1. postsynaptic receptors
protein embedded in membrane
mechanism for neurotransmitter to influence postsynaptic activity by binding to receptor

2. Neurotransmitters and Receptors
There are different varieties of receptors.
Some respond fast
Called Ionotropic
Direct reaction to the transmitter

3. Neurotransmitters and Receptors
Different varieties of receptors:
Other types of receptors respond more slowly.
Indirectly
Called Metabotropic, or G protein-coupled
Initiates a second signal (messenger) inside the neuron.

4. Neurotransmitters and Receptors
Inactivation: Termination of Synaptic Transmission
Metabolism
Re‑uptake

5. E

6. Neurotransmitters and Receptors
Acetylcholine—first to be recognized, because of peripheral actions
Synthesis
Acetyl-CoA (in mitochondria) + choline (from diet)

7. Choline+ Acetyl cOA Acetylcholine (ACh) Acetylcholine
cHat (choline acetyl transferase)
Acetylcholine (ACh)
Choline +acetate
AChE
(Acetylcholinesterase)

8. Neurotransmitters and Receptors
Inactivation:
Acetylcholinesterase (AChE)
After action in postsynaptic cleft, AChE degrades ACh to choline and acetate, which are taken back up into the neuron.

9. ACh
found in both CNS (brain and SC) and PNS (Somatic and autonomic NS)

10. Acetylcholine (ACh) Functions (in PNS)
Functions (in CNS)
memory, sensory processing, movement, REM sleep
Functions (in PNS)
many psychotropics have anti ACh effects

11. Acetylcholine (ACh) cholinergic receptor subtypes
2 classes
labeled by agents that act as agonists at receptor

12. Acetylcholine (ACh)
nicotinic – muscle, neuronal - majority are ionotropic
at least 17 subtypes
some muscular; some CNS
number of nicotinic receptors are growing…..

13. Nicotinic drugs….. nicotinic agonists – nicotinic antagonist
varenicline (Chantix) – smoking cessation
partial agonist
nicotinic antagonist
“botox”- botulism toxin

14. Acetylcholine (ACh) muscarinic –
5 subtypes discovered so far; all metabotropic
(M1-M5)

15. Some Pharmacological Actions for M ACh antagonists
scopolamine – motion sickness
some meds for asthma
treating side effects of some PD meds

16. Acetylcholine (ACh) malathion, parathion, (pesticides)
ways to alter ACh activity
AChE inhibitors
some “irreversible” AChE inhibitors:
malathion, parathion, (pesticides)
nerve gas (Sarin)
“reversible
cognitive enhancers
donepezil (Aricept)

17. Disease states that involve ACh neurons
MG – myasthenia gravis
autoimmune disease affecting NMJ
Alzheimers Disease - AD
temporary “fixes” for these disease states
“reversible” AChE inhibitors -tacrine (Cognex), donepezil (Aricept)
Strategy in both cases………

18. Anticholinergic Side Effects
can include confusion, blurred vision, constipation, dry mouth, light-headedness, urinary retention, loss of bladder control.

19. choline rich foods
Whole eggs, liver, beef steak, and soy are among foods naturally rich in choline.

20. catecholamines
Dopamine (DA)
Norephinephrine (NE)

21. catecholamines
NE and E are synthesized from their precursor DA with the appropriate enzymes present

22. tyrosine hydroxylase
DA decarboxylase
DA β hydroxylase
PNMT

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

24. Neurotransmitters and Receptors
Catecholamines
Synthesis
Tyrosine
Dopamine
Norepinephrine
Termination
Re-uptake
Monoamine oxidase (MAO)

25. metabolism metabolism – MAOA AND MAOB enzymes
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

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

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

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

29. DA receptor subtypes DA receptor subtypes
2 major families – D1 and D2 families

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

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

32. 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……

33. 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

35. 5HT behavioral role (CNS): sleep, aggressive behavior
abnormal function implicated in:
schizophrenia, depression, phobic disorders, OCD, eating disorders, migraine, etc

36. 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

37. 5HT reuptake main mechanism for terminating
SSRIs
breakdown – major metabolite 5HIAA

38. 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

39. 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

40. 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

41. 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
anticonvulsants are being considered for various psychiatric disorders

43. modulatory effects

44. glutamate found in high concentrations in brain serves many functions
receptor subtypes:
tremendous work done in recent years

46. glutamate receptor subtypes: current potential interests
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?

47. Neurotransmitters and Receptors
Peptides
Opioids Mu
Delta
Kappa
Endorphins and enkephalins are opioids
Substance P