Neurohumoral transmission in CNS

Neurohumoral transmission in CNS-
The term neurohumoral transmission designates the transfer of a nerve impulse from a presynaptic to a postsynaptic neuron by means of a humoral agent e.g. a biogenic amine, an amino acid or a peptide.

1. Neurohumoral Transmission In Central Nervous System BY- SANCHIT DHANKHAR m.Pharmacy

2. Overview:- Neurohumoral Transmission Steps Involved in Neurohumoral Transmission Introduction. GABA Glycine. Glutamate. Serotonin. Dopamine. Histamine.

3. Neurohumoral Transmission Neurohumoral transmission refers to the transmission of nerve impulse through synapse & Neuroeffector junction by the release of h umoral (chemical) substance e.g. a biogenic amine, an amino acid or a peptide. Information is communicated from Nerve to Nerve, from Nerve to Effector Organ, by the process called Neurohumoral Transmission

4. Steps Involved in Neurohumoral Transmission Impulse Conduction. Neurotransmitter Release. Neurotransmitter Action on Post junction Membrane. Post junction Activity. Termination of Neurotransmitter Action.

5. Impulse Conduction Refers to Passage of an Impulse along nerve fibre. After receiving an information from a Peripheral Organ through Sensory Nerve. CNS sends message or Impulse through efferent autonomic nerve. Impulse Conduct by generating Action Potential. Action Potential is self propagating & is conducted along Axonal Fibre. Note: Resting Potential is - 70mv ( negative Inside Neuron) Depolarization – Influx of Na+ Repolarization – Efflux of K+ Repolarization is Shorter than Depolarization.

6. Neurotransmitter Release Depolarisation leads to stimulation and opening of voltage sensitive Ca+ Channel. Ca+ helps in fusion between Axoplasmic Membrane and Synaptic Vesicle (Store house of Neurotransmitter) Neurons release by Exocytosis.

7. Neurotransmitter Action on Post - Junctional Membrane The Released Transmitter combines with specific receptors on the post junctional membrane Depending on its Nature induces an :- 1. Excitatory Post Synaptic Potential. 2. Inhibitory Post Synaptic Potential.

8. Post Junctional Activity Excitatory Post synaptic Potential generates a propagated post Junctional Action Potential, which results :- Nerve impulse in Neurons Contraction in Muscles Secretions in Glands An Inhibitory Post Synaptic Potential Stabilize Post junctional membranes and Resist Depolarization stimuli.

9. Termination of Transmitted Action It is either Locally Degraded or Partly taken back into Pre junctional Neuron by active Reuptake. It Can also be explained easily by the following Diagram :-

10. CNS- Central Nervous System It consist of Brain and Spinal Cord

11. Gamma Aminobutyric Acid (GABA) Gaba is the main inhibitory Neurotransmitter in CNS, Synthesized in Brain. It acts by binding to specific receptor on both Pre and Post synaptic Membrane. Synapses using GABA are referred to as GABAergic synapses.

12. Glycine Simplest Amino acid, semi essential Amino acid. Major Inhibitory neurotransmitter in CNS also known as Inhibitory chloride Channel Protein. They are Present in abundance in Spinal cord. Glycine receptor is a member of Nicotinic receptor superfamily . To prevent Tissue Injury. To enhance anti – oxidant Capacity. To promote protein synthesis and wound healing. Used in Spasticity For biosynthesis of Heme, Creatinine & Glutathione. Function

13. Synthesis serine +  tetrahydrofolate  → glycine +   N 5 ,N 10 -Methylene tetrahydrofolate + H 2 O

14. Receptor The Glycine receptor responsible for inhibition is a Cl- Channel. It is Ionotropic in Nature & is Pentamer made up of two subunits. The ligand- Binding Alpha Subunit. The Structural Beta Subunit.

15. Glutamate They are Excitatory Amino Acid. Principal excitatory neurotransmitter in CNS, stored in Neuronal cell membrane. Glutamate comes into the CNS mainly by glial cells and by Kreb’s Cycle. Responsible for neural communication, memory formation, learning and regulation. Glutamate Comes from glial cells in the neuron. In the neurons the glutamine is converted into glutamate with the help of glutaminase enzyme Glutamate is stored in the synaptic vesicles. From synaptic vesicles glutamate release by the process of exocytosis which is Ca+ dependent. Synthesis

16. Receptors Glutamate receptors are synaptic receptors located primarily on the membranes of Neuronal cells. Glutamate (glutamic acid ) is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body’s most prominent neurotransmitter, the brain’s main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate – mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

17. SEROTONIN The scientific name for serotonin is 5-hydroxytryptamine, or 5-HT It is a monoamine neurotransmitter. About 90% of is found/localized in the intestines: the rest in brain and platelets. The level of 5-HT in whole blood is in the range of 65–250 mg/ml It is popularly thought to be a contributor to feelings of well-being and happiness it is a key mediator in the physiology of mood, vascular function and gastrointestinal motility. This explains the number of therapeutic agents that act targeting the serotonergic system such as: 5-HT3 antagonists, SSRIs and triptans

18. Disturbance in the Serotonin levels may cause :-

19. ACTION AND FUNCTIONS OF SEROTONIN

20. PERIPHERAL MEDIATED PHYSIOLOGICAL FUNCTIONS OF 5-HT RECEPTORS In periphery Peristalsis Vomiting Platelet aggregation and haemostasis Inflammatory mediator Sensitization of nociceptors (Pain receptors) Microvascular control

21. Central effects of serotonin receptor Neuronal inhibitions through decrease of cAMP Behavioral effects sleep mood feeding thermoregulatory anxiety Cerebral vasoconstrictions

22. Serotonin pathways in the Brain  Serotonin pathways that are located in the brainstem area “the Raphe nuclei” these neurons control muscle activity, 5-HT receptors trigger vomiting. The serotonin neurons in frontal cortex, regulate cognition and memory. The serotonin neurons in the hippocampus regulate memory. The serotonin neurons in the other limbic areas regulate mood. ( basal ganglia and cerebral cortex). SSRI’s work in this pathway.

23. Drugs acting on 5-HT receptors

24. Drugs acting on serotonergic neurotransmission

25. MAO inhibitors ;- Monoamine oxidase is a key enzyme for serotonin, dopamine and norepinephrine inactivation. MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess neurotransmitter to diffuse into the synaptic space. This class of agents is used in the treatment of depression ( phenelzine , tranylcypromine , selegiline ) and Parkinson’s disease ( selegiline ). Dietary restrictions (because of tyramine toxicity) limit their widespread use. Inhibitors of serotonin storage ;- They interfere with the ability of synaptic vesicles to store monoamines; displace serotonin, dopamine and norepinephrine from their storage in presynaptic nerve terminals. Agents that share this mechanism of action include amphetamine, methylphenidate and modafinil

26. The Side Effects of Selective Serotonin Reuptake Inhibitor’s Dry mouth Sweating Headaches Sedation Dizziness Nausea Somnolence ( Sleepeness ) Insomnia Diarrhea

27. Serotonin agonist

28. Serotonin receptors agonists have wide clinical applications, from treatment of depression to abortive medications for migraine headache. According to the receptor they activate, they can be divided into: 5-HT1A agonists ;- Buspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression. 5-HT1B and 5-HT1D agonists ;- The “ triptans ” are a drug class useful as abortive medication for the treatment of acute migraine headaches. They are very effective in causing cranial vasoconstriction and decreased release of neuropeptides involved in “sterile inflammation”.

29. 5-HT2C agonist ;- Trazodone was previously believed to be a 5-HT2C receptor antagonist. However, recent publications report that trazodone would behave as a 5-HT2C agonist. This drug is used generally as somnorific . 5-HT4 agonists ;- Cisapride is a serotonin and cholinergic agonist used as a prokinetic drug, it was withdrawn from the U.S. market because of cardiovascular toxicity. Non-selective agonists ;- Ergotamine activates a more than one subtype of 5-HT receptor, it binds to 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable treatment for migraine attacks. LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic properties.

30. 5-HT2 Antagonist Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. In addition to its serotonin antagonism, it has affinity for alpha-1 receptors, which may contribute to its antihypertensive effect.

31. Clozapine is an atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high affinity for dopamine receptors, the involvement of 5-HT has possibly increased the chances of greater efficacy and reduction in negative symptoms of schizophrenia. Agomelatine is a new antidepressant with agonist action at the melatonin receptor and antagonism at the 5-HT2C receptor. 5-HT3 antagonists -- This class includes drugs such as ondansetron, palonosetron and others. These agents are particularly useful in the treatment of chemotherapy induced nausea and vomiting .

32. Serotonin Syndrome – What Happens When Your Serotonin Levels Are Too High?

33. Tips for naturally boosting serotonin 1. Get morning sunlight, its more intense and this can boost your body’s production melatonin. 2. Get plenty of exercise, researchers have found that exercise boost serotonin 3. Reduce your stress (both physical and emotional), prolonged stress produce adrenaline and cortisol which interfere with serotonin 4. Eating foods that are high in protein because of high percentage of tryptophan 5. Also food containing carbohydrates as they produce insulin which helps tryptophan go into the brain

34. Dopamine Dopamine belongs to the family of catecholamines Hormones Epinephrine and Norepinephrine (other catecholamines ) are derived from Dopamine. Significant role in learning, goal-directed behavior, regulation of hormones, motor control

35. Storage and Release

36. Metabolism

37. Receptors Metabotropic G-protein coupled receptors D1 – like family: Includes subtypes D1 and D5 Activation is coupled to Gαs ; activates adenylyl cylcase which leads to increase in concentration of cAMP D2 – like family: Includes D2, D3 and D4 Activation is coupled to Gαi ; inhibits adenylyl cyclase leading to decrease in concentration of cAMP

38. Physiological roles

39. Major Dopamine pathways

40. Control of movement The largest Dopamine tract in the brain which contains about 80% of brain’s dopamine in the nigrostriatal system. Assisted in learning coordinated movements.

41. Parkinson’s Disease Substantial loss of Dopamine in the striatum (70 – 80%) Loss of dopamine neurons in other systems also (Mesolimbic, Mesocortical and Hypothalamic systems) Treatment strategy includes increasing dopamine levels by administering ;-  Dopamine precursor : Levodopa ( l-dopa ) (b) Peripheral decarboxylase inhibitors : Carbidopa,. (c) Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole (d) MAO-B inhibitor: Selegiline (e) COMT inhibitors: Entacapone, Tolcapone (f) Dopamine facilitator: Amantadine

42. Schizophrenia Defective dopamine neurotransmission – relative excess of central dopaminergic activity An increase in DA function in the mesolimbic system and a decreased function in the mesocortical DA systems Behavior similar to the behavioral effects of psychostimulants Antipsychotics such as chlorpromazine, bind to D 2 dopamine receptors and reduced positive psychotic symptoms

43. Parmacological effects

44. Histamine Introduction Histamine is a biogenic amine found in many tissues, including mast cells, basophils, lymphocytes, neurons, and gastric enterochromaffin-like cells. It is an autacoid—that is, a molecule secreted locally to increase or decrease the activity of nearby cells. Histamine is a major mediator of allergic and inflammatory processes. It also has significant roles in the regulation of gastric acid secretion, neurotransmission, and immune modulation.

45. Storage and Release Histamine synthesis and storage can be divided into two “pools”: a slowly turning over pool a rapidly turning over pool The slowly turning over pool is located in mast cells and basophils. Histamine is stored in large granules in these inflammatory cells, and the release of histamine involves complete degranulation of the cells. The rapidly turning over pool is located in gastric ECL cells and in histaminergic CNS neurons. These cells synthesize and release histamine as required for gastric acid secretion and neurotransmission, respectively.

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