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Monoamine neurotransmitters

dopamine serotonin noradrenaline adrenaline also acetylcholine

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Monoamine neurotransmitters

  1. 1. Dr. M.G.SRINIVAS ROLE OF MONOAMINE NEUROTRANSMITTERS IN PSYCHIATRY
  2. 2. CONTENTS  DISCOVERY OF 1ST NEUROTRANSMITTER  DEFINITION OF NEUROTRANSMITTER  CRITERIA FOR NEUROTRANSMITTER  7 PROCESSESS IN NEUROTRANSMITTER ACTION  FATE OF NEUROTRANSMITTERS  CLASSIFICATION OF NEUROTRANSMITTERS  BIOGENIC AMINES  DOPAMINE  SEROTONIN  EPINEPHRINE & NOREPINEHRINE  HISTAMINE  ACETYLCHOLINE
  3. 3. DISCOVERY OF 1st NEUROTRANSMITTER  Acetylcholine - The first neurotransmitter identified, in 1926, by Otto Loewi.  He demonstrated that Acetylcholine carried a chemical signal from vagus nerve to the heart that slowed the cardiac rhythm.  Got NOBEL in physiology & medicine in the year 1936
  4. 4. NEUROTRANSMITTERS DEFINITION  Neurotransmitters are chemical signals released from presynaptic nerve terminals into the synaptic cleft.  The subsequent binding of neurotransmitters to specific receptors on postsynaptic neurons (or other classes of target cells) transiently changes the electrical properties of the target cells, leading to an enormous variety of postsynaptic effects.
  5. 5. CRITERIA FOR NEUROTRANSMITTERS 1. Molecule is synthesized in neuron 2. Molecule is present in presynaptic neuron & is released on depolarisation in physiologically significant amount 3. When administered exogenously as a drug, the exogenous molecule mimics the effect of endogenous neurotransmitter 4. A mechanism in neurons or synaptic cleft acts to remove or deactivate the neurotransmitter
  6. 6. MAJOR STEPS IN NEUROTRANSMITTER PROCESSING are: 1. SYNTHESIS 2. STORAGE 3. RELEASE 4. RECEPTION 5. INACTIVATION
  7. 7. FATE OF NEUROTRANSMITTERS 1. It is consumed ( broken down or used up) at postsynaptic membrane leading to action potential generation. 2. Degraded by enzymes present in synaptic cleft. 3. Reuptake mechanism( reutilization), this is the most common fate.
  8. 8. CLASSIFICATION OF NEUROTRANSMITTERS
  9. 9. Amine neurotransmitters: 1. Catecholamines Dopamine norepinephrine epinephrine 2. Indolamines Serotonin (5-hydroxytryptamine; 5-HT) 3. Histamine 4. Acetylcholine
  10. 10.  All monoaminergic systems share common anatomical features.  Each has a cluster of cell bodies in a few restricted sub cortical or brainstem regions, which then send long and extensively branched axonal processes into multiple cortical and limbic target regions.  The precise evolutionary reasons for this organization are unclear, although it could in principle allow monoaminergic systems to coordinately control spatially distant brain
  11. 11. DOPAMINE
  12. 12. DOPAMINE HISTORY  The function of DA as neurotrasmitter was discovered in1958 by arvid carlsson & nils ake hillarp.  ARVID CARLSSON got NOBEL for physiology or medicine in 2000 for showing that DA is not Just a precursor of NE & E but a Neurotransmitter as well.
  13. 13. DOPAMINE DEGRADATION
  14. 14. DOPAMINE PATHWAYS 5 dopamine pathways in the brain: 1. The MESOLIMBIC DA pathway, 2. The MESOCORTICAL DA pathway, 3. The NIGROSTRIATAL DA pathway, 4. The TUBEROINFUNDIBULAR DA pathway, 5. The THALAMIC DA pathway  DA pathways in the brain can explain the symptoms of schizophrenia as well as the therapeutic effects
  15. 15. (1) THE MESOLIMBIC DOPAMINE PATHWAY projects from the midbrain ventral tegmental area to the nucleus accumbens, a part of the limbic system
  16. 16. MESOLIMBIC PATHWAY role in -emotional behaviour -pleasure -motivation -reward
  17. 17. HYPERACTIVITY OF MESOLIMBIC PATHWAY -positive psychotic symptoms accompanying mania, depression, dementia. INCLUDES: -delusion -hallucination -aggression -hostility -euphoria in drug abusers
  18. 18. HYPO ACTIVITY OF MESOLIMBIC PATHWAY  lack of general motivation & interest,  anhedonia  negative symptoms,  drug abuse.
  19. 19. (2) MESOCORTICAL DOPAMINE PATHWAY projects from midbrain ventral tegmental area & sends its axons to areas of the prefrontal cortex Dorsolateral prefrontal cortex, DLPFC Ventromedial prefrontal cortex, VMPFC
  20. 20. MESOCORTICAL pathway  dorsolateral prefrontal cortex role -Regulates cognition & -Executive functions Hypofunction: -Cognitive deterioration -Negative symptoms in schzophrenia
  21. 21. Ventromedial prefrontal cortex Regulates- emotions & affect Hypo function- affective & negative symptoms
  22. 22. (3) The NIGROSTRIATAL dopamine pathway,
  23. 23.  Chronic D2 blockade –leads to neuroleptic induced Tardive dyskinesia
  24. 24. (4) TUBEROINFUNDIBULAR DA PATHWAY
  25. 25. TUBEROINFUNDIBULAR DA PATHWAY Activity - decrease in prolactin release • Postpartum- increase in prolactin • Antipsychotics - increase in prolactin -galactorrhoea -amenorrhoea -sexual dysfunction
  26. 26. (5) THALAMIC DA PATHWAY arises from multiple sites, -periaqueductal gray, -ventral mesencephalon, -hypothalamic nuclei, & -lateral parabrachial nucleus, projects to the thalamus.  Function is not currently well known.  In primates it involves in sleep & arousal mechanisms No evidence of it’s involvement in
  27. 27. DOPAMINE RECEPTORS. 5 Types – D1, D2, D3, D4, D5. 2 Groups D1 Like D2 Like D1, D5 D2, D3,D4 Cyclic AMP Cyclic AMP D2- Striatum
  28. 28.  -D2 receptor was initially distinguished from the D1 receptor on the basis of its high affinity for butyrophenones  Moreover D2 receptor stimulation was observed to inhibit rather than stimulate adenylate cyclase activity.  Unlike D1-like receptors, D2 receptor may have either a postsynaptic function or an auto receptor function
  29. 29. D2 auto receptors may be found on dopaminergic terminals or on the cell bodies and dendrites of dopaminergic neurons, where they mediate the inhibition of evoked dopamine release and the inhibition of dopaminergic neuronal firing. Furthermore, the over expression of striatal D2 receptors during brain development can cause long-lasting defects in prefrontal dopaminergic transmission and working memory in mice, a finding relevant to neurodevelopmental hypotheses of schizophrenia.
  30. 30.  D2 receptors are also expressed in the anterior pituitary and mediate the -dopaminergic inhibition of prolactin and -a-melanocyte-stimulating hormone release.  Molecular cloning has revealed long and short forms of the D2 receptor  Auto receptor functions are mediated by the short form of this receptor
  31. 31. • Catalepsy induced by neuroleptics such as haloperidol appears to be largely mediated by the long form of the D2 receptor • Post mortem analyses of schizophrenic brains reveals elevations in D2 receptor density. • Furthermore, radioligand binding studies have revealed -a correlation between the clinical efficacy of antipsychotic drugs and their antagonist affinities for this receptor subtype.
  32. 32.  This finding has contributed significantly to the “dopamine hypothesis” of schizophrenia. The extrapyramidal side effects of antipsychotic drugs have been attributed to blockade of striatal D2 receptors.
  33. 33. D3, D4 receptors •D3 receptor expression is highest in the nucleus accumbens. The highest levels of D4 receptors are expressed in -frontal cortex, -midbrain, -amygdala, -hippocampus, and medulla D4 receptors are abundant in the heart and kidney.
  34. 34.  The D3 receptor may play a role in the control of locomotion.  Elevated D4 receptor levels have been found in post-mortem schizophrenic brains.  Moreover, the atypical antipsychotic drug clozapine has a high affinity for the D4 receptor.
  35. 35. SEROTONIN
  36. 36. IMPORTANT PERSONALITIES IN DISCOVERY OF SEROTONIN A.BETTY TWAROG B.ARDA GREEN C.MAURICE RAPPORT D. IRVINE PAGE
  37. 37. Dr. VITTORIO ERSPAMER (1909 – 1999)
  38. 38. SEROTONIN 2% in CNS 98% in PERIPHERY 5HT Cannot cross B.B.B. 80% in G.I. Tract(motility & contractility) 15-18% in Mast cells & platelets(aggreg. & clotting) -
  39. 39. Serotonin Synthesis & degradation
  40. 40. SEROTONIN PATHWAYS  Clustered in midline raphe nuclei of brainstem 1)ROSTRAL NUCLEI- sends ascending axonal projections throughout the brain 2)CAUDAL NUCLEI – sends projections to medulla, cerebellum & spinal cord • Innervation of dorsal horns – implicated in suppression of noceceptive pathways, relate to
  41. 41. Rostral System:  The Rostral midbrain cluster of cells (raphe nuclei) are distributed throughout the midbrain, it provides over 80% of the 5-HT innervation of the forebrain.  Sends projections to –Prefrontal cortex, -basal forebrain, - striatum, -nucleus accumbens, -thalamus, -hypothalamus, -amygdala, -hippocampus
  42. 42.  A cluster of cells located medially and another located dorsally  MEDIAN RAPHE NUCLEUS: sends projections predominantly to Limbic system including hippocampus.  DORSAL RAPHE NUCLEUS: sends predominantly to striatum & thalamus.  Projections from these nuclei course through the MEDIAN FOREBRAIN BUNDLE before diverging to many regions. Innervation of forebrain structures by serotonergic processes is complementary to that
  43. 43. OTHER SYSTEMS:  In addition to the above two pathways, another 5-HT pathway projects partially from one of the Rostral nuclei and partially from two caudal nuclei to innervate the cerebellar cortex and deep cerebellar nuclei.  There is also a widespread 5-HT projection to structures within the brainstem, including the locus coeruleus, several cranial nuclei, inferior olivary nucleus, and nucleus solitarius.
  44. 44. SEROTONIN RECEPTORS  7 types of serotonin receptors are now recognized: 5-HT1 through 5-HT7, with numerous subtypes, totaling 14 distinct receptors  The 5-HT1- is the largest serotonin receptor subfamily, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, & 5-HT1F  The most intensively studied of these has been
  45. 45. 5HT1A  Postsynaptic membranes of forebrain neurons primarily in the -hippocampus, -cortex, -septum and -on serotonergic neurons, • Where it functions as an inhibitory somatodendritic auto receptor •There is significant interest in the 5-HT1A receptor as a modulator of both anxiety and depression
  46. 46.  The down regulation of 5-HT1A auto receptors by the chronic administration of serotonin reuptake blockers has been implicated in their antidepressant effects  SSRIs may produce some behavioral effects via increase in hippocampal neurogenesis mediated by postsynaptic 5-HT1A receptor activation.  Partial 5-HT1A receptor agonists such as buspirone display both anxiolytic and antidepressant properties.
  47. 47. 5HT1B & 5HT1D  Resemble each other in structure and brain localization, although the 5-HT1D receptor is expressed at lower levels. 5HT1B -implicated in the modulation of loco motor activity levels, consistent with its high level of expression in basal ganglia -also been suggested as a modulator of aggression, although 5-HT1B receptor agonist drugs have shown limited clinical efficacy as anti aggressive agents.
  48. 48.  In addition, 5-HT1B and the 5-HT1D receptors are found in the cerebral vasculature and the trigeminal ganglion, respectively, and are stimulated by the anti migraine drug sumatriptan.  These receptors may therefore be involved in the therapeutic efficacy of this drug, possibly mediating vasoconstriction and inhibition of noceceptive transmission.
  49. 49. 5-HT1E Receptors -striatum and -entorhinal cortex, 5-HT1F Receptors -dorsal raphe nucleus, -hippocampus, -cortex, and -striatum.
  50. 50.  5HT2A Receptors -neocortex -platelets and - smooth muscle •Much recent attention has focused on the contributions of 5-HT2A/C receptors to the actions of atypical antipsychotic drugs such as clozapine, risperidone and olanzapine. •5-HT2A receptor has also been implicated in the cognitive process of working memory, a function believed to be impaired in schizophrenia.
  51. 51. 5-HT2B, -contributes to the contractile effects of serotonin in the stomach fundus and plays important roles in cardiac development.
  52. 52.  5HT2C Receptors -hippocampal formation, -prefrontal cortex, -amygdala, -striatum, -hypothalamus, & -choroid plexus  Stimulation of 5-HT2C receptors has been proposed to produce anxiogenic effects as well as anorectic effects, which may result from interactions with the hypothalamic melanocortin and leptin pathways.
  53. 53. 5-HT2C -also play a role in the weight gain and development of type II diabetes mellitus associated with atypical antipsychotic treatment.  Alterations in 5-HT2C receptor mRNA editing have been found in the brains of suicide victims with a history of major depression, and SSRIs have been shown to alter these editing patterns.
  54. 54. 5HT3 -hippocampus, -neocortex, -amygdala, -hypothalamus, -brainstem, including the area postrema.  Peripherally-pituitary gland and enteric nervous system  5-HT3 receptor antagonists such as ondansetron are used as antiemetic agents and are under evaluation as potential antianxiety and cognitive-enhancing agents.
  55. 55. 5HT4 –Partial agonists used in IBS (TEGASEROD) 5HT5, 5-HT6, 5HT7 receptors – Unclear action -Antagonists may have antidepressant action
  56. 56.  Serotonin is a key regulatory of appetite, sleep, and aggression.
  57. 57. ROLE IN PSYCHIATRY
  58. 58. Affective Disorders:  Low levels of 5-HT and metabolites are associated severe depression  Recent studies indicate that this type of 5-HT influence may start early in life; low levels of 5HIAA have been found in children and adolescents with disruptive behavioral disorders. Obsessive Compulsive Disorder: 5-HT dysfunction has been associated with obsessive compulsive disorder. Accordingly, selective 5-HT uptake blockers are used as a therapy for this condition.
  59. 59. Schizophrenia: Antipsychotic drugs are producing favourable results in treating the symptoms of schizophrenia. These drugs are interesting pharmacologically in that they block both DA and 5-HT receptors as well as ACh and HA. Migraine Headaches. 5-HT1 agonists are used for the treatment of migraine headache. Insomnia. The role of 5-HT in sleep regulation has lead to the hypothesis that reduced levels of 5-HT may induce insomnia.
  60. 60. Norepinephrine and Epinephrine
  61. 61.  Norepinephrine is the more important and more abundant of the two related neurotransmitters in the brain, although adrenally derived epinephrine is more abundant than norepinephrine in the serum. Norepinephrine and Epinephrine
  62. 62. Dopamine ↓Dopamine Beta- Hydroxylase (DBH) Norepinephrine ↓ (PNMT) Epinephrine -locus coeruleus is the origin of most norepinephrine in the brain followed by the lateral tegmental area . -Levels of epinephrine in the CNS are only about 10% of the levels of norepinephrine -Norepinephrine, as with other Catecholamines, itself cannot cross the blood- brain barrier SYNTHESI S
  63. 63.  In neurons that release norepinephrine, the enzyme dopamine β-hydroxylase converts dopamine to norepinephrine; neurons that release dopamine lack this enzyme.  In neurons that release epinephrine, the enzyme phenyl ethanolamine-N- methyltransferase (PNMT) converts norepinephrine into epinephrine.  Neurons that release either dopamine or norepinephrine do not have PNMT.  As with dopamine, the two major routes of deactivation are uptake back into the presynaptic neuron and metabolism by MAO and COMT
  64. 64. PATHWAY  The major concentration of noradrenergic (and adrenergic) cell bodies that project upward in the brain is in the compact locus coeruleus in the Pons.  The axons of these neurons project through the medial forebrain bundle to the cerebral cortex, the limbic system, the thalamus, and the hypothalamus
  65. 65. NA & ADR RECEPTORS  The two broad groups: α-adrenergic receptors and the β-adrenergic receptors. The advances of molecular biology have now sub typed these receptors into three types of α1-receptors (α 1A, α 1B, and α 1D), three types of α 2-receptors (α 2A, α 2B, α 2C), and three types of β -receptors (β 1, β 2, and β 3).  All α 1-receptors are linked to the phosphoinositol turnover system. α -receptors inhibit formation of cAMP, and β -receptors stimulate formation of cAMP.
  66. 66. NE & DRUGS  The psychiatric drugs that are most associated with norepinephrine are the classic antidepressant drugs, the tricyclic drugs.  Venlafaxine(SNRI), bupropion, and nefazodone: block the reuptake of norepinephrine and serotonin into the presynaptic neuron MAO inhibitors: block the catabolism of norepinephrine and serotonin. • Thus, the immediate effect is to increase the concentrations of norepinephrine and serotonin in the synaptic cleft.
  67. 67. Antidepressants:  Serotonin-norepinephrine reuptake inhibitor (SNRIs): class of antidepressant for treatment of depression, mood disorders, anxiety.  Benzodiazepines, the primary antianxiety drugs, decreases firing in the locus coeruleus causing sleep  The beta-adrenergic blocking drugs (propranolol) act as antianxiety and inhibit the formation of traumatic memories.
  68. 68. HISTAMINE
  69. 69. HISTAMINE SYNTHESIS HISTIDINE L histidine decorboxylase HISTAMINE  This enzyme is not normally saturated with substrate, so synthesis is sensitive to histidine levels.  Thus peripheral administration of histidine elevates brain histamine levels.
  70. 70. HISTAMINE: ANATOMY -Histaminergic cell bodies -the posterior hypothalamus termed the tuberomammillary nucleus  project diffusely throughout brain and spinal cord
  71. 71.  Ventral ascending projections course through the medial forebrain bundle and then innervate the hypothalamus, diagonal band, septum, and olfactory bulb.  Dorsal ascending projections innervate the thalamus, hippocampus, amygdala, and Rostral forebrain.
  72. 72.  Descending projections • travel through the midbrain central gray to the dorsal hindbrain and spinal cord.
  73. 73.  The hypothalamus receives the densest histaminergic innervation, consistent with a role for this transmitter in the regulation of autonomic and neuroendocrine processes.  Additionally, strong histaminergic innervation is seen in monoaminergic & cholinergic nuclei.  Histamine is distributed throughout most tissues of the body, predominantly in mast cells.
  74. 74. HIATAMINE RECEPTORS  Histaminergic systems have been proposed to modulate -arousal, -wakefulness, -feeding behaviour, and -neuroendocrine responsiveness  Four histaminergic receptor subtypes have been identified and termed H1, H2, H3, and H4.
  75. 75.  H1 receptors are expressed throughout the body, particularly in smooth muscle of the gastrointestinal tract and bronchial walls as well as on vascular endothelial cells.  H1 receptors are widely distributed within the CNS, with particularly high levels in the thalamus, cortex, and cerebellum. These receptors are the targets of classical antihistaminergic agents used in the treatment of allergic rhinitis and conjunctivitis.
  76. 76.  The well-known sedative effects of these compounds have been attributed to their actions in the CNS and have implicated histamine in the regulation of arousal and the sleep–wake cycle. H2 receptors  widely distributed throughout the body and are found in gastric mucosa, smooth muscle, cardiac muscle, and cells of the immune system. Within the CNS, H2 receptors are abundantly expressed in the neocortex, hippocampus, amygdala, and striatum.
  77. 77. • H2 receptor antagonists are widely used in the treatment of peptic ulcer disease. •In contrast, the functional significance of central H2 receptors is unclear, although several studies indicate that the stimulation of these receptors produces antinociceptive effects. •H2 receptors may also be involved in the control of fluid balance, possibly along with H1 receptors, via the stimulation of vasopressin release.
  78. 78. H3 receptors  located presynaptically on axon terminals Those located on histaminergic terminals act as auto receptors to inhibit histamine release. In addition, H3 receptors are located on nonhistaminergic nerve terminals, where they act as heteroreceptors to inhibit the release of a variety of neurotransmitters—including norepinephrine, dopamine, acetylcholine, and serotonin.
  79. 79.  Particularly high levels of H3 receptor binding are found in the frontal cortex, striatum, amygdaloid complex, and substantia nigra  Lower levels are found in peripheral tissues such as the gastrointestinal tract, pancreas, and lung.  Antagonists of H3 receptors have been proposed to have appetite suppressant, arousing, and cognitive-enhancing properties.
  80. 80. The H4 receptor Detected predominantly in the periphery, in regions such as the spleen, bone marrow, and leukocytes
  81. 81. Acetylcholine
  82. 82. Acetylcholine synthesis
  83. 83. Acetylcholine in the PNS • Produced by: – Motor neurons – Parasympathetic Both pre- and post-ganglionic neurons – Sympathetic pre-ganglionic neurons some post-ganglionic neurons that innervate sweat glands and blood vessels
  84. 84. Central Cholinergic Projections • Basal forebrain – Nucleus basalis (of Meynert), septal nuclei. . • Brainstem reticular formation (“Ponto-mesencephalotegmental complex”) – Project to thalamus, brainstem, basal forebrain • Cholinergic interneurons – caudate-putamen, n. accumbens
  85. 85.  In Alzheimer's disease there is significant degeneration of neurons in the nucleus basalis, leading to substantial reduction in cortical cholinergic innervation  Cholinergic neurons may continue to fire during REM sleep and have been proposed to play a role in REM sleep induction
  86. 86.  The modulation of striatal cholinergic transmission has been implicated in the anti parkinsonian actions of anticholinergic agents.
  87. 87.  Peripheral acetylcholine mediates the characteristic postsynaptic effects of the parasympathetic system, including bradycardia and reduced blood pressure, and enhanced digestive function.  Cholinesterase inhibitors are also used in the treatment of myasthenia gravis, a disease characterized by weakness due to blockade of neuromuscular transmission by auto antibodies to acetylcholine receptors
  88. 88. CHOLINERGIC RECEPTORS
  89. 89.  Two major classes of cholinergic receptors exist: -G-protein-coupled muscarinic receptors and - Nicotinic ligand-gated ion channels
  90. 90.  In the periphery, muscarinic receptors mediate the effects of postganglionic parasympathetic nerve release of acetylcholine.  Central muscarinic receptors have been implicated in learning and memory, sleep regulation, pain perception, motor control, and the regulation of seizure susceptibility.  Five muscarinic receptor subtypes have been cloned, and these may be divided
  91. 91. Types of Receptors  The M1, M3, and M5 receptors activate Gq, leading to phosphatidylinositol turnover and an increase in intracellular calcium  The M2 and M4 receptors may act as inhibitory autoreceptors and heteroreceptors to limit presynaptic release of neurotransmitters.
  92. 92. M1  M1 receptors are the most abundantly expressed muscarinic receptors in the forebrain, including the cortex, hippocampus, and striatum.  Pharmacological evidence has suggested their involvement in memory and synaptic plasticity
  93. 93. M2  In addition to being the predominant muscarinic receptor subtype in the heart where they function to lower heart rate, M2 receptors are widely distributed throughout the brain  M2 receptors appear to mediate tremor, hypothermia, and analgesia induced by muscarinic agonists
  94. 94. M3  M3 receptors are found in smooth muscles and salivary glands and appear to play a major role in smooth muscle contraction in the gastrointestinal and genitourinary tracts and to mediate salivation.  Although M3 receptors are found at modest densities in many areas of the CNS, no central role has been elucidated
  95. 95. M4  M4 receptors are expressed in the hippocampus, cortex, striatum, thalamus, and cerebellum  Striatal M4 receptors may oppose the effects of D1 dopamine receptors and have been implicated as putative targets for anticholinergics used as antiparkinsonian agents—although other muscarinic receptor subtypes may also be involved
  96. 96. M5  M5 receptors are expressed in various peripheral and cerebral blood vessels and comprise a very small percentage of muscarinic receptors in the brain  They may mediate cholinergic cerebral arterial vasodilation.
  97. 97. Nicotinic Receptors  Nicotinic acetylcholine receptors, like 5- HT3 receptors, are members of the ligand- gated ion channel superfamily and mediate rapid, excitatory signaling  Nicotinic acetylcholine receptor subunits are heterogeneous and associate in varied combinations
  98. 98.  These various nicotinic acetylcholine receptor subunits can be categorized into three general functional classes: (1) skeletal muscle subunits (α1, β1, δ and ε), (2) Standard neuronal subunits (α2–α6 and β2–β4), and (3) Subunits capable of forming homomeric receptors (α7–α9).
  99. 99.  In the periphery, nicotinic acetylcholine receptors are found in skeletal muscle, autonomic ganglia, and the adrenal medulla  In the brain, they are found in many locations including the neocortex, hippocampus, thalamus, striatum, hypothalamus, cerebellum, substantia nigra, ventral tegmental area, and dorsal raphe nucleus
  100. 100.  Most nicotinic acetylcholine receptors in mammalian brain contain either α4β2 or α7 subunit combinations  They frequently appear to mediate presynaptic enhancement of neurotransmitter release, influencing the release of acetylcholine, dopamine, norepinephrine, serotonin, as well as GABA and glutamate
  101. 101.  Nicotinic receptors have been implicated in cognitive function, especially working memory, attention, and processing speed  Cortical and hippocampal nicotinic acetylcholine receptors appear to be significantly decreased in Alzheimer's disease, and nicotine administration improves attention deficits in some patients  The acetyl cholinesterase inhibitor galantamine used in the treatment of Alzheimer's disease also acts to positively
  102. 102.  The α7 nicotinic acetylcholine receptor subtype has been implicated as one of many possible susceptibility genes for schizophrenia, with lower levels of this receptor being associated with impaired sensory gating  Some rare forms of the familial epilepsy syndrome autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) are associated with mutations in the α4 or β2 subunits of the nicotinic acetylcholine receptor
  103. 103.  Finally, the reinforcing properties of tobacco use are proposed to involve the stimulation of nicotinic acetylcholine receptors located in mesolimbic dopaminergic reward pathways
  104. 104. Acetylcholine and Drugs  The most common use of anticholinergic drugs in psychiatry is in treatment of the motor abnormalities caused by the use of classic antipsychotic drugs (e.g., haloperidol).  The efficacy of the drugs for that indication is determined by the balance between acetylcholine activity and dopamine activity in the basal ganglia.
  105. 105.  In healthy people, the activity of the nigrostriatal dopamine pathway is partially balanced by the activity of cholinergic pathways in the basal ganglia.  Blockade of D2 receptors in the striatum upsets this balance, but the balance can be partially restored, albeit at a lower set point, by antagonism of muscarinic receptors
  106. 106. Blockade of those receptors leads to the commonly seen adverse effects of blurred vision, dry mouth, constipation, and difficulty in initiating urination. Excessive blockade of CNS cholinergic receptors causes confusion and delirium. Drugs that increase cholinergic activity by blocking breakdown by acetyl cholinesterase (e.g., donepezil ) have been shown to be effective in the treatment of dementia of the Alzheimer's type
  107. 107. Acetylcholine and Psychopathology  The most common association with acetylcholine is dementia of the Alzheimer's type and other dementias  Acetylcholine may also be involved in mood and sleep disorders.
  108. 108. CONCLUSION  Neurotransmission is the communication b/w genomes of two neurons, through signal transduction cascade, leading to gene activation & biological response.  Understanding neurotransmitters, their receptor partners & other near/distant relations (transporters & transduction), is essential for our approaches to define & treat psychiatric disorders.
  109. 109. •Exploring the physiological & genetic basis of neurotransmitter function may pave the way in understanding psychopathology & nosology. •Future researches clearly have potential to further advance our knowledge in areas of psychopathology, pharmacotherapy & pharmacogenomics.
  110. 110. REFERENCES 1. KAPLAN AND SADDOCK’S COMPREHENSIVE TEXTBOOK OF PSYCHIATRY. 9th ed. 2. STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY: NEUROSCIENTIFIC BASIS AND PRACTICAL APPLICATIONS. 4th ed. 3. GUYTON & HALL PHYSIOLOGY 12th ed. 4. NEUROSCIENCE ONLINE LECTURE BY Jack C. Waymire, Ph.D., Department of Neurobiology and Anatomy, The UT Medical School at Houston 5. KAPLAN & SADDOCKS SYNOPSIS OF PSYCHIATRY 10th ed.

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dopamine serotonin noradrenaline adrenaline also acetylcholine

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