Neurotransmitters

1. Neurotransmitters

2. Neurotransmitters A chemical released by one neuron that affects another neuron or an effector organ (e.g., muscle, gland, blood vessel) • Excitatory neurotransmitters – cause depolarization • Inhibitory neurotransmitters – cause hyperpolarization

3. Attributes of “classical” neurotransmitters • Synthesized in the presynaptic cell • Stored in membrane-bound vesicles (synaptic vesicles) • Released from the presynaptic vesicle in response to membrane depolarization • Induction of a physiological response in the post synaptic cell (by depolarizing or hyperpolarizing its membrane) • inactivated (rapidly) in the synaptic cleft

4. Classification of neurotransmitters GROUPEXAMPLES amines acetylcholine (Ach), norepinephrine, epinephrine, dopamine, 5-HT amino acids glutamate, GABA purines ATP, adenosine gases nitric oxide peptides endorphins, tachykinins, many others

5. Excitatory/inhibitory neurotransmitters EXCITATORY Acetylcholine Glutamate NorepinephrineAspartate Epinephrine Histamine INHIBITORY GABA Glycine MIXED Dopamine Serotonin

6. Release of neurotransmitters

7. Neurotransmitters bind to receptors Ionotrophic receptors: these act as ion channel themselves to produce their effects. Metabotrophic receptors: these activate second messenger system (cAMP, PIP3) to produce their effects.

8. biogenic amines

9. Neurotransmitters – biogenic amines • Catecholamines • Dopamine • Norepinephrine • Epinephrine • Indoleamines • Serotonin (5-HT) • Melatonin

10. Catecholamines – functions • Dopamine: control of voluntary movement (nigrostriatal tract), emotional responses • and memory (limbic system) • Norepinephrine: “fight or flight response” such as stimulation of heart rate, sweating, skin vasoconstriction and bronchodilation (sympathetic nervous system), state of alertness (brain stem) • Epinephrine: response to stress, redirection of blood from skin to heart, glycogen metabolism, blood pressure (adrenal medulla under influence of Ach-containing nerves)

11. Catecholamines - Synthesis Tyrosine BH4 Tyrosine hydroxylase BH2 L-Dihyroxyphenylalanine (DOPA) NEURONS Dopadecarboxylase PLP CO2 ADRENAL MEDULLA Dopamine O2 Cu++, Vit C Dopamine βhydroxylase Norepinephrine SAM Vit B12Folate Phenylethanolamine N-methyltransferase SAH Epinephrine

12. Parkinson’s disease • Degeneration of nigrostriatal dopamine neurons in the brain resulting in a deficiency of Dopamine • Symptoms include trembling of hands, arms, legs, jaw and face; stiffness of the arms, legs and trunk; slowness of movement; poor balance and coordination • Treatment with L-DOPA which enters the brain and is decarboxylated to dopamine. • L-DOPA is given together with carbidopa, DOPA carboxylase inhibitor that cannot enter the brain, preventing unwanted formation of dopamine outside the brain

13. Indoleamines – functions Serotonin: involved with mood, anxiety, appetite, sleep induction, memory and learning Melatonin: involved in response to light-dark cycle organizing seasonal and circadian rhythms, regulating reproductive functions

14. Synthesis – indoleamines Tryptophan BH4 Tryptophan hydroxylase BH2 5’hyroxytryptophan Dopadecarboxylase PLP CO2 Serotonin Acetyl CoA CoASH SAM Vit B12Folate SAH Melatonin

15. Degradation–Norepinephrine

16. Degradation–monoamines Norepinephrine epinephrine Dopamine Serotonin MAO-A,-B COMT MAO-B COMT MAO-A Vanillylmandelic acid Homovanillic acid Hydroxyindoleacetic acid Endocrine tumors (pheochromocytoma, Carcinoid syndrome) diagnosed by the measurements of these breakdown products in urine.

17. monoamines- release and uptake

18. Monoamines and depression • “amine theory of depression” states that depression is caused by a relative deficiency of amine neuro-transmitters at central synapses • Prevention of catabolism of catecholamines and serotonin reduce depression by elevating the levels of these compounds. MAOA inhibitors act as antidepressants • Inhibitors of norepinephrine and serotonin transport into neurons also act as antidepressants (e.g. prozac; serotonin reuptake inhibitor)

19. Histamine

20. Histamine – Functions • Dilates blood vessels, increases capillary permeability, contracts bronchial and intestinal smooth muscle, stimulates gastric acid secretion and nasal fluid discharge

21. Histamine - synthesis and degradation

22. Acetylcholine

23. Acetylcholine - functions • Major neurotransmitter at the neuromuscular junctions to induce muscle contraction • Play an important role in attention, learning, reward pathways and memory by reinforcing the ability to detect and respond to meaningful stimuli • Neurons associated with Ach degenerate in Alzheimer's disease resulting in declining language and perception, confusion and memory loss.

24. Acetylcholine – synthesis and degeneration

25. Acetylcholine- release and inactivation

26. Disorders of acetylcholine metabolism Myasthenia gravis: a disease characterized by muscle weakness. Autoimmune disorder due to formation of antibodies against the nicotinic Ach recptors, preventing trnsmission of nerve impulses to muscles. Treated by inhibitors of Ach esterase (pyridostigmine, neostimine) and corticosteroids Lambert-Eaton myasthenic syndrome:  autoimmune disorder also characterized by muscle weakness. Due to auto-antibodies against the presynaptic voltage-gated calcium channels

27. Acetylcholinesterase inhibitors • Organophosphate insecticides and nerve gases (sarin) inhibit acetylcholinesterase resulting in an excess of Ach, initially causing uncontrolled muscle contraction and eventually paralysis. Treatment by atropine.

28. Amino acids as neurotransmitters

29. Amino acids as neurotransmitters • Recruited as neurotransmitters by packaging into synaptic vesicles • Their action is terminated by sodium dependent high affinity uptake with need for any specific degradative enzymes • EXICTATORYINHIBITORY • Glutamate Glycine • Aspartate GABA

30. Glutamate/GABA - synthesis

31. Inhibitors of Amino Acid NT • Benzodiazapines (valium, Xanax) bind GABA receptors reducing anxiety, inducing sleep and guarding against seizures (anticonvulsants) • Barbiturates produce a wide spectrum of effects, from mild sedation to total anesthesia by potentiating inhibitory GABA receptors and inhibiting excitatory AMPA glutamate receptors • Strychnine binds to glycinerectorss leading to convulsions, spastic contraction of skeletal muscles and death due to impairment ot muscles of respiration.

32. NITRIC OXIDE

33. NITRIC OXIDE • NO is not stored in vesicles but released directly into the extracellular space • Functions • Relaxation of vascular and intestinal smooth muscle • Neural transmission • Regulation of mitochondrial energy production • Cytotoxic action on parasites and tumor cells

34. NITRIC OXIDE - synthesis

35. Peptides

36. Peptides • Over 80 peptides shown to influence neural functions • Synthesized as precursor proteins, packaged into vesicles and cleaved to the active form by peptidases • e.g. • Opioids peptides (endorphins, enkephalins) • Regulate pain and pleasure pathways • Substance P • transmits signals in response to pain

37. Peptides inhibitors • Opioid receptors are sites of action for morphine and codeine which are powerful analgesics • Opiates affect pleasure pathways in the brain resulting in the associated euphoric effects. • Endorphins released after strenuous exercise give the so-called “jogger's high”

38. the end!!