSRIs used to treat depression
treatment for anxiety
Busiprone = 5-HT1A receptor partial agonist (anxiolytic)
5-HT1A receptor = inhibitory autoreceptor
activating it will REDUCE 5-HT release initially
but over time it is thought that this may lead to desensitisation of 5-HT1A receptors and ultimately INCREASED synaptic 5-HT
most important site of NA in the brain
cells in locus ceruleus which project to hippocampus, cortex and cerebellum
Synthesis, storage, release termination, metabolism of NA
- Tyrosine is taken into neuron via carrier mediated transport
- tyrosine is converted to NA in 3 steps catalysed by tyrosine hydroxylase and dopamine β-hydroxylase
- dopamine is actively packaged into vesicles by an amine transporter and conversion to NA then occurs
- release is via classical Ca2+-mediated exocytosis
- termination is via uptake by a NA transporter
- degradation is via monoamine oxidase, aldehyde dehydrogenase and catechol-o-methyltransferase
receptor targets
α-adrenoceptors
α1 via Gq (PLC and increased IP3/DAG)
α2 via Gi (AC and decreased cAMP)
β-adrenoceptors
β1 via Gs (AC and increased cAMP)
β2 via Gs (AC and increased cAMP)
β3 via Gs (AC and increased cAMP)
physiological response of α-adrenoceptors
widespread in the brain
located both pre and postsynaptically
presynaptic - function as inhibitory receptors and autoreceptors and autoreceptors reducing NA release
physiological response of β-adrenoceptors
widespread in the brain
located both pre and postsynaptically
inhibitory and excitatory effects on pre and postsynaptic neurons
what behaviours is NA responsible for
mood
CNS arousal
pathophysiology of depression
deficiency in monoamine (NA and 5-HT) transmission is thought to underlie depression
biological symptoms of depression
slowness of thought and action
loss of libido
sleep disturbances
loss of appetite
unipolar vs bipolar depression
unipolar - mood swings in same direction
bipolar - depression alternates with mania
mania =
- excessive exuberance, enthusiasm, self-confidence
- impulsive actions
- irritability, impatience, aggression
- grandiose delusions
monoamine theory of depression
most established - underpins current drug therapy
depression is caused by a deficit of monoamines NA and/or 5-HT in certain sites in the brain
neuroendocrine theory of depression
depression is caused by overactivity in the stress responsive hypothalamic pituitary adrenal (HPA) axis
trophic factor theory of depression
caused by reduced levels/functional activity of brain-derived neurotrophic factor (BDNF)
glutamate theory
depression is caused by excessive glutamate activity at NMDA receptors
Neurodegeneration theory
depression is caused by neurodegeneration and reduced neurogenesis in the hippocampus
HYPOTHESIS for depressive symptoms
categories of monoamine reuptake inhibitors (type of antidepressant drug)
SSRIs
TCAs
Serotonin/NA reuptake inhibitors (SNRIs)
NA reuptake inhibitors
other reuptake inhibitors e.g. St Johns Wort and hyperforin (this inhibits monoamine oxidase - not a pure compound)
3 MOA for antidepressants
monoamine reuptake inhibitors
monoamine receptor antagonists
monoamine oxidase inhibitors
how do monoamine reuptake inhibitors work
block reuptake of
- NA and 5-HT (TCAs and SNRIs)
- 5-HT selectively (SSRIs)
- NA selectively
how do monoamine receptor antagonists work
block the action of NA at α2 receptors and/or 5-HT at 5-HT receptors
exert their effect very quickly but mood doesn’t change immediately
adaptive process takes place
chronic MOA of antidepressants
given that the clinical effects of antidepressants take weeks to develop, their acute pharmacological effects cannot account for their antidepressant activity
- Some NA receptors are consistently downregulated (especially β1 and β2)
- 5HT1A receptor (inhibits 5-HT release) may become desensitised over time, leading to increased synaptic 5-HT levels
- possible changes in gene expression via transcription factors (e.g. CREB, Fos, NF-κB), leading to neurogenesis
main SSRIs
fluoxetine - prozac (also antagonist activity at 5-HT2C receptors)
fluvoxamine
paroxetine
citalopram
escitalopram
sertraline
vortioxetine (also agonist/antagonist activity at several 5-HT receptors)
vortioxetine - where else does it function (apart for serotonin reuptake)
agonist/antagonist activity at several 5-HT receptors
where else does fluoxetine act (apart from serotonin reuptake)
antagonist activity at 5-HT2C receptors
what else do SSRIs treat
less SEs than TCAs
less dangerous in overdose than TCAs
no “cheese rxn”
also treat various anxiety disorders
treat premature ejaculation
Side effects of SSRIs
severe side effects when given with __________
Nausea
anorexia
insomnia
loss of libido and failure to orgasm
not recommended for children < 18 yrs - potential risk of suicide ideation
when given in combination with MAO inhibitors they can lead to serotonin syndrome - tremor, hyperthermia, CV collapse
what are the main TCAs
imipramine
desipramine
clomipramine
amitriptyline
nortriptyline
what else are TCAs used to treat
neuropathic pain (persistent pain following nerve damage)
Side effects of TCAs
normal clinical doses
anticholinergic effects (due to muscarinic block)
⇒ dry mouth, constipation, blurred vision, urinary retention
postural hypotension (due to α-adrenoceptor block)
sedation (due to H1 block)
⇒ often causing daytime drowsiness and difficulty in concentrating
potentiation of the effects of alcohol
⇒ can lead to respiratory depression and even death
overdose
ventricular dysrhythmias - sudden cardiac death
excitement, delirium and convulsions
respiratory depression and coma
examples of SNRIs
venlafaxine
desvenlafaxine
duloxetine
also used to treat anxiety disorders, menopause symptoms, neuropathic pain, fibromyalgia, urinary incontinence
NA reuptake inhibitors
bupropion
reboxetine
atomoxetine
also used to treat nicotine dependence, ADHD
risk with St Johns Wort
serious risk of drug-drug interactions due to effects on CYP450 enzymes
main monoamine receptor antagonists
mirtazapine (antagonist at α2, 5-HT2A, 5-HT2C, 5-HT3)
trazodone (antagonist at 5-HT2A, 5-HT2C)
mianserin (antagonist at α1, α2, 5-HT2A, histamine H1)
where is the α2 adrenoceptor
α2 adrenoceptor is on the presynaptic terminals of 5-HT neurons where it reduces 5-HT release
therefore antagonising it will enhance 5-HT release
main non-selective MAO inhibitors
phenelzine
tranylcypromine
isocarboxazid
main MAO-A selective inhibitors
moclobemide
clorgyline
what are the isoforms of MAO
MAO-A
MAO-B
what does MAO-A metabolise
5-HT
NA
dopamine
what does MAO-B metabolise
NA
dopamine
phenylthylamine
what do MAO inhibitors interact with and what does this cause
SSRIs
- serotonin syndrome
Pethidine (opiate analgesic)
- may lead to severe hyperpyrexia (high fever) with restlessness, coma and hypotension
- reason is unclear, but likely that an abnormal pethidine metabolite is produced due to inhibition of normal pethidine metabolic enzymes
what happens when MAO inhibitors interact with certain foods
TYRAMINE
indirectly acting sympathomimetic amine
diet derived (e.g. fermented meats, ripe cheese, beers, marmite, bovril)
normally metabolised by MAOs in gut so does not reach circulation but serious drug-drug interaction with MAOIs when tyramine enters blood stream
EFFECTS:
potentially fatal hypertensive crisis
severe throbbing headaches
intracranial haemorrhage
