protein%20embedded%20in%20membrane

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postsynaptic receptors

• protein embedded in membrane
• mechanism for neurotransmitter to influence
  postsynaptic activity by binding to receptor

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Neurotransmitters and Receptors

• There are different varieties of receptors.
• Some respond fast
• Called Ionotropic
• Direct reaction to the transmitter

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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.

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Neurotransmitters and Receptors

• Inactivation Termination of Synaptic
  Transmission
• Metabolism
• Re-uptake

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E
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Neurotransmitters and Receptors

• Acetylcholinefirst to be recognized, because of
  peripheral actions
• Synthesis
• Acetyl-CoA (in mitochondria) choline (from diet)

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

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ACh

• found in both CNS (brain and SC) and PNS (Somatic
  and autonomic NS)

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Acetylcholine (ACh)

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

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Acetylcholine (ACh)

• cholinergic receptor subtypes
• 2 classes
• labeled by agents that act as agonists at
  receptor

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Acetylcholine (ACh)

• nicotinic muscle, neuronal - majority are
  ionotropic
• at least 17 subtypes
• some muscular some CNS
• number of nicotinic receptors are growing..

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Nicotinic drugs..

• nicotinic agonists
• varenicline (Chantix) smoking cessation
• partial agonist
• nicotinic antagonist
• botox- botulism toxin

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Acetylcholine (ACh)

• muscarinic
• 5 subtypes discovered so far all metabotropic
• (M1-M5)

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Some Pharmacological Actions for M ACh
antagonists

• scopolamine motion sickness
• some meds for asthma
• treating side effects of some PD meds

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Acetylcholine (ACh)

• ways to alter ACh activity
• AChE inhibitors
• some irreversible AChE inhibitors
• malathion, parathion, (pesticides)
• nerve gas (Sarin)
• reversible
• cognitive enhancers
• donepezil (Aricept)

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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

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Anticholinergic Side Effects

• can include confusion, blurred vision,
  constipation, dry mouth, light-headedness,
  urinary retention, loss of bladder control.

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

• Dopamine (DA)
• Norephinephrine (NE)

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catecholamines

• NE and E are synthesized from their precursor DA
  with the appropriate enzymes present

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tyrosine hydroxylase
DA decarboxylase
DA ß hydroxylase
PNMT
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How are catecholamines taken removed from the
synapse?

• Catecholamines removed by reuptake
• DAT DA transporter
• NET NE transporter

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Neurotransmitters and Receptors

• Catecholamines
• Synthesis
• Tyrosine
• Dopamine
• Norepinephrine
• Termination
• Re-uptake
• Monoamine oxidase (MAO)

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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

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• Major metabolites
• Important when trying to study potential
  differences
• DA - dopac and HVA
• NE - MHPG -(3-methoxy-4-hydroxy-phenethyleneglyco
  l)

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

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

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DA receptor subtypes

• DA receptor subtypes
• 2 major families D1 and D2 families

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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

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NE receptor subtypes

• receptor subtypes
• alpha 1 and 2 ß 1 3

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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

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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

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5HT

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

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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

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5HT

• reuptake main mechanism for terminating
• SSRIs
• breakdown major metabolite 5HIAA

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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

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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

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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

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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

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modulatory effects
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glutamate

• found in high concentrations in brain
• serves many functions
• receptor subtypes
• tremendous work done in recent years

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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?

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Neurotransmitters and Receptors

• Peptides
• Opioids
• Mu
• Delta
• Kappa
• Endorphins and enkephalins are opioids
• Substance P