NOVEL NEUROTRANSMITTERS-2 psychiatry ppt

Novel neurotransmitter

1. NOVEL NEUROTRANSMITTERS PRESENTED BY DR JAYAKRISHNA CHAIRED BY DR ANJU MATHEW

2. NEUROTRANSMITTERS Chemicals that amplify or inhibit the depolarization signal from one neuron to that of adjacent neuron

3. Classical definition of neurotransmitter Synthesis in a presynaptic neuron Storage and release from a presynaptic neuron Binding to receptor on a post synaptic membrane Removal from synaptic cleft by reuptake and degradation

4. TYPES GASES ENDOCANNABINOIDS EICOSANOIDS N EUROSTEROIDS

5. NITRIC OXIDE

6. Mechanism Of Action of Nitric Oxide Cyclic GMP Pathway S- Nitrosylation pathway

7. cGMP Pathway

8. S- Nitrosylation Pathway

9. NITRIC OXIDE AND NEUROTRANSMISSION

10. NITRIC OXIDE AND BEHAVIOR Role in aggression Promotes REM sleep Innervate blood vessels of penis

11. NITRIC OXIDE AND MOOD DISORDERS SSRI inhibit NOS activity NO inhibit neurogenesis

12. NITRIC OXIDE AND SCHIZOPHRENIA Schizophrenia associated SNPs are found in CAPON (protein that associates with nNOS ) Autopsy samples-abnormally localized NOS expressing neurons in prefrontal cortex, hippocampus, lateral temporal lobe.

13. Neuropathologic roles of NO Protein Nitration Excitotoxicity- Ischaemic stroke Sporadic Parkinson disease( nitrosylate PARKIN—E3ubiquitin ligase) Nitrosylation of Protein disulfide isomerase…..in Alzheimer's disease

14. CARBON MONOXIDE Air pollutant Also physiologically produced

15. Enzymatic generation of CO

16. MOLECULAR ACTIONS OF CO Freely diffuse across cell membrane and activate guanylyl cyclase

17. CO and neurotransmission Odorant perception Adaptation to chronic pain GIT Role in ejaculation

18. Neuroprotective role of the hemeoxygenase pathway Impaired in Alzheimer’s disease

19. HYDROGEN SULPHIDE(H2S) Produced from cysteine and water Generated by two enzymes-CBS (cystathionine beta synthase) &CSE ( Cystathione gamma lyase). In brain CBS is abundant. In the brain H2S is at concentration as high as 160 micromolar=role in regulating brain function

20. FUNCTION OF H2S H2S potentiates NMDA receptor currents Can activate ATP sensitive potassium channels, dilate arterioles and increase activity of signaling kinase ERK

21. ENDOCANNABINOIDS Cannabinoids-active components of marijuana Endogenous cannabinoid/Endocannabinoids-endogenous brain ligand for CB1 receptor

22. Anandamide was the first endocannabinoid to be discovered. 2-arachidonyl glycerol(2-AG) N- arachidonyl dopamine(NADA) 2-arachidonyl glycerol ether( noladin ether) Virodhamine

23. BIOSYNTHESIS

24. Inactivation of endocannabinoids is by Fatty acid amide hydroxylase

25. Cannabinoid receptors CB1 Most abundant GPCRS in brain Highest density-cerebellum, basal ganglia, hippocampus, hypothalamus, cerebral cortex Presynaptic receptors CB 2 WBC (predominantly), brainstem

26. Effects on neurotransmission Inhibition of adenylyl cyclase-leads to decrease in Camp Activation of potassium channels and inhibition of N type calcium channels Activates mitogen activated protein kinase Inhibit release of GABA ,norepinephrine and acetyl choline Increase release of brain endorphin and dopamine in nucleus accumbens

27. Retrograde neurotransmission by endocannabinoids

28. Endocannabinoids in anxiety and mood Important regulator of anxiety Enhancing level of endocannabinoids may represent a therapeutic target for anxiety Mood disorders

29. ADDICTION Increases release of dopamine in nucleus accumbens -key reward area of brain implicated in addiction

30. PSYCHOSIS can produce psychotic symptoms Worsen schizophrenia Cannabinoid system appears to increase the release of dopamine

31. Endocannabinoids in brain injury and pain Neuroprotective Stress induced analgesia Endocannbinoids can promote analgesia via CB1 CB2 receptors but can increase pain via TRP channels

32. FEEDING Appetite stimulant CB1 receptor antagonist –Rimonabant for weight loss

33. Eicosanoids Eicosapentanoic acid Docosahexanoic acid Ethyl- eicosapentanoic acid

34. EFFECTS Protect neuron from inflammatory and oxidative toxicities Increases serotonin and dopamine Regulation of corticotrophin releasing factor

35. THERAPEUTIC INDICATIONS Negative correlation between fish consumption and mood disorder Adjunctive to Li ,significant improvement in Hamilton Rating Scale Low EPA and DHA high risk for post partum depression Consumption of DHA in pregnancy- increased problem solving skills in children

36. NEUROSTEROIDS Synthesized from cholesterol in the brain. Receptors are located on nucleus, membrane or microtubules of CNS and PNS. Most well known effect of neurosteroids is on the GABA-A receptor Act via a non genomic pathway to regulate neuronal excitability via their effects on the neurotransmitter gated ion channels

37. Act at GABA, NMDA, AMP, glycine, nicotinic acetyl choline receptor etc Egs -Allopregnanolone, pregnenolone, tetrahydrodeoxycorticosterone , progesterone Most prevalent neurosteroid -Dehydroepiandrosterone sulphate (DHEA)

38. FUNCTIONS Neurosteroids stimulate axonal growth and promote synaptic transmission Neuroprotective

39. Role of neurosteroids in mental illness DEPRESSION Antidepressants specially fluoxetine have been shown to increase the levels of neurosteroids ANXIETY DISORDER Homeostasis characterized by normal GABA ergic activity is restored after panic attacks as neurosteroids are released in response to stress

40. PSYCHOTIC DISORDERS DHEA-decrease anxiety in schizophrenia Decrease GABAergic transmission ADHD Clinical symptoms of ADHD are inversely correlated with DHEA and pregnenolone levels

41. Substance Abuse Alcohol can regulate GABA receptor and induce denovo steroid synthesis in brain Eating Disorder DHEA can decrease food intake, temper obesity, moderate insulin resistance, lower lipids by regulating serotonergic system

42. Postpartum Disorders Low post partum DHEA linked to mood instability Allopregnalone levels correlate with mood disorders in pregnancy and in PMS

43. Memory and Ageing DHEA supplementation can prevent or slow cognitive declines associated with ageing process Inconsistent evidence

44. SUMMARY Novel neurotransmitters don’t fit into the classical definition of neurotransmitters There are many types of novel neurotransmitters. They play an important role in various psychiatric disorders They are the potential targets for new drugs

45. REFERNCES Kaplan’s and Sadocks Comprehensive Text Book of Psychiatry Tenth Edition Novel neurotransmitters and their neuropsychiatric relevance;Solomon H et al; American Journal of Psychiatry 2000

46. THANK YOU