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Chapter 5 Opener. 5.1 Structural features of catecholamines. How enzymes affect the molecule Hydroxylase adds a hydroxyl group (OH) Decarboxylase removes a carboxyl group (COOH). 5.2 Catecholamines are synthesized in a multi-step pathway . Synthesis of the catecholamines.

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slide3
How enzymes affect the molecule
    • Hydroxylase adds a hydroxyl group (OH)
    • Decarboxylase removes a carboxyl group (COOH)
synthesis of the catecholamines
Synthesis of the catecholamines
  • Begins with the amino acid tyrosine
  • Obtained from dietary protein
  • Transported from blood to the brain
  • Dopamine neurons
    • contain only the first two enzymes
      • Tyrosine hydroxylase (TH)
      • Aromatic amino acid decarboxylase (AADC)
  • Norepinephrine neurons
    • Also contain
      • Dopamine β-hydoroxylase (DBH)
slide6
Conversion of tyrosine to DOPA is the slowest
    • Thus, tyrosine hydroxylase (TH) is the rate limiting enzyme.
      • Lots of DA or NE in a cell inhibits TH
      • High firing rates increases TH
drugs that affect synthesis
Drugs that affect synthesis
  • Catecholamine formation can be increased by administration of a biochemical precursor
    • L-DOPA
    • Treatment for Parkinson’s Disease
  • Drugs that reduce catecholamine synthesis
    • Inhibit a synthesizing enzyme
    • AMPT (α-methyl-para-tyrosine)
      • Blocks TH (tyrosine hydroxylase)
      • Depletes catecholamines
      • Causes return of depressive symptoms in patients treated with antidepressants
drugs that affect storage
Drugs that affect Storage
  • Catecholamines are stored in and released from synaptic vesicles
    • Provides a means of release
      • Several thousand molecules per vesicle
    • Protects neurotransmitter from degradation by enzymes in the terminal button.
slide9
VMAT
  • Vesicular monoamine transporter (VMAT)
    • A protein in the membrane of the vesicle
    • Pulls catecholamines into the vesicle
  • Reserpine blocks VMAT
    • DA and NE are thus not encased in a vesicle
      • Broken down by enzymes
      • Low levels of DA and NE
    • Causes sedation in animals
    • Depressive symptoms in humans
      • Effects can be reversed with DOPA
        • Led to the catecholamine theory of depression
        • Depression – too little catecholamine activity
drugs that affect release of catecholamines
Drugs that affect release of catecholamines
  • Normally nerve impulse reaches the terminal button
    • Causes exocytosis
  • Some drugs cause exocytosis independently of nerve firing
    • amphetamine and methamphetamine
    • Causes behavioral activation
      • Notice opposite effect of reserpine
    • Can cause stereotypy at high doses
      • Sniffing, licking, biting, repetitive head movement
  • In humans
    • increased alertness
    • energy
    • euphoria
    • insomnia
drugs that affect autoreceptors
Drugs that affect autoreceptors
  • Work by inhibiting the amount of Ca++ that enters the terminal button in response to an action potential reaching the terminal button
    • Less DA or NE released when next action potential arives
  • D2 = DA autoreceptor
  • α2 = NE autoreceptor
    • Agonists of these receptors = decrease release
    • Antagonists of these receptors = increase release
drugs that affect the transporter
Drugs that affect the transporter
  • Transporters cause reuptake from the synapse
    • The neurotransmitter is then either repackaged in vesicle, or broken down by enzymes
  • Transporter blocking drugs
    • Tricyclic antidepressants
    • SSRIs
    • NSRIs
    • cocaine
drugs that affect metabolizing enzymes that break down catecholamines after reuptake
Drugs that affect metabolizing enzymes that break down catecholamines after reuptake
  • Catechol-O-methyltransferase (COMT)
  • Monoamine oxidase (MAO)
  • Breakdown of DA
    • Homovanillic acid (HVA)
  • Breakdown of NE
    • 3-methoxy-4-hydroxy-phenylglycol (MHPG)
  • Concentrations of these metabolites in blood and urine play a role in determining the involvement of DA and NE in mental disorders (e.g., depression and schizophrenia).
mao and comt inhibitors
MAO and COMT inhibitors
  • MAO inhibitors
    • used to treat depression
  • COMT inhibitors
    • Often prescribed with L-DOPA in Parkinson’s disease to prevent the break down of L-DOPA prior to reaching the brain.
the a system from the swedes
The A system = from the Swedes
  • A = cells that stain for NE or DA
  • A 1-7 = noradrenergic
  • A 8-16 = dopaminergic
organization of the da system
Organization of the DA system
  • Three main pathways
    • 1. Nigrostratal tract (movement)
      • Starts in A9 – substantia nigra (in mesencephalon)
      • projects to the striatum (caudate and putamen).
slide24
2. Mesolimbic dopamine pathway (reward)
    • Starts in A10 – ventral tegmental area (in mesencephalon.
    • Projects to limbic system (in particular nucleus accumbens and olfactory tubercules).
slide26
3. Mesocortical dopamine pathway (reward)
    • Starts in A10 – VTA
    • To cortex (primarily prefrontal cortex)
5 subtypes of dopamine receptors
5 subtypes of dopamine receptors
  • D1 like
    • D1 and D5
  • D2 like
    • D2, D3, and D4
  • All are metabotropic receptors
  • Both families are largely found in the striatum and nucleus accumbens
d1 and d2 effects on camp
D1 and D2 effects on cAMP
  • In general, increased postsynaptic DA receptor stimulation decreases nigrostriatal DA activity
    • D1 and D2 receptors work together
      • Synergistic relationship
slide30
D1
  • D1 activation – Gs protein
    • increases cAMP synthesis
    • D1 receptor activation may be necessary for full expression of D2 effects
slide31
D2
  • D2 activation – Gi protein
    • decreases cAMP synthesis
    • Autoreceptors inhibit DA synthesis and release
    • Post synaptic receptors slow firing rate
      • Inhibition of Ca++ entry
      • Opening of K+ channels
slide33
Agonists
    • D1
      • SKF 38393 – elicits grooming behavior
    • D2
      • Quinpirole – locomotion and sniffing
  • Antagonists
    • D1
      • SCH 23390 – decreased activity
    • D2
      • Haloperidol – decreased activity
ascending noradrenergic system
Ascending noradrenergic system
  • Starts in the pons and medulla
    • A6 – locus coeruleus
  • Axons extend throughout the forebrain
    • Also cerebellum and spinal cord
slide37
Sleeping or inactive rats
    • Slow firing of cells in LC
  • Novel sensory stimuli
    • Fast firing of cells in LC
  • Thus, LC may play a role in vigilance
    • Being alert to stimuli in the environment
slide39
α and β receptors
    • β1 and β2 receptors are like D1
    • α2 similar to D2
    • α1 works somewhat differently – phosphoinositide second messenger
  • Adrenergic agonists increase arousal and eating behavior
  • Adrenergic antagonists
    • Treat hypertension = α1
    • Impotence = α2
      • Increase parasympathetic; decrease sympathetic
    • Generalized anxiety disorder = β blockers
      • Reduce sympathetic response
slide40
α and β receptors
    • β1 and β2 receptors are like D1 – increase cAMP
    • α2 similar to D2 – decrease cAMP
    • α1 works somewhat differently – phosphoinositide second messenger
  • Adrenergic agonists increase arousal
    • Animals sleep less
  • Adrenergic antagonists
    • Treat hypertension = α1
    • Impotence = α2
      • Increase parasympathetic; decrease sympathetic
    • Generalized anxiety disorder = β blockers
      • Reduce sympathetic response
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