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Neuropharmacology > Chapter 5: Catecholamines > Flashcards

Chapter 5: Catecholamines Flashcards

1
Q

Catcholamines

A

Part of monoamine or biogenic amine group

  • dopamine- dopaminergic
  • norepinephrine- noradrenergic
  • epinephrine- adrenergic
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2
Q

Catecholamines are synthesized from the amino acid […]

A

Tyrosine

  • is obtained from the diet (protein)
  • Transported from blood to brain
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3
Q

Tyrosine —>

A

DOPA

DOPA

Enzyme: tyrosine hydroxylase (TH)

   - rate-limiting enzyme
   - adds -OH group
   - regulated by how much DA or NE is present in nerve terminals
               - high catecholamine levels inhibit TH (negative feedback)

Cofactors: Fe2+, O2, BH4

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4
Q

DOPA —>

A

Dopamine

Enzyme: Aromatic amino acid decarboxylase (AADC)

      - nonselective
      - removes -COOH group

Cofactors: pyridoxal phosphate (vitamin B6)

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5
Q

Dihydroxyphenylalanine (L-DOPA)

A

Converted to dopamine (DA) in the brain

  • administered with peripheral decarboxylase inhibitors
  • crosses BB and then is decarboxylated
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6
Q

Dopamine —>

A

Norepinephrine

Enzyme: dopamine beta- hydroxylase (DBH)
- adds -OH group

Cofactors: Cu2+, O2, Ascorbic acid (vitamin C, reducing agent)

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7
Q

Norepinephrine —>

A

Epinephrine

Enzymes: para-N-methyltransferase (PNMT)
- adds methyl group

Cofactors: S-adenosylmethionine (SAM)
- methyl donor

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8
Q

TH is critical point in catecholamine synthesis

A
  • TH is rate-limiting enzyme
  • TH is regulated by end- product inhibition
    - negative feedback
    - more DA and DOPA, less TH activity (reduces speed)
  • Activated by phosphorylation
    - increases neural activity increases TH activity
    - PKA, PKC/ERK, CaMKII (increases Ca2+ release)
    - Ser 40, Ser 31, and Ser 19 in the regulatory domain of TH
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9
Q

Catecholamine are loaded into vesicles by […]

A

Vesicular monoamine transporter (VMAT)

Vesicular packaging- protects NT from degradation by enzymes within nerve terminals

  • blocked from DAT located on nerve terminal
  • blocked by reserpine
    - DA and NE are no longer protected from breakdown in nerve terminal
    - causes sedation in animals and depression in humans
  • energy provided by a proton gradient
    - ATP- drive H+ pump acidified vesicles lumen

VMAT 1- found in adrenal medulla
VMAT 2- in brain

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10
Q

Alpha- methyl-para-tyrosine (AMPT)

A

Depletes catecholamines by inhibiting tyrosine hydroxylase

- causes return of depressive symptoms

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11
Q

Reserpine

A

Depletes catecholamines by inhibiting vesicular uptake

  • found in snake root
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12
Q

6- hydroxydopamine (6-OHDA)

A

Damages or destroys catecholaminergic neurons

     - taken up by DAT in nerve terminals
     - interrupts oxidative phosphorylation and kills nerve terminals
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13
Q

Psychostimulants […] and […] cause release of catecholamines independently of nerve terminals

A

Psychostimulants amphetamine and methamphetamine cause release of catecholamines independently of nerve terminals

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14
Q

Release of catecholamines is decreased by […]

A

Release of catecholamines is decreased by autoreceptor activation

  • occurs when nerve impulse enters terminal vesicles to release contents into synaptic cleft through exocytosis
  • located on cell bodies, terminals, and dendrites of DA and NE neurons
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15
Q

Dopamine D2 autoreceptors

A
  • terminal autoreceptors (synapse activity)
  • inhibition of voltage-gated Ca2+ channels (reduce DA release by reducing amount of activity-mediated Ca2+ for exocytosis)
  • activation of voltage-gated K+ channels (indirectly reduce Ca2+ influx by shortening duration of AP entering terminal)
  • DA released by first few impulses stimulates terminal autoreceptors and reduces amount of DA released by later APs
  • Autoreceptors inhibit release indirectly by reducing rate of firing of cell
  • Firing pattern of neuron also influence catecholamine release
    - Tonic release of DA: single-spiking mode (cell generates APs that appear at irregular intervals but with average frequency of 4-5 Hz)
    - Phasic release of DA: burst mode (trains of 2-20 spikes at 20 Hz)
  • Both DA and NE axons form en passant synapses where fibers swell (varicosities_ along lengths filled with synaptic vesicles and represent sites of neurotransmitter release
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16
Q

Noradrenergic alpha2 autoreceptors

A
  • alpha2 agonist clondine (Catapres)
  • alpha2 antagonist yohimbine
    - antagonist- enhance rate of release by preventing normal inhibition
    - yohimbine- increase NE cell firing and NE release (can induce anxiety)
  • clinically important in opioid withdrawal and anxiety/ stress- related disorders
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17
Q

Catecholamine releases leads to […] and […] at high doses

A

Catecholamine releases leads to behavioral activation and stereotyped behavior at high doses

  • stereotyped behavior- intense sniffing, repetitive movements and licking and biting
  • comes from increasing stimulation of DA receptors from nucleus accumbens and striatum
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18
Q

Inactivation mechanisms are important targets of psychoactive substances

A

Reuptake:

  • DA transporter (DAT)
  • NE transporter (NET)
  • Na+/MA-ATPase

Enzymatic Degradation:

  • Monoamine oxidase (MAO)
    - MAO-A: NE metabolism
    - MAO-B: DA metabolism
  • Catechol-O-methyl transferase (COMT): DA metabolism
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19
Q

Metabolites

A

Breakdown products

DA metabolites:

  • homovanillic acid (HVA)
  • Dopac
  • used as rough estimate of how much DA is used

NE metabolites:

  • 3- methoxy-4-hydroxyphenylglycol (MHPG)
  • vanillymandelic acid (VMA)
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20
Q

Phenelzine (Nardil)

A

Increases catecholamine levels by inhibiting monoamine oxidase (MAO)

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21
Q

Amphetamine

A

Releases catecholamines

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22
Q

Cocaine and methylphenidate

A

Inhibit catecholamine reuptake

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23
Q

There are 2 primary groups of DA neurons, that give rise to 3 pathways

A 
Substantia Nigra (A9)
         - nigrostriatal pathway

Ventral Tegmental Area (VTA) (A10)

     - Mesolimbic pathway
     - mesocortical pathway
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24
Q

Substantia Nigra (A9)

A
  • projects to the striatum
  • nigrostriatal pathway- pathway from substantia nigra to dorsal striatum
  • substantia nigra ascend to caudate-putamen or dorsal striatum
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25
Q

Ventral tegmental area, VTA (A10)

A

Projects to lambic structures and cortex- includes nucleus accumbens, septum, amygdala, and hippocampus

  • mesolimbic pathway- has affects on prefrontal cortex
  • mesocortical pathway
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26
Q

DA cell groups and pathways

A

Substantia Nigra (A9)

  • Nigrostriatal
    - Activation
    - Motivation
    - Cognition
    - Facilitate voluntary movement

VTA (A10)

  • Mesolimbic
    - Behavioral arousal
    - Reward learning
  • Mesocortical
    - Attention
    - Working memory

Hypothalamus (A12): paraventricular nucleus—> median eminence

  • Tuberohypophyseal- collection of nerves in tubular part of hypothalamus
    - prolactin release
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27
Q

Parkinson’s disease

A

Loss of DA neurons in substantia nigra and denervation of dorsal striatum

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28
Q

Al DA receptors are […]

A

GPCRs

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29
Q

There are […] types of DA receptors

A

There are 5 types of DA receptors

D1- like:

  • D1 and D5
  • Gs coupled
  • Stimulate adenylyl cyclase activity

D2- like:

  • D2, D3, D4
  • Gi coupled
  • inhibit adenylyl cyclase activity
  • increase gk, hyperpolarize
30
Q

Nigrostriatal pathway components

A

Caudate-putamen

Globus pallidus

31
Q

Mesolimbic pathway components

A

Olfactory tubercule

Nucleus accumbens

32
Q

Mesocortical pathway components

A

Anterior olfactory nucleus
Cerebral cortex
Hippocampus
Lateral septum

33
Q

Apomorphine

A

Stimulates DA receptors general (agonist)

  • D1/ D2 agonist- promote behavioral activation
  • hyperlocomotion
  • behavioral stereotypies
  • intense sniffing
  • head bobbing
  • licking, biting
34
Q

SKF 38393

A

Stimulates D1 receptors (agonist)

  • selective D1 agonist
  • promotes grooming
35
Q

Quinpirole

A

Stimulates D2 and D3 receptors (agonist)

  • D2/ D3 agonist
  • increases exploratory behaviors- locomotion, sniffing
36
Q

SCH 23390

A

Blocks D1 receptors (antagonist)

- cataleptic

37
Q

Haloperidol

A

Blocks D2 receptor (antagonist)

  - inhibits behavioral activation - cataleptic - antipsychotic
38
Q

DA regulates […] along a continuum

A

DA regulates behavioral activation along a continuum

Lethargy—> locomotion (normal) —-> stereotypies

39
Q

Reducing DA synthesis or release impairs behavioral activation

A

AMPT blocks TH activity

Reserpine blocks VMAT

40
Q

[…] blocks TH activity

A

AMPT blocks TH activity

  • associated with relapse into depression following positive response to antidepressant medication
41
Q

Reserpine block […]

A

Reserpine block VMAT

  • sedation in animals
  • depression in humans
42
Q

Neurotoxic damage to DA neurons impairs […]

A

Neurotoxic damage to DA neurons impair behavioral activation

  • 6-OHDA selectively damages DA neurons
    - 6-OHDA is reuptaken by DAT
  • Bilateral central lesions induce:
    - sensory neglect/ processing deficits
    - motivational deficits (cease eating or drinking)
    - Parkinsonism motor deficits (loss of nigrostriatal neurons)
43
Q

Unilateral 6-OHDA lesions to the SNpc

A

Ipsilateral rotation:

  • always move towards lesioned side
  • loss of DA input to lesion side
  • DA releases behavior on the intact side

Contralateral rotation:

  • behavioral super-sensitivity
  • D2 receptor up-regulation
44
Q

VTA DA neurons involved in reward get input from […] and project to […]

VTA DA neurons involved in aversive stimuli get input from […] and project to […]

A

VTA DA neurons involved in reward get input from lateral dorsal tegmentum (LDT) and project to nucleus accumbens (NAc) [mesolimbic]

VTA DA neurons involved in aversive stimuli get input from lateral have null (LHb) and project to medial PFC (mPFC) [mesocortical]

45
Q

Behavioral deficits in KO mice are generally similar

A

TH -/- knock-out (KO)

 - lethal-loss of NE results in abnormal heart development
 - knockout at birth: die at birth

Dopamine-deficient (DD) mice

  - helps look at selectivity
  - deficient feeding, drinking, grooming, locomotor, behaviors
  - deficits can be rescued by restoring DA to the nigrostriatal pathway and caudate-put amen (dorsal striatum)
  - ability to synthesize catecholamines was lacking only in DA cells
  - DA neurons aren’t damaged; just can’t produce DA
   - DD mice lack DA throughout development bc genetic manipulations are performed at early embryonic stage
46
Q

D2 receptors are both […] and […]

A

D2 receptors are both autoreceptors and normal postsynaptic receptors

     - leads to inhibition of prolactin secretion
     - have higher affinity for DA than D1 receptors
47
Q

D1 vs D2 receptors

A
  • D1 receptors stimulate adenylyl cyclase which synthesizes cAMP
  • D2 receptors inhibit adenylyl cyclase, which decreases cAMP synthesis
  • D2 stimulate activation of G-protein that enhances K+ channel opening
48
Q

D1 and D2 receptor agonists promote […]

DA receptor antagonists suppress spontaneous behaviors ([…])

A

D1 and D2 receptor agonists promote behavioral activation
- apomorphine, SKF 38393, quinpirole

DA receptor antagonists suppress spontaneous behaviors (catalepsy)
- haloperidol, SCH 23390

49
Q

Loss of DA transmission results in behavioral super-sensitivity due to receptor up-regulation

A

6- OHDA lesions

 - ipsilateral rotation
 - contralateral rotation when challenged with apomorphine

Chronic D2 antagonist

   - haloperidol
   - behavioral supersensitivity
50
Q

Receptor Up-Regulation

A

Lack of normal NT input causes neurons to increase sensitivity by making more receptors

51
Q

Behavioral Supersensitivity

A

Haloperidol treatment stopped to unblock D2 receptors and subjects are given DA agonists, they respond more strongly than controls not treated with haloperidol

  • 6-OHDA can also cause behavioral sensitivity
    - long-lasting depletion of DA
52
Q

DA: sedation, catalepsy

A
  • AMPT
  • reserpine
  • 6- OHDA
  • SCH 23390, D1
  • haloperidol, D2
53
Q

Hyperlocomotion, behavioral stereotypies

A
  • amphetamine
  • cocaine, methylphenidate
  • apomorphine, D1/ D2
  • SKF 38393, D1
  • quinpirole, D2/ D3
54
Q

NE- containing neurons are found in parts of brain stem called […] and […]

A

NE- containing neurons are found in parts of brain stem called pons and medulla

55
Q

Central NE arises from the […]

A

Central NE arises from the locus coeruleus (A6)

  • nearly all the NE innervation to cortex, diencephalon, lambic system, cerebellum, spinal cord, thalamus and hypothalamus
56
Q

NE neurons in Sympathetic NS

A

Autonomic ganglia

Chromaffin cells of the adrenal medulla

57
Q

LC NE neuron firing=

A

LC NE neuron firing= arousal

  • Projections from LC to medial septal, medial preoptic, and lateral hypothalamus areas have been implicated in wakefulness- promoting effects of NE
58
Q

There are […] groups of adrenergic receptors

A

There are 2 groups of adrenergic receptors

  • Alpha and beta
59
Q

Alpha- AR

A
  • a1 Gq- couples to phospholipase C (PLC)
    - increase [Ca2+]i
  • a2 Gi- coupled to adenylyl cyclase
    - decrease cAMP
    - terminal autoreceptor
    - cause inhibition of noradrenergic cell firing and reduction in NE release from terminals
60
Q

Beta- AR

A

Beta1 and Beta2

Both B1 and B2 are Gs- coupled to adenylyl cyclase
- increase cAMP

61
Q

Adrenoreceptors

A

Founds in cerebral cortex, thalamus, hypothalamus, and cerebellum, hippocampus, and amygdala

62
Q

Phenylephrine

A

Stimulate a1- receptors (agonist)

63
Q

Clonidine

A

Stimulates a2- receptors (agonist)

64
Q

Prazosin

A

Blocks a1- receptors (antagonist)

65
Q

Yohimbine

A

Blocks a2- receptors (antagonist)

66
Q

Propranolol

A

Blocks B-receptors generally (antagonist)

67
Q

Adrenergic agonists in the LH promote […]

A

Adrenergic agonists in the LH promote wakefulness

  • Phenylephrine
  • Isoproterenol
68
Q

Phenylephrine

A

a1- AR agonist

  • reduced time in slow-wave and REM
  • increased time awake
69
Q

Isoproterenol

A

Non-selective B-AR agonist

  • increased wake-time/ reduced REM
  • no effect on slow-wave
70
Q

Adrenergic input to the PFC can improve or impair […]

A

Adrenergic input to the PFC can improve or impair working memory

  • a2-AR
    - high affinity for NE
    - improves performance
  • a1- AR
    - low affinity for NE
    - impairs performance
71
Q

a2- AR agonists

A
  • guanfacine and clonidine

- improve performance on delayed response task

72
Q

Noradrenergic control of […]

A

Noradrenergic control of emotional memory

Passive avoidance learning
- foot shock induces fear/ stress

EPI and GC’s released from the adrenal glands; NE from LC

    - EPI activates B-AR’s on vagaries afforestation and in liver
    - CNS NE potentiates central fear/ anxiety mechanisms

*info transmitted by vagus could reach LC and engage memory mechanisms by stimulating release of central NE

Neuropharmacology (15 decks)

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