Neurotransmitters Flashcards
Glutamate
major excitatory amino acid small molecule neurotransmitter in the CNS
GABA
- main inhibitory NT in brain
- synthesised from Glutamate by glutamic acid decarboxylase
- loaded into synaptic vesicles by VIAAT
- cleared by GATs - Na+ dependent co-transporters
GABA receptors
- GABAa ionotropic (chloride channels)
- GABAb metabotropic (inactivated K+ channels or inhibit Ca2+ channels)
GABAa receptor pharmacology
- agonists widely used sedatives, anxiolytics, anti-convulsants, anaesthetics
- barbiturates e.g. pentobarbittal activate
- benzodiazepines enhance
- inhibitors used experimentally as convulsants (epilepsy models)
GABA modulation - clinical application
- GABAa receptor antagonists e.g. flumazenil used clinically for benzodiazepine overdose
- GABAb receptor agonists e.g. baclofen used for spasticity
- GABA reuptake inhibitors e.g. tiagabine/gabitril used for anxiety and epilepsy
- GABA analogues e.g. gabapentin used for seizures and neuropathic pain
Why is GABA excitatory in early development/immature nervous system
- immature neurons express high levels of NKCC1 which transports chloride into cells
- high intracellular concentration of ch
Glycine
- main inhibitory neurotransmitter in the spinal cord and brainstem
- synthesised from ser by serine hydroxylmethyltransferase
- loaded into synaptic vesicles by VIAAT
- cleared by specific GlyT (mutations give hyperglycaemia, lethargy, seizures, MR)
Glycine receptors
- ionotropic (CL- channels)
- 5 subunits, each 4 TM
- clustered
- specifically inhibited by strychnine - induces seizures
Purines
- ATP excitatory NT in CNS and PNS
- ATP rapidly catabolised to adenosine
- ionotropic receptors for ATP (P2X), metabotropic receptors for ATP (PY2) and adenosine (P1)
In what are purinergic receptors modulated for therapeutic benefit
for signalling roles outside the CNS - e.g. P2Y12 inhibitors anti-platelet agents
biogenic amines
- Catecholamines (dopamine, norepineprhine, noradenaline
- imidazoleamine - histamine
- indoleamine - serotonin
What is the pathway by which catecholamines are synthesised
L-TYROSINE converted into L-DOPA converted into DOPAMINE converted into NORADRENALINE and ADRENALINE
What are the commonalities of catecholamine synthesis
- loaded into vesicles by VMAT
- catabolised by MAO and COMT
- targets of recreational drugs
Dopamine functions and disease
- REDUCED in parkinson’s
- motivation, reward and enforcement (drug addiction)
- cognition and emotion (schizophrenia dopamine theory - antipsychotics target D2 dopamine receptors)
Dopaminergic projections
- From substantia nigra via nigrstriatal pathway to striatum
- From VTA via mesostriatal pathway from midbrain to stratum
- mesocortical pathway (midbrain out to cortex)
what is the relation of the dopaminergic projections to dopamine function
- mesocortical pathway (cognition and emotion)
- pathway to nucleus accumbens (reward and addition)
Dopamine neurobiology
- loaded into vesicles by H+ dependent VMAT
- removed by DAT (inhibited by cocaine)
- catabolised by MAO and COMT
- MAO-B inhibitors used in early PD
- COMT inhibitors used with levodopa in PD
Dopamine receptors
- D1 via Gs (stimulatory G protein - increase cyclic AMP levels)
- D2 via Gi (inhibitory G protein - reduce cyclic AMP levels)
Norepinpehrine/noradrenaline
- sleep, wakefulness and attention
- major CNS source is locus coeruleus
Histamine
- arousal and attention
- main neurons in the hypothalamus
- metabotropic receptors
- antihistamines that cross the BBB e.g. promethazine acts as a sedative
Serotonin
- mood, sleep, wakefulness, nausea, appetite etc.
- anti-depressants and anxiolytics (increase serotonin)
- cleared by SERTs (targets of fluoxetine//prozac etc. SSRIs)
- excess serotonergic agonism leads to serotonin syndrome range from mild (shivering and diarrhoea) to severe (rigidity, fever and seizures)
Serotonin receptor subtypes
- mainly metabotropic
- 5-HT1 to 7
5-HT pharmacology
- Sumatriptan ( agonists of class 2 receptors) - treat severe migraine
- inhibitors of serotonin transporters (anti-depressants)
- LSD - agonists for class 2 receptors
- Antipsychotics
- Ionotropic (ondansetron) - used to prevent nausea and vomiting in chemotherapy
- Fenfluramine (acts on serotonin transporter) - fen-phen withdrawn diet pill
Peptide neurotransmitters features
- generally synthesised as pre-propteins
- multiple neuroactive peptides can be released from single vesicle
- complex responses in conduction with small molecule neurotransmitters
- active at low concentrations
- metabotropic receptors
Peptide neurotransmitter functions
- Pain (substance P and opioid peptides)
- stress responses (CRH/CRF)
- food intake (NPY, melancortins)
- pituitary peptides (vasopressin, oxytocin)
- hypothalamic- pituitary adrenal axis (mediates stress response, dysfunction associated with psychiatric disorders, execs cortisol leads to Cushing’s disease)
