Neurotransmitters Flashcards
Neurotransmitter Characteristics
o Synthesized in neurons
o Found in the presynaptic terminal at concentrations high enough to exert an effect
o Released in response to membrane depolarization and Ca2+ influx
o Has specific receptors on the postsynaptic cell
o When given exogenously, it mimics the endogenous response
o Specific mechanisms to terminate NT action
NT Life Cycle/Mechanism
o Synthesized within neurons stored in vesicles released into synaptic cleft postsynaptic receptor interaction termination via re-uptake, catabolism, or diffusion
Each step can be targeted by drugs and neurotoxin
NT Classification
o Small molecules
Amino acids – used in neural signaling
• glutamate, GABA, and glycine
Biogenic amines – have short and long projections; used as trans-system modulators
• acetylcholine, serotonin, and histamine
• Catecholamines – norepinephrine, epinephrine, and dopamine
o Neuropeptides – used as within-system modulators
3-36 amino acids long; ex: substance P, opioid
NT Functional Classification
o Neural signaling – AA (glutamate, GABA, glycine)
Major NTs of the brain; involved in communication between neurons
o Trans-system modulators – biogenic amines – modulates neurons in multiple systems
o Within-system modulators – neuropeptides – modulates info by neurons within systems
Acetylcholine
o Synthesis (one step): choline + acetylcholine coenzyme A + choline acetyltransferase (ChAT)
Transported into vesicles for storage until AP triggers release
o ACh Cell Body Locations: medial septal nucleus, nucleus basalis, and a series of brainstem nuclei with projections into the cerebral cortex and hippocampus
Alzheimer’s Disease – significantly low levels of ACh in cerebral cortex (emotion & sensory input) and hippocampus (memory)
o Termination of Signal: acetylcholine esterase (AChE) in synaptic cleft choline + acetate
Nerve gases and insecticides alter AChE and cause dysregulation of ACh in the brain
Choline + acetate taken back up by presynaptic terminal
o Rate Limiting Step: transport of choline back into axon terminal through choline transporter due to low levels in ECF
Catecholamines
o Synthesis: catechol + ethylamine followed by sequential modifications OR begins with tyrosine from our diet; each neuron produced ONLY 1 type of catecholamine and can be identified by the last enzyme present in the chain
Tyrosine (tyrosine hydroxylase) L-dopa
• One of most highly regulated enzymes via transcriptional, translational, and post-translational (phosphorylation) mechanisms and product feedback inhibition
• Found in ALL catecholamine neurons
L-dopa (dopa decarboxylase) dopamine
• Found in all catecholamine neurons
• Cytoplasmic enzyme requiring pyridoxal phosphate as cofactor
Dopamine (dopamine-beta-hydroxylase) norepinephrine
• Found in norepinephrine neurons
• Vesicle-associated enzyme that requires Cu2+ and abscorbic acid as cofactors
o Enzyme, Cu2+ and abscorbic acid released with norephinephrine
Norepinephrine (phentolamine-N-methyltransferase) epinephrine
• Found in epinephrine neurons and adrenals
• Requires SAM as cofactor
o Rate Limiting Step: tyrosine hydroxylase converts tyrosine to L-dopa
o Termination of Signal: sequentially degraded by monoamine oxidase and catechol-O-methyl transferase in the synaptic cleft
Primary termination mechanism is re-uptake into presynaptic vesicles
CNS Catecholamine Neuron Characteristics
o Tyrosine is precursor to all catecholamines and found in high concentration in brain (only 2% of total tyrosine is used for CA synthesis)
o CNS contains DA, NE, and E containing neurons
o Development of specific antibodies against synthetic enzymes help to localize neurons using immunohistochemical techniques
Norepinephrine
o Termination of Signal: primarily by reuptake by plasma membrane transporters
Metabolism by monoamine oxidase and catechol-O-methyl transferase
Modulation of autoreceptor activity regulating further release or synthesis
Depletion of dopamine-beta-hydroxylase
o NE and DA neurons - important target of drugs that treat depression, anxiety, and hypertension
Reserpine – blocks vesicular reuptake
Amphetamines – inhibits reuptake and stimulates release
Desipramine – antidepressant – blocks the reuptake
o Neuron Location: locus ceruleus with projections in nearly every part of brain and spinal cord
Play role in regulation of sleep-wake cycles, fear, and stress responses
Dopamine Neuron Locations
o Substantia nigra pars compacta – projections to the straiatum forms the nigrostriatal system – involved in movement
Parkinson’s Disease –low striatal L-dopa levels due to degeneration of this system
o Ventral tegmental area – projections to the nucleus accumbens, prefrontal cortex, and cingulate cortex forms the mesolimbocortical DA system – involved in drug reward pathways
o Arcuate nucleus of hypothalamus – with projections to the pituitary that affect secretions
Serotonin
o Only 1% is found in CNS; the rest is in mast cells and platelets
o Location of Neurons: Raphe nuclei of brainstem with sparse but widespread projections
o Synthesis (two-steps): serotonin cannot cross BBB so neurons must make their own
Tryptophan (tryptophan-5-hydroxylase) 5-hydroxytryptophan
• Rate-limiting Step
5-hydroxytryptophan aromatic L-amino acid decarboxylase serotonin
o Termination of Signal: re-uptake or degradation by monoamine oxidase
o Drugs: selective serotonin reuptake inhibitors (SSRIs) are major pharmacological agent used in depression, anxiety, eating disorders, migrains, PTSD, substance abuse, OCD and are HIGHLY selective for serotonin
Cocaine and amphetamine are not very selective
• Cocaine – inhibits reuptake of 5HT, NE, and DA
• Amphetamine – inhibits reuptake and stimulates release of 5HT, NE, and DA
Histamine
o Low amounts in CNS; majority are in mast cells with sparse but widespread projections
o Location of Neurons: tuberomammillary nucleus of the hypothalamus
o Synthesis (one-step): histidine (histidine decarboxylase) histamine
Rate Limiting Step
o Termination of Signal: metabolically degraded by diamine oxidase and histamine methyltransferase
o Drugs: histamine antagonists used to treat nausea, allergies, and produce sedation
Excitatory and Inhibitory AA
- Excitatory AA Neurotransmitters – glutamate, aspartate, cysteate
- Inhibitory AA Neurotransmitters – GABA (gamma aminobutyric acid) and glycine
Glutamate
o Synthesis (one-step): glutamine (glutaminase) glutamate
Rate limiting step
Get glutamine from glucose in Krebs cycle and glial cell synthesis
Packaged in vesicles
o Termination of Signal: reuptake by BOTH neurons and glial cells
o Regulation of synaptic glutamate levels is important to MINIMIZE potential neuronal damage
o Excessive Levels can lead to: epilepsy, anxiety, addiction, ischemic brain damage
o Physiological Process Involved in: neuroplasticity, neuronal development, learning/memory
GABA
o High concentrations in brain and spinal cord; trace amounts in peripheral nerves
o Synthesis (one-step): glutamate (glutamic acid decarboxylase) + pyridoxial phosphate cofactor GABA
Rate limiting step; GAD is only found in brain tissue
o Termination of Signal: re-uptake by BOTH neurons and glial cells
Metabolized ONLY when alpha-ketoglutarate is present to accept the amino group
o Regulation is important because it also provides control over glutamate levels in CNS
o GABA Shunt: glia cells can shuttle glutamate or GABA to neurons
GABA-T enzyme can interchange glutamate to alpha-ketoglutarate
o Drugs that enhance GABA’s effects are CNS depressants
o Drugs that interfere with GABA’s effects can cause seizures
Glycine
o Location of Neurons: spinal cord (interneurons) and brain stem
o Synthesis: serine (serine transhydroxy-methylase) glycine
Serine is found in all tissues and fluids
o Termination of Signal: reuptake by BOTH neurons and glial cells
