Novel neurotransmitters

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1. 1 / 65 NOVEL NEUROTRANSMITTERS Dr Sudip Aryal Resident Dept of Psychiatry and Mental Health IOM, TUTH 2. 2 / 65 Overview ● Introduction ● Classifcation ●…
  • 1. 1 / 65 NOVEL NEUROTRANSMITTERS Dr Sudip Aryal Resident Dept of Psychiatry and Mental Health IOM, TUTH
  • 2. 2 / 65 Overview ● Introduction ● Classifcation ● Structural and Functional Considerations ● Historical Perspectives ● Novel Neurotransmitters – Gases , Endocannabinoids, Eicosanoids, Neurosteroids ● Summary ● References
  • 3. 3 / 65 Neurotransmitters ● Neurotransmitters are chemicals that amplify or inhibit the depolarization signal from one neuron to that of an adjacent neuron.
  • 4. 4 / 65 Classifcation Chemical Group Examples Choline Ester Acetylcholine Monoamine s Catechol : Dopamine, Noradrenaline, Adrenaline Indole : Serotonin Imidazole : Histamine Amino Acids Acidic : Glutamate Basic : GABA, Glycine Peptides Enkephalins, Endorphins, Cholecystokinin, Substance-P Purines ATP, Adenosine
  • 5. 5 / 65 Click to add Title Steroids Pregnenalone, Dehydroepiandrosterone Nitric Oxide Eicosanoids Prostaglandin
  • 6. 6 / 65 Structural and Functional Considerations
  • 7. 7 / 65 Structure of Neuron
  • 8. 8 / 65 Neurotransmitter-Synaptic Arrangements
  • 9. 9 / 65 Postsynaptic Events: Ionic basis
  • 10. 10 / 65 Types of Receptors
  • 11. 11 / 65 Presynaptic Control
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  • 13. 13 / 65 Agonists & Antagonists
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  • 15. 15 / 65 Historical Perspectives ● Acetylcholine : 1st NT identifed and characterized ● Early criteria for NT : Just like Ach – Localized to neuron – Specifc bio-synthetic enzyme – Released in Ca-dependent fashion when nerve is depolarized – mimic the actions of the endogenous transmitter when applied to postsynaptic cells
  • 16. 16 / 65 – Bind to receptor protein localized to the external surface of the target cell’s plasma membrane – Degradation and inactivation at synapse by enzyme near the receptor
  • 17. 17 / 65 Change in concept : 1960s ● Reuptake mechanism : – Noepinephrine, Serotonin, Dopamine – GABA, Glutamate, Glycine ● Histamine – No evidence of reuptake – Metabolizing enzymes do not inactivate
  • 18. 18 / 65 ● Glutamate and Glycine : Biosynthetic enzymes not identifed ● By the end of the 1960s, acetylcholine, biogenic amines, and amino acids had been generally accepted as neurotransmitters
  • 19. 19 / 65 1970s-1980s: Neuropeptides ● Concept of Cotransmitters ● Specifc Peptidase not identifed ● Neuromodulation, rather than excitation/inhibition ● Mid 1980s: Neuropeptides Accepted as NT’s
  • 20. 20 / 65 Novel Neurotransmitters ● Gases – Nitric Oxide – Carbon Monoxide – Hydrogen Sulphide ● Endocannabinoids ● Eicosanoids ● Neurosteroids
  • 21. 21 / 65 Nitric Oxide ● Not stored in or released from vesicles – Diffuses into target neuron ● Target is not a receptor on surface – Intracellular protein ● No reuptake mechanism, – short half life, enzymatic degradation postulated
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  • 26. 26 / 65 Nitric Oxide and Behaviour ● nNOS defcient male mice : aggressive tendencies , increased sexual activity ● Sleep-wake cycle – nNOS expressing neurons occur in several areas that initiate REM sleep – NO releasing subs: decrease wakefulness, increase slow wave sleep – NOS inhibitors : decrease slow and deep wave sleep
  • 27. 27 / 65 Nitric Oxide and mood disorder ● NOS expressing neurons : Areas implicated in depression: DRN, PFC ● SSRI Inhibit NOS activity: Antidepressant Response ● Plasma NO in Bipolar > Control ● Depression: low NO, high nitrite (by-product)
  • 28. 28 / 65 Nitric Oxide and Schizophrenia ● Two genetic studies have identifed schizophrenia-associated single nucleotide polymorphisms (SNPs) in CAPON, a protein that associates with nNOS ● Autopsy studies : NOS changes ● Elevated NOS activity in platelet
  • 29. 29 / 65 Neuropathological role of Nitric Oxide ● Combines with superoxide to cause toxic damage to cells ● Involved in cell loss resulting from ischemic stroke
  • 30. 30 / 65 Carbon Monoxide ● Far better known for its toxic effects than its activities at physiologic concentrations
  • 31. 31 / 65 Carbon Monoxide and Neurotransmission ● Appears to participate in the neurotransmission of odorant perception ● Odorants lead to carbon monoxide production and subsequent cGMP synthesis that promotes long-term adaptation to odor stimuli ● Potential to regulate a variety of perceptual and cognitive processes , yet untested ● May also participate in adaptation to chronic pain
  • 32. 32 / 65 ● GI : NT to relax internal anal sphincter in response to nonadrenergic noncholinergic (NANC) nerve stimulation and vasoactive intestinal peptide (VIP)
  • 33. 33 / 65 ● Heme Oxygenase Pathway: Neuroprotective role – HO defcient mice: increased susceptibility to traumatic brain injury and stroke damage – Neuroprotective function of HO inhibited in Alzheimer’s – Amyloid precursor proteins: Inhibit HO – APP mutants: early onset Alzheimer’s
  • 34. 34 / 65 Hydrogen Sulphide ● At least two enzymes can generate hydrogen sulfde: Cystathionine β-synthase (CBS) and cystathionine γ -lyase (CSE) ● Role in regulating brain function ● CBS-defcient mice have altered hippocampal LTP, and hydrogen sulfde potentiates NMDA receptor currents.
  • 35. 35 / 65 Endocannabinoids
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  • 37. 37 / 65 Cannabinoid Receptors ● CB 1 receptors are possibly the most abundant G-protein-coupled receptors in the brain ● Highest density in the basal ganglia, cerebellum, hippocampus, hypothalamus, anterior cingulate cortex, and cerebral cortex, particularly the frontal cortex
  • 38. 38 / 65 ● CB 1 : axons and nerve termini, neuronal dendrites and the cell body. ● CB 1 : presynaptic rather than postsynaptic side of the neuronal cleft, suggesting a role in regulation of neurotransmission. ● CB2 : surface of WBC’s of the immune system, but small amounts appear to be present in the brainstem
  • 39. 39 / 65 Efects on Neutotransmission ● CB1 receptor : G protein coupled, inhibit Adenylyl cyclase decrease cAMP→ ● CB1 activation: activate K-channel, inhibit N-type Ca-channel block neurotransmission→ ● Also tend to block GABA, norepinephrine, and acetylcholine ● Overall inhibitory effect
  • 40. 40 / 65 Endo-CBD in Anxiety and Mood ● THC : tranquilising effect ● CB-1 receptor defcient animal: more pronounced anxiety behaviour ● Possible role in PTSD and Phobias
  • 41. 41 / 65 Endo-CBD in addiction ● CB1 defcient mice : resistant to behavioural effects of CBD, reduced opioid addiction and withdrawal, reduced alcohol intake ● CBD-Opioid system interaction – CBD increase Dopamine release: requires Mu opioid receptors
  • 42. 42 / 65 Endo-CBD in Psychosis ● Heavy CBD use : Psychosis ● CBD use often worsens psychosis in Schizophrenia
  • 43. 43 / 65 Endo-CBD and feeding ● THC use : increase appetite ● Food deprivation : increased Endo-CBD in hypothalamus and limbic system ● CB 1 antagonist, rimonabant, facilitate weight loss
  • 44. 44 / 65 Endo-CBD: Brain Injury and Pain ● Mice models :Traumatic Injury – 2-AG : neuroprotective, reducing brain edema, infarct size, and cell death, improving functional outcomes ● Anandamide protected against brain injury in a model of multiple sclerosis (MS) ● FAAH inhibitors improved motor symptoms in a mouse model of Parkinson's disease
  • 45. 45 / 65 ● THC & CBD Agonist : Benefcial in acute and chronic pain ● Analgesic effects lost when CB Antagonist given ● Endo-CBD and opioid analgesia : distinct but may share overlapping neural pathways.
  • 46. 46 / 65 Eicosanoids ● Dietary supplements of omega-3 fatty acids, eicosapentaenoic acid (EPA), its ester ethyl- eicosapentaenoic (E-EPA), and docosahexaenoic acid (DHA), help relieve symptoms of depression, bipolar illness, schizophrenia, and cognitive impairment ● DHA and EPA may help reduce behavioral outbursts and improve attention in children.
  • 47. 47 / 65 ● Negative correlation between fsh consumption and depressive symptoms ● Reduced DHA in the orbitofrontal cortex in Post mortem studies of depressive patients ● Omega-3 FA adjunct t/t with Lithium/Valproate in Bipolar& unipolar depression : Better control than drug alone
  • 48. 48 / 65 ● Problem solving skills, Visual acuity, eye development – Better in infants of mother who consumed DHA-rich food ● English prisoners consuming higher amt of seafoods : Low assault rate
  • 49. 49 / 65 ● Improvement in +ve and -ve symptoms of schizophrenia with omega-3 FA supplementation ● Low EPS of Haloperidol : when combined with antioxidants and omega-3 FA
  • 50. 50 / 65 Neurosteroids ● Synthesized from cholesterol in the brain ● Independent of peripheral formation in the adrenals and gonads ● produced by enzymatic processes – CYP-450 and non-CYP enzymes, – Within or outside the mitochondria – CNS and PNS cells
  • 51. 51 / 65 ● Operate through a nongenomic pathway to regulate neuronal excitability through their effects on neurotransmitter-gated ion channels ● GABA receptor, particularly GABAA ● Allopregnanolone (3a, 5a-tetrahydro progesterone), pregnanolone (PREG), and tetrahydrodeoxycorticosterone (THDOC)
  • 52. 52 / 65 ● Dehydroepiandrosterone sulfate (DHEA-S), the most prevalent neurosteroid, acts as a noncompetitive modulator of GABA ● DHEA: inhibitory effects at the GABA receptor
  • 53. 53 / 65 NS in Neurodevelopment & Neuroprotection ● General Effects – stimulate axonal growth and promote synaptic transmission ● DHEA – Regulate brain serotonin and dopamine levels, suppress cortisol, increase hippocampal primed burst potentiation and cholinergic function, decrease amyloid-/3 protein, inhibit the production of proinfammatory cytokines, and prevent free radical scavenging
  • 54. 54 / 65 ● DHEA and DHEA-S – glial development and neuronal growth and to promote their survival in animals ● Progesterone – repair of damaged neural myelination ● Allopregnanolone – reduction of contacts during axonal regression
  • 55. 55 / 65 Role of Neurosteroids in Mental illness ● Depression ● Anxiety d/o ● Eating d/o ● Psychotic d/o ● Childhood Mental illness ● Substance abuse ● Memory and aging
  • 56. 56 / 65 Depression ● Low plasma and CSF concentrations of allopregnanolone, Inverse relation with severity ● Fluoxetine increase level of certain neurosteroids ● Debate over therapeutic properties
  • 57. 57 / 65 Anxiety disorders ● Allopregnanolone stimulates GABAergic activity with 20 times the strength of benzodiazepines and 200 times the potency of barbiturates. ● Both positive and negative regulation of the GABAA receptor are correlated with anxiolytic and anxiogenic action, respectively
  • 58. 58 / 65 Psychotic disorders ● DHEA : decrease anxiety in patients with schizophrenia, ● DHEA and DHEA-S suppress GABA inhibition, heighten the neuronal response at the NMDA and sigma receptors. ● DHEA and DHEA-S levels are typically elevated in the initial episode of a patient with schizophrenia
  • 59. 59 / 65 Childhood Mental Illnesses ● ADHD – Clinical symptomology inversely correlated with DHEA and pregnenolone levels
  • 60. 60 / 65 Substance Abuse ● Alcohol – Regulate GABA receptor, induce denovo steroid synthesis in the brain – Sharp increase in alcohol : mimic acute stress response, elevate neurosteroid conc by HPA axis ● Drug abuse – DHEA-S : increased after cocaine abstinence, decreased after relapse
  • 61. 61 / 65 Eating disorders ● DHEA: – diminish food intake, temper obesity, moderate insulin resistance, and lower lipids in rats with a model of youth-onset, hyperphagic, and genetic obesity ● Low DHEA and DHEA-S recorded in young women with anorexia nervosa ● Oral DHEA supplementation increased bone density and tempered the emotional problems associated with the disorder
  • 62. 62 / 65 Memory disorders and aging ● DHEA level at age 70 : 20% of that at late 20’s ● DHEA supplementation prevent or slow the cognitive declines associated with the aging process (conficting results) ● DHEA levels markedly decreased in Alzheimer’s
  • 63. 63 / 65 What is novel about Novel NT’s? ● Gases, cannabinoids, and eicosanoids : not stored in vesicles , generated & released on demand ● Endocannabinoids transmit signals backward, , from the postsynaptic neuron to the presynaptic neuron. ● Gases: do not act on membrane receptor, diffuse into cell and act on cellular proteins ● Nitric Oxide, Arachidonic Acid, CBD,CO : Retrograde Transmitters – diffusing back to the presynaptic neuron to facilitate further neurotransmission
  • 64. 64 / 65 Summary ● Scientifc research in last decades has led to discovery of novel neurotransmitters ● Novel neurotransmitters challenge the classical criteria of Neurotransmitter ● Research into and understanding of Novel neurotransmitters is important for better understanding and future directions in treatment of a large number of psychiatric illnesses
  • 65. 65 / 65 References ● Kaplan and Saddock’s Comprehensive Textbook of Psychiatry , 9th Edition, 2009 ● Kaplan and Sadock’s Synopsis of Psychiatry, 11th Edition, 2015 ● Webster R.A;Neurotransmitters, Drugs and Brain Function,2001 ● Snyder S.H. et. al; Novel Neurotransmitters and Their Neuropsychiatric Relevance, American Journal Of Psychiatry, Nov. 2000
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