2. some controversy……..

4. Muscarinic agonists – Muscarine

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

8.  DA – dopamine  NE – norepinephrine  5HT - serotonin

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

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

11.  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.  receptor subtypes ◦ alpha 1 and 2; β 1 – 3

13.  Catecholamines removed by reuptake: ◦ DAT – DA transporter ◦ NET – NE transporter

14.  metabolism – ◦ far slower than ACh by AChE

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

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

20.  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.  behavioral role (CNS): sleep, aggressive behavior  abnormal function implicated in: ◦ schizophrenia, depression, phobic disorders, OCD, eating disorders, migraine, etc

22.  synthesis ◦ amino acid precursor – tryptophan

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

25.  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.  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.  reuptake main mechanism for terminating ◦ SSRIs  breakdown – major metabolite 5HIAA

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

36.  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.  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.  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. ◦ 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 system 2 components- autonomic and somatic 1. autonomic nervous system -“involuntary” - role in emotion and stress - controls smooth muscles, cardiac muscles and glands

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

46.  Maintain homeostasis, energy restoration ◦ physiological changes:

48.  voluntary nervous system ◦ sensory and motor nerves ◦ connection between all motor nerves and muscle (NMJ – neuromuscular junction) are nicotinic ACh synapses

50.  CNS – Central Nervous System ◦ brain, spinal cord  PNS – Peripheral Nervous System ◦ Somatic, autonomic

51.  3 main divisions of brain ◦ hindbrain; midbrain; forebrain

52. hindbrain Medulla

53.  medulla ◦ Contains part of the reticular formation – (nuclei involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness)

54.  medulla ◦ Contains part of the reticular formation – (nuclei involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) as well as ◦ Nuclei important for vital functions

55.  medulla ◦ Contains part of the reticular formation – (nuclei involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) as well as ◦ Nuclei important for vital functions ◦ Various ascending and descending pathways

56. medulla hindbrain

57.  pons ◦ Contains part of the reticular formation  Nuclei important for sleep and arousal

58.  pons ◦ Contains part of the reticular formation  Nuclei important for sleep and arousal ◦ Specific nuclei include  Raphe (5HT) – sleep and dreaming  Locus coerulus (NE) - arousal

59.  pons ◦ Contains part of the reticular formation  Nuclei important for sleep and arousal ◦ Specific nuclei include  Raphe (5HT) – sleep and dreaming  Locus coerulus (NE) - arousal  Cerebellum

60.  Sensory information ◦ reticular formation  movement ◦ substantia nigra -

61.  cortical and subcortical structures

62. frontal parietal temporal occipital

63.  Frontal ◦ Motor function ◦ Prefrontal – higher “executive function”

64.  Frontal ◦ Motor function  Prefrontal – higher “executive function”  Parietal ◦ Somatosensory function  Temporal ◦ Audition ◦ emotion  Occipital ◦ vision

65. Prefrontal cortex

68.  thalamus

69. The thalamus communicates with much of the cerebral cortex - serving as a sensory and motor information relay.

70.  thalamus  hypothalamus

71.  thalamus  hypothalamus  limbic system

73.  thalamus  hypothalamus  limbic system  basal ganglia

78.  Mesolimbic/cortical – ◦ Involved in reward, possible role in schizophrenia  Projects to nucleus accumbens and parts of the limbic system  nigrostriatal – ◦ Important in initiation of movement; system that degenerates in Parkinsons disease  projections from the substantia nigra to the basal ganglia  tuberofundibular – ◦ Important for hormonal release via hypothalamus and pituitary gland

81. Peptides  Opioids ◦ Mu ◦ Delta ◦ Kappa ◦ Endorphins and enkephalins are opioids  Substance P