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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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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)


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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


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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.


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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




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Drugs that affect release of catecholamines depressant effects of reserpine

  • 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


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Drugs that affect autoreceptors depressant effects of reserpine

  • 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



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Drugs that affect the transporter on the membrane of its terminals

  • 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



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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).


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MAO and COMT inhibitors catecholamines after reuptake

  • 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.


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The A system = from the Swedes catecholamines after reuptake

  • A = cells that stain for NE or DA

  • A 1-7 = noradrenergic

  • A 8-16 = dopaminergic


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Organization of the DA system catecholamines after reuptake

  • Three main pathways

    • 1. Nigrostratal tract (movement)

      • Starts in A9 – substantia nigra (in mesencephalon)

      • projects to the striatum (caudate and putamen).





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  • 2. Mesolimbic dopamine pathway (reward) Dopaminergic Neurons? (Part 2)

    • Starts in A10 – ventral tegmental area (in mesencephalon.

    • Projects to limbic system (in particular nucleus accumbens and olfactory tubercules).



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5 subtypes of dopamine receptors pathways (Part 3)

  • 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


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D1 and D2 effects on cAMP pathways (Part 3)

  • In general, increased postsynaptic DA receptor stimulation decreases nigrostriatal DA activity

    • D1 and D2 receptors work together

      • Synergistic relationship


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D1 pathways (Part 3)

  • D1 activation – Gs protein

    • increases cAMP synthesis

    • D1 receptor activation may be necessary for full expression of D2 effects


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D2 pathways (Part 3)

  • 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


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5.9 Signaling mechanisms of D pathways (Part 3)1 and D2 receptors


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  • Agonists pathways (Part 3)

    • D1

      • SKF 38393 – elicits grooming behavior

    • D2

      • Quinpirole – locomotion and sniffing

  • Antagonists

    • D1

      • SCH 23390 – decreased activity

    • D2

      • Haloperidol – decreased activity



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Ascending noradrenergic system pathways (Part 3)

  • Starts in the pons and medulla

    • A6 – locus coeruleus

  • Axons extend throughout the forebrain

    • Also cerebellum and spinal cord



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  • Sleeping or inactive rats noradenergic neurons

    • 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



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  • α noradenergic neuronsand 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


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  • α noradenergic neuronsand 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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