Neurchemistry-Slide 8 By: Nesrin Sultan Intrductin: It s the study f chemical inter-neurnal cmmunicatin. Wilhelm and Santiag (late 19 th century): brain cnsists f individual cells rather than a mass f cytplasm. A search was initiated fr the mediatrs f intercellular effects f cmmunicatin. By the turn f the 20 th century the effects f extracts f the adrenal glands n sympathetic nerve tissue was explained. Sn scientists discvered chemicals in the brain (neurtransmitters) Later Karl Lashley envisined the entire basic apparatus f chemical neurtransmissin (neurtransmitter + specific receptr mlecules). In the middle f 20th century the majr bigenic amine neurtransmitters were characterized and discveries cntinue. Criteria fr Neurtransmitters: n Synthesized in the neurn. n Present in the pre-synaptic neurn and released n deplarizatin. n When administered exgenusly has the same effect as the endgenus neurtransmitter. n A mechanism in the neurn /synaptic cleft acts t remve /deactivate the neurtransmitter. Classificatin: n Bigenic amines (catechlamines and indlamines) (best understd). n Amin acids n Peptides
1. Bigenic Amines n The mnamines( Dpamine,Nradrenaline & Adrenenaline) are prducts f the catechl amines synthetic pathway starting frm the amin acid Tyrsine. n The indlamines (sertnin, acetylchline & histamine) are derived frm distinct precursrs. n These neurtransmitters are very imprtant in the etilgy f psychiatric disrders. a. Dpamine: CNS dpaminergic tracts: Nigrstriatal-prjects frm substantia nigra t the crpus striatum (parkinsnism, depressin). Meslimbic-mescrtical tract, VTA t crtex (schiz.) Tuberinfundibular (hypthalmic-pituitary) tract, cell bdies are in the arcuate nucleus and the periventricular area f the hypthalamus and prjects t the infundibulum and the anterir pituitary.(prlactin, gynecmastia, galactrrhea). Medullary tract (vmiting) Dpamine Receptr Types: (5 subtypes, 2 grups): D1+D5: stimulate the frmatin f camp, by activating the stimulatry G prtein G8, D5 has higher affinity fr Dpamine than D1.
D2, D3, D4: D2 inhibit the frmatin f camp by activating the inhibitry G prtein G1,prbably D3,D4 receptrs act similarly. D2 are cncentrated mainly in the striatum,d3 in the nucleus acumbens and D4 in the frntal crtex. Dpamine thery f Schizphrenia: The thery grew frm the bservatin that drugs which stimulate Dpamine can induce schizphrenic symptms, and drugs which blck Dpamine can imprve schizphrenic symptms. Dpamine may als be invlved in the pathphysilgy f md disrders (amphetamine is an antidepressant and Levdpa cause mania ) b. Nrepinephrine: The majr cncentratin f the brain f nradrenergic cell bdies is in the lcus ceruleus in the pns and prjects t cerebral crtex, limbic system, thalamus and hypthalamus. The key enzyme invlved in metablism is MAO. Adrenergic Receptrs: Alpha adrenergic receptrs : a1(a1a,a1b,a1d),a2(a2a,a2c,a2b),a3. They inhibit the frmatin f camp Beta adrenergic receptrs (b1,b2,b3 ) they stimulate the frmatin f camp The signal transductin f adr. Rec. are regulated by phsphrylatin and changes in prtein-prtein interactin
B1, b2 regulates the functin f nearly every rgan in the bdy ften in antagnism t the effects f a receptrs, b3 regulates energy metablism, expressed in adipcytes, their activatin reduces bdy fat. b. Sertnin (5-HT): The majr site f sertnergic cell bdies is the upper pns, midbrain (raphe nuclei, lcus ceruleus) prjects t basal ganglia, limbic system, and cerebral crtex. Precursr is Tryptphan. The enzyme invlved in the metablism f sertnin is MAO. Primary metablite is 5HIAA Sertnin deficiency causes depressin and ver activity may be invlved in the etilgy f schizphrenia. Sertnergic receptrs: n Seven types f sertnin receptrs are nw recgnized 5HT1-5HT7 with numerus subtybes ttaling 14 distinct receptrs. n Busirne, an anxilytic, is 5HT1a agnist. n Clzapine, an antipsychtic, is a 5HT2 antagnist n Fluxetine is a 5HT reuptake inhibitr (increase it) (antidepressant) Bigenic amine thery f depressin: states that depressin is caused by reduced amunt f bigenic amines (nrepinephrine, 5HT, dpamine) in the brain r reduced sensitivity f their receptrs. And mania is caused by increase f their amunt.
2. Peptide Neurtransmitters: A peptide is a shrt prtein made f less than 100 aminacids As many as 300 peptide neurtransmitters may be fund in the human bdy. Endgenus piids act n 3 receptrs m,k d, and are believed t be invlved in the regulatin f stress,pain and md. Three classes f endgenus piids: encephalines, endrphines and dynrphines. Substance P(pain) Neurtensin (schizphrenia) Chlecystkinin (schizphrenia, Eating disrder) Smatstatin (Huntingtns chrea Alzheimers,) 3. Amin Acid Neurtransmitters: The tw majr amin acid neurtransmitters are: -GABA (an inhibitry amin acid) -Glutamate (an excitatry amin acid) Sme suggest that a simplified way t lk at the brain is as a balance between just thse tw neurtransmitters, with all the bigenic amines and peptide neurtransmitters simply invlved in mdulating that balance. Benzdiazepines, Barbiturates and several anticnvulsants act primarily thrugh GABA and PCP acts at glutamate receptrs. Histamine: Neurns that release histamine as their neurtransmitter are lcated in the hypthalamus and prjects t the cerebral crtex, the limbic system and thalamus There are 3 types f histamine receptrs: H1,H2, H3 Anti-allergic drugs act by blcking H1 receptrs and causing sedatin. H3 receptrs are invlved in vascular tne cntrl Acetylchline: CNS chlinergic tracts : A grup f chlinergic neurns in the nucleus basalis f Meynert prjects t the cerebral crtex and limbic system. Other chlinergic neurns in the reticular system prject t the crtex,limbic system, hypthalamus and thalamus. Sme patients with Alzheimer s, dementia r Dwn syndrme have specific degeneratin f the neurns in the nucleus basalis f Meynert. Synthesized in the chlinergic axn terminal frm acetylcenzyme A and chline by the enzyme chline acetyltransferase and metablized by acetylchlinesterase. Drugs used in the treatment f Alzheimer s and dementia are acetylchlinesterase inhibitrs
Neurmdulatrs: ü In cntrast t the characteristically immediate and shrt - lived effect f a neurtransmitter, a neurmdulatr, as the name implies, mdulates the respnse f a neurn t a neurtransmitter. ü The mdulatry effect may be present fr a lnger time than is usual fr a neurtransmitter mlecule t be present. ü Thus, a neurmdulating substance may have an effect n a neurn ver a lng perid f time, and that effect may be mre invlved with fine tuning than with activating r directly inhibiting the generatin f an actin ptential. ü When a hrmne c-exists and is c-secreted with a neurtransmitter, it may be referred t as a neurmdulatr. Sme hrmnes r neurmdulatrs have been shwn t meet criteria fr neurtransmitters themselves. ü A neurhrmne is distinguished by the fact that it is released int the bld stream, rather than int the extraneurnal space in the brain. ü Once in the bld stream, the neurhrmne can then diffuse int the extraneurnal space and have its effect n neurns. ü Hrmne secretin is stimulated by the actin f a neurhrmne, a neurnal secretry prduct f neurendcrine transducer cells f the hypthalamus. Examples n Neurhrmnes: Crtictrpin- releasing hrmne CRH which stimulates adrencrtictrpic hrmne ACTH Thyrtrpin- releasing hrmne TRH- which stimulates release f thyrid-stimulating-hrmne TSH. Gnadtrpin releasing hrmne GnRH which stimulates release f luteinizing hrmne LH - and fllicular stimulating hrmne FSH Grwth- hrmne-releasing hrmne GHRH - which stimulates release f the grwth hrmne. Smatstatin inhibits grwth hrmne. Chemical signals cause the release f these neurhrmnes frm the median eminence f the hypthalamus int the prtal hypphyseal bld stream and their transprt t the anterir pituitary t regulate the release f target hrmne. Pituitary hrmnes in turn, act directly n target cells, e.g.: ACTH n the adrenal gland, r stimulate release f ther hrmnes frm peripheral endcrine rgans. In additin, these hrmnes have feedback actin that regulates neurhrmne secretin and has effects in the brain itself, bth directly and as mdulatrs f neurtransmitter actin (neurmdulatin).
Past Paper Questins: All f the fllwing are neurtransmitters except: a- dpamine b- Epinephrine c- Nrepinephrine d- Vaspressin e- Sertnin One f the fllwing is nt a bigenic amine: Thyrxine Mdulatrs wrng ---> shrt duratin Which f the fllwing is false abut neurmdulatrs? a- released int the bld stream b- Sme meet the criteria f neurtransmitters c- >>>shrt lived effect d- Fine tne the effect f neurtransmitter Which f the fllwing dn't meet the criteria f a neurtransmitter? a- synthesized in neurn b- Present pre-synaptically and released upn deplarizatin c- Similar effect if administrated endgenusly d- Released t synaptic cleft e- >>>remains withut change after release Which f the fllwing is nt a bigenic amine? a- sertnin b- adrenaline c- nrepinephrein d- dpamine e- >>>smatstatin Which f the fllwing is false? >>> Dpamine deficiency results in psychsis True abut Dpamine tyrsine is its precursr True abut neurmdulatrs sme satisfy the criteria f neurtransmitters Nt a neurtransmitter angitensin Neurreceptr =specific fr neurtransmitter
The fllwing are criteria f a neurtransmitter except ne A The mlecule is synthesized in the neurn B The mlecule is present in the pre-synaptic neurn C When given exgenusly has the same effect as the endgenus substance. D Is released by deplarizatin E When released t the synaptic cleft remains there* The fllwing statements are true abut neurtransmitters except ne A Tyrsine is the precursr f catechlamines. B - The indlamines include sertnin and acetylchline. C Dpamine deficiency is thught t cause psychsis * D- MAO enzyme is invlved in nradrenline metablism E -A peptide is a shrt prtein made f < 100 aminacids The fllwing are bigenic amines except A- Dpamine. B- Sertnin C- Nradrenaline D- Acetylchline. E- Neurtensin.*