Neurotransmitters and Their Role in Brain Function
Excitatory or inhibitory, synthesis, storage, inactivation, receptors, sources, role, toxins
ACh: E, choline+acetyl coenzyme A (CAT), trans to vesicles by ST, acetylcholinesterase (breakdown in synaptic cleft), nicotinic (iono) and muscarinic (meta), nucleus basalis/septal nuclei, neuro-muscular junction, memory, attention, cholinergic degeneration. 1st stage of Alzheimer’s, organophosphates (pesticides and Sarin) inhibit acetylcholinesterase
Glutamate: E, glutamine, trans. to ves, by st, EAAT into glia and presynaptic cell, AMPA (primary excitatory receptor in brain), NMDA (needs post. synaptic depolarization, plays role in plasticity), kainate (fast rising current w slow decay), found everywhere in brain, primary excitatory neurotransmitter, key transmitter underlying excitotoxicity
GABA/Glycine: (GABA) glucose->glutamate->GABA. GAD key molecule converting glutamate->GABA, trans. into ves. by st, pre-synaptic cell and glia, ionotropic (GABAa and c and glycine receptors conduct Cl-) metabotropic (GABAb), everywhere most released by interneurons, GABA inhibitory in brain glycine key inhibitory neurotransmitter in spine, barbiturates and benzodiazepines are GABA agonists, alcohol also increased conduction of GABA rec. strychnine = glycine antagonist
Dopamine (Catecholamines): tyrosine->DOPA via tyrosine hydroxylase. DOPA-> dopamine, reuptake (DAT (transporter)), breakdowns (MOA and COMT), metabotropic, substantia nigra and ventral tegmental area. have deep projections to frontal cortex, striatum and amygdala, high DA implicated in schizophrenia. Parkinson’s due to die off of dopaminergic neurons in substantia nigra, mediate experience of wanting, to visualize, use tyrosine hydroxylase with specific antibodies, with PET, radioactive ligands to specific dop. receptor subtype (D2) to see in humans, drugs: MOA and COMT inhibitors are antidepressants, L-DOPA used to treat Parkinson’s, cocaine and amphetamines interfere with DAT
Norepinephrine: from dopamine, norepinephrine trans (NET) and breakdown (MOA and COMT) metabotropic alpha and beta receptors, locus coeruleus, attention, locus coeruleus neurons activated by alerting, primary neurotransmitter in sympathetic nervous system (fight/flight), NET inactivated by amphetamines, so they increase norepinephrine. B receptors blocked by ‘beta-blockers’ used to treat migraines and stage fright, Epinephrine: synthesized from norepinephrine. Known as adrenaline in peripheral nervous system, don’t know role in brain
Serotonin (5-HT in monoamine family): tryptophan via tryptophan-hydroxylase, via serotonin transporters, both ionotropic (5-HT3) and metabotropic (more common), raphe nuclei (brain), a separate group of neuron in pons supplies serotonin to spinal cord. regulation of sleep, wakefulness and mood, many antidepressants are selective serotonin reuptake inhibitors (SSRIS), selective blockers of 5-HT3, used to prevent nausea, LSD targets serotonin receptors.
ATP and Adenosine: co-released from all synaptic vesicles, ATP converted into adenosine in synaptic cleft, Adenosine rec. are target of caffeine and theobromine
Peptide neurotransmitters: soma, 5 categories of pep, trans.: brain-gut (substance P), opioids (endorphins, enkephalins, dynorphins), pituitary (vasopressin, oxytocin), hypothalamic releasing hormones, other (neuropeptide Y), opioids part of endogenous system for regulating pain, vasopressin and oxytocin = role in pair bonding (vole studies), oxytocin produced in hypothalamus, vasopressin produced in amygdala
Endocannabinoids: endogenous endocannabinoids: anandamide, 2-AB, synthesized from membrane lipids, unconventional = retrograde, no synaptic storage, re-uptake by releasing neuron, metabotropic, best known is CB1, in areas of brain involved with motivation (striatum), memory (hippocampus) and coordination (cerebellum), feedback control of some GABAergic synapses, regulation of plasticity, THC = agonist causing high, rimonabant = antagonist suppressing hunger and leading to depression
Nitric oxide: gas = diffuses through membranes and not stored in cell, synthesized by NOS, triggered by Ca+, causes vasodilation and other stuff, drugs: nitroglycerine causes increase in availability of NA and can cause dilation of blood vessels in heart
Effector pathways associated with G-Protein-coupled receptors: Neurotransmitter, receptor, G-protein, effector protein, second messengers, late effectors, target action = 1. Norepinephrine->b-adrenergic->Gs->adenylyl cyclase->cAMP->protein kinase A->increase protein phosphorylation. 2. Glutamate ->mGluR->Gq-phospholipase C->2 paths 1. diacylglycerol->protein Kinase C 2. IP3->Ca release->both pathways lead to increase protein phosphorylation and activate Ca-binding proteins.
LTD perkinje: Glutamate binds to MGluR->activates phospholipase C->creates DAG and IP3->IP3 triggers Ca release->climbing fiber depolarized purkinje cell causing entry of Ca via voltage-gated Ca channels->Ca potentiates IP3 and triggers more Ca release from endosome->increased Ca in presence of DAG activates PKC->PKC leads to phosphorylation of AMPA receptors, reducing the amount of NA they allow into cell->weakens synapse for hours or longer causing LTD
ACh: binds to mAChR->GDP converts to GTP and gamma/beta bind to K channels-> causing hyperpolarization of cell by opening normally closed K channel
Norepinephrine a2-adrenergic is metabotropic. NE binds to a2-adrenergic receptor->release gamma & beta subunits binding to voltage-gated Ca channel->causes conformational change which decreases probability channel will open->Ca mediates neurotransmitter release->reduction Ca=reduction neurotransmitter release