some controversy……..

2. some controversy……..

4. some controversy…….. Muscarinic agonists – Muscarine

6. some controversy…….. Muscarinic agonists – Muscarine Muscarinic antagonists Synthetic and natural-

8. monoamines • DA – dopamine • NE – norepinephrine • 5HT - serotonin

9. DA (dopamine) • CNS - reward, movement, motivated behaviors, executive function? • numerous DA pathways in CNS of importance for psychotropics…..

10. DA receptor subtypes • DA receptor subtypes • 2 major families – D1 and D2 families

11. NE (norepinephrine) • In CNS- arousal; role in depression, possible role in spinal analgesia, possible motivated behaviors such as hunger, thirst, sex, anxiety, attention? • NE is in both the CNS and PNS

12. NE receptor subtypes • receptor subtypes • alpha 1 and 2; β 1 – 3

13. How are catecholamines taken removed from the synapse? • Catecholamines removed by reuptake: • DAT – DA transporter • NET – NE transporter

14. metabolism • metabolism – • far slower than ACh by AChE

15. metabolism • metabolism – • far slower than ACh by AChE • MAO enzymes (monoamine oxidase)

16. metabolism • metabolism – • far slower than ACh by AChE • MAO enzymes (monoamine oxidase) • MAOA AND MAOB enzymes • MAO A – more selective for NE and 5HT

17. metabolism • metabolism – • far slower than ACh by AChE • MAO enzymes (monoamine oxidase) • MAOA AND MAOB enzymes • MAO A – more selective for NE and 5HT • MAO B- more selective for DA

18. Major metabolites: • Important when trying to study potential differences • DA - dopac and HVA • NE - MHPG -(3-methoxy-4-hydroxy-phenethyleneglycol)

19. Tyrosine catecholamines Tyrosine hydroxylase (rate limiting step) TH DOPA Aromatic acid decarboxylase mao homovanillic acid (HVA) Dopamine (DA) DA-β-hydroxylase MHPG mao pnmt Epinephrine (E) Norepinephrine (NE)

20. 5HT • more recent in our history of studying NT • similarity to LSD • found early in high concentrations in the gut • found in many non neuronal cells (only ~ 1 – 2% of 5HT in whole body is in brain) • cannot cross bbb so……

21. 5HT • behavioral role (CNS): sleep, aggressive behavior • abnormal function implicated in: • schizophrenia, depression, phobic disorders, OCD, eating disorders, migraine, etc

22. 5HT • synthesis • amino acid precursor – tryptophan

24. 5HT • synthesis • amino acid precursor – tryptophan • elimination of dietary tryptophan can significantly lower brain 5HT levels

25. 5HT • synthesis • amino acid precursor – tryptophan • elimination of dietary tryptophan can significantly lower brain 5HT levels • foods high in tryptophan; • nuts (ie walnuts, almonds), tofu, milk, eggs, certain cheeses, turkey, seafood, seeds

26. 5HT • receptor subtypes- many – at least 18 subtypes have been identified - probably best way to group 5HT1 and 5HT2 families; - some are metabotropic; some ionotropic

27. 5HT • reuptake main mechanism for terminating • SSRIs • breakdown – major metabolite 5HIAA

28. amino acid neurotransmitters • pervasive throughout the brain • classified into 2 general categories • excitatory (glutamate, aspartate) • inhibitory (GABA, glycine) • amino acids are more difficult to classify as nt

29. GABA • first identified in leg of lobster • causes hyperpolarization of neurons • highest concentrations in brain and spinal cord and virtually absent in peripheral nerve or other organs • does not cross bbb easily

30. GABA • stored in synaptic vesicles (like other nt) • usually removed from synapse via transporter (GAT) • GABA also found in glia • receptor subtypes: • GABA A – ionotropic – clinically important • GABA B - metabotropic

31. GABA A • mediates anxiolytic, sedative, anticonvulsant, muscle-relaxant and amnesic activity • subunit compositions appear to vary from one brain region to another and even between neurons within a given region • linked to chloride channel

33. modulatory effects

34. glutamate • found in high concentrations in brain • serves many functions • GAD (enzyme – can convert glutamate to GABA)

36. glutamate • found in high concentrations in brain • serves many functions • GAD (enzyme – can convert glutamate to GABA) • receptor subtypes: • tremendous work done in recent years

38. glutamate • receptor subtypes: • NMDA, ionotropic, various other receptors including metabotropic GLU R (mGLUR) • families within these • role of neuromodulators • current potential interests • reducing neurotoxicity, psychiatric disorders, substance use disorders, Alzhemiers Disease?

39. memantine • 2005 – first non AChE inhibitor for treating AD • Only approved for advanced (not early stage) • uncompetitive low-to-moderate affinity NMDA receptor antagonist • Multiple other uses possible

40. More about histamine • acts as a neurotransmitter; also released during immune response; also found in gut • antihistaminergic effects: • drowsiness, dry mouth, dizziness, sleepiness, upset stomach, decreased coordination, fatigue, weight gain, dry mouth and throat, upset stomach, fluttery heartbeat, loss of appetite, hives, sleepiness, vision problems

41. Overview of nervous system

43. PNS - peripheral nervous system2 components- autonomic and somatic 1.autonomic nervous system - “involuntary” - role in emotion and stress - controls smooth muscles, cardiac muscles and glands

44. Autonomic NS has two components 1. Sympathetic NS “fight or flight” activated during emergencies, stress and/or arousal

46. 2. Parasympathetic nervous system • Maintain homeostasis, energy restoration • physiological changes:

48. 2nd part of the PNS is the somatic nervous system • voluntary nervous system • sensory and motor nerves • connection between all motor nerves and muscle (NMJ – neuromuscular junction) are nicotinic ACh synapses

50. 2 divisions of the nervous system • CNS – Central Nervous System • brain, spinal cord • PNS – Peripheral Nervous System • Somatic, autonomic