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Neurotransmitter Location in Brain Synthesis and storage Catecholamines: Norepinephrine (NE) -locus coeruleus & other parts of RAS --project rostrally to the hypothalamus, hippocampus, amygdale, and cerebral cortex -project dorsally to cerebellum -project caudally to lower brainstem and spinal cord -LC acts as filter to suppress irrelevant stimuli? -in nerve terminal -tyrosineDOPA dopamineNE using: -tyrosine hydroxylase: rate limiting; inhibited by α-methylp-tyrosine -aromatic L-amino acid decarboxylase -dopamine-β-hydrogenase: on luminal surface of vesicles; nonspecific, false nt -uneven, 80% in striatum, cell body clusters in midbrain -4 pathways: 1.)nigrostriatal: cell body in substantia nigra and axons that project to daudate-putamen 2.)mesolimbic pathway with bodies in ventral tegmental and axons to limbic structures (accumbens, hippo, lateral septum, amygdale 3.) mesocortical path with bodies in VTA and axons in cerebral cortex 4.)tuberoinfundibular path w/ bodies in arcuate nucleus of hypthal and proj to pituitary salk, where tonically inhib prolactin tyrosine->DOPAdopamine Catecholamines: Dopamine Receptors and Signal Transduction α1: coupled to Gq to stimulate phospholipase C; also cAMP; neuronal -α2:coupled to Gi to inhibit adenylate cyclase; glial and vascular -β1 &β2: both ↑cAMP including presyn β2 which facilitate NE release. β2 have ↑affinity for EPI than for NE, thus EPI regulates NE Inactivation -D1-D5: all metabotropic and act on G proteins -1 & 5=excitatory and ↑cAMP by acting on Gs -2,3,4=inhibitory and ↓cAMP via Gi -2= enhance K+ channel opening =hyperpolarization -dopamine transporter -MAO and COMT -main metab= HVA -reuptake: - NE transporter = uptake 1 -uptake 2 = glial cells -enzyme degradation: -monoamine oxidase (mitochondrial outer membrane) – phenelzine and tranycypromine – inhibit both MAO-A and MAO-B -COMT- extraneuronal catecholamine metab metab=VMA, MHPG Acetylcholine (Ach) Serotonin (5-HT) GABA Location in Brain Synthesis and Storage -bodies in nucleus basalis and a few other regions w/ axons in cerebral cortex, hippo, and other limbic areas via basal forebrain cholinergic system -cholinergic interneurons in striatum that reg motor f’n; inhibitie by nigrostriatal DA neurons and lead to Park’s sx when DA inhib deficient -bodies midline of brainstem in clusters called dorsal and medial raphe nucleus -axons: neocortex, striatum, accumbens, thala, hypothal, hippo, amygdale, spetal area -via choline acetyltransferase: choline + acetyl CoAAch -40% terminals in cerebral cortex, hipp, and substantia nigra -in cortex and hipp mainly in interneurons -proj from striatum to golus pallidus and substania nigra -uptake and storage in vesiclesthe Ach transporter is located in an intron of the choine acetyltransferase gene and thus synthesis and storage are coupled tryptophan 5hydroxytryptophan 5hydroxytryptamine (5-HT) -1st catalyzed by tryptophan hydroxylase= rate limiting -2nd L-aromatic amino acid decarboxylase storage: vesicles using same monoamine transporter (VMAT2) as catecholamines glutamateGABA via glutamic acid decarboxylase storage: taken up into vesicles via vesicular GABA transporter VGAT Receptors and Signal Transduction -nicotinic receptors (Nn more sensitive in brain than Nm in neuromusc j’n) -muscarinic M1-5- all metabot -some activate phosphoinositide 2nd mess sys, inhibit cAMP, or stim K+ opening -high density in forebrain -release regulated by terminal and somatodendritic 5HT autorecpetors Inactivation acetylcholinesterase -modulation by drugs: choline transporter blocker; blocker of acetyl CoA synthesis; inhibi of vesicular transporter; Ca++ transport; vesicle-dock blockers; cholinesterase inhibitors reuptake back in presyn nerve terminal via transporter SERT catabolism by MAO -15 receptors known -all metab exept 5HT3 -GABAa: inonotropic, Cl channel, when openhyperpolar. -GABAb:metabo, inhibit cAMP and open K+ -modulation -drugs:HT1 agon=buspirone; LSD by 2a; atypical antipsy via 2a -diet: low protein/high carb ↑5HT -reuptake into nerve terminal via GAt-1 -GAT-2 and -3 into glia -in both some broken down by GABA transaminase to glutamate and can be reconverted modulation: -benzo, barbit, etoh=sedation GABAa -vigabatrin irrev inhibi of metabolism -baclofen= agonist GABAb Glutamate Location in Brain Synthesis and storage -pyramidal cells of cerebral cortex that proj to subcortical structures such as striatum, thal, limbic areas and brain stem -mainly from glutamine Neuropeptides -storage: vesicles -3 vesicular transporters: VGLUT1-3 promote packaging into vesicles -synth in ribosomes in bodies and transported to terminal in large dense-cored vesicals via fast axonal transport -reg of synth = slow -small amt in terminal -receptors gen require low conc and removal is slow Receptors and Signal Transduction -both iono and metabo -aka AA receptors sinc aspartate works too -3 types iono (all exite): -AMPA – depol via Na+into cell -kainate – depol via Na+into cell (epilepsy) -NMDA – depol via Na & Ca++ into cell (schizophren) -metabotropic activating G-prot -co-released with small nt -acts as co-transmitter -f’n of peptide to ↑time/strength of signal, but no effect itself=neuromodulator -release of some is freq dep -Corticotropin-releasing hormone (CRH) -Substance P -Opioid Peptides -41aa peptide -paraventricular nucleus PVN of hypthal -neuroendo f’n -11aa neuropeptide -tachykinin family -wide distrib, hypthal, corpus strit to nigra -family derived from 267 aa long precursor propiomelancortin (POMC -syth from precursor peptides that are cleaved to active neropep -in the PVN is released into pituitary portal capillaries causing co-release of ACTH and β-endorphin during stress respo -released from afferent sensory neurons in spinal cord to transmit painsignals -endogenous peptides -endorphins -CRH1=dominates pituitary -CRH2 -NK1-3 -1 on 5Ht, DA, and NE neurons and have been found to have anti depressant effects -βendorphin most potent -CRF causes large ↑in release of POMC from pituitary gland with subsequent ↑ACTH and βendorphin Inactivation -reuptake via 5 excitatory AA transporters (EAAT1-5) which also do aspart -mod: MSG can damage by excitotoxicity; PCP and ketamine are NMDa antagonists -diffusion & proteolysis -not recycled -cleaved molc may have postsyn effect