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Neuro-pharmacology > orexigenic peptides > Flashcards

orexigenic peptides Flashcards

1
Q

orexigenic peptides

A

Peptides having an orexigenic effect – stimulating the appetite or
increasing food intake

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2
Q

Orexigenic peptides Most originally identified in the

A

– esp as GI
hormones

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3
Q

Orexigenic peptides Many function as both

A

peptide hormones and as
neuromodulators in the CNS

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4
Q

Many function as both peptide hormones and as
neuromodulators in the CNS (3)

A
  • Neuropeptide Y
  • Ghrelin
  • Orexins
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5
Q
  • Gut-brain axis is responsible for
A

control
of energy homeostasis

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6
Q

GUT TO THE BRAIN

A

Microbial-derived signalling molecules
Immune mediators
(cytokines)
Gut hormones
Vagal afferents
Spinal afferents

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7
Q

brain to gut

A

Sympathetic efferents
Parasympathetic efferents
Neuroendocrine
- Adrenal cortex
- Adrenal
medulla

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8
Q

Leptin

A

NOT a neuropeptide

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9
Q

Leptin Obese mice (ob
/ob) carried a
recessive mutation leading to
spontaneous hyperphagy and weight
gain
* Later identified as a

A

mutation in the
leptin gene

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10
Q

Leptin is

A

orexilytic

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11
Q

orexilytic

A

increases apetite

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12
Q

Leptin is a 16 kDa (167 amino acids) protein hormone released from

A

adipose tissue to attenuate appetite

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13
Q

Leptin Release signals from site of energy storage to

A

decrease caloric
intake

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14
Q

Leptin receptors are found in the

A

arcuate nucleus of the
hypothalamus (main site of action)

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15
Q

Inability to signal satiety in ob/ob mice leads to

A

constant hunger

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16
Q

Neuropeptide Y
(NPY) Expressed from the NPY gene as

A

preproNPY

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17
Q

NPY expression is highest in the

A

arcuate nucleus of the
hypothalamus

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18
Q

Orexigenic effects of NPY

A

IV administration of NPY increases food intake in rodents

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19
Q

Agonists of NPY increase

A

food intake

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20
Q
  • IV administration of NPY increases food intake in rodents Hypothalamus has increased permeability of the BBB for
A

monitoring of
blood-borne hormones and release of hypothalamic hormones

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21
Q

Antagonists of NPY receptors

A

decrease food intake

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22
Q

Antagonists of NPY receptors decrease food intake 5 types of NPY GPCRs

A

NPYR 1,5 are orexigenic
* NPYR 2,4 are autoreceptors (selective agonists decrease food intake)

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23
Q

NPY and obesity

A

Genetically obese mice tend to have high levels of
NPY in the hypothalamus

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24
Q

NPY interacts with

A

environmental stress

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25
Q

NPY interacts with environmental stress Monkeys subject to chronic stress show

A

increased NPY
levels

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26
Q

Chronic stress and a high calorie diet lead to increased

A

abdominal adipose deposits (trunk obesity)

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27
Q

Therapeutic potential of NPY

A

NPY, as with other neuropeptides, has poor pharmacokinetics

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28
Q

NPY, as with other neuropeptides, has poor pharmacokinetics * Short

A

half-life in circulation

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29
Q
  • NPY, as with other neuropeptides, has poor pharmacokinetics IV administration
A

required (peptides are both highly hydrophilic and
sensitive to acid hydrolysis)

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30
Q

NPY receptor antagonism leads to

A

transient effects on NPY
signalling

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31
Q

NPY receptor antagonism leads to transient effects on NPY
signalling Short-term

A

efficacy only – NPY levels readily compensate for changes

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32
Q

NPY receptor antagonism leads to transient effects on NPY
signalling Pharmacodynamic

A

tolerance

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33
Q

Ghrelin (GHRL)

A

GHRL gene expresses preproghrelin and obestatin (which may not have
much to do with obesity)

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34
Q

GHRL functions as a classic

A

gastrointestinal hormone and is released from
the GI to stimulate hunger

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35
Q
  • GHRL is released constitutively but is inhibited by
A

a mechanosensitive process
when the stomach is stretched

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36
Q

GHRL release

A

stimulates hunger (orexigenic) and inhibition attenuates hunger

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37
Q

Ghrelin acts at the growth hormone
secretagogue type 1A receptor

A

(GHSR)

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38
Q

GHSR is expressed widely in the

A

periphery (esp. vagus nerve) and in
the CNS on NPY secreting cells of the
arcuate nucleus of the hypothalamus.

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39
Q

GHSR activation leads to

A

secretion of
NPY

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40
Q

Orexigenic effects of ghrelin

A
  • Systemic administration of ghrelin
    increases food intake
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41
Q

Gastric bypass surgery

A

decreases
ghrelin levels in obese patients

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42
Q

Ghrelin also interacts with

A

numerous aspects of mood, stress,
and diet to affect food intake

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43
Q

Ghrelin increases

A

hedonic aspects
of food intake

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44
Q

GHSR expression in the CNS in addition to the hypothalamus, GHSR is expressed in

A

the ventral tegmental area, substantia nigra, raphe
nuclei, hippocampus (dentate gyrus)

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45
Q

Ghrelin has pronounced effects on the

A

e mesolimbic
cholinergic-dopaminergic reward network

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46
Q

Ghrelin has pronounced effects on the mesolimbic
cholinergic-dopaminergic reward network

A
  • Natural role for ghrelin in signalling reinforcing aspects of
    food reward
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47
Q

Posttranslational
modification of
GHRL

A

Ghrelin is modified at the S3 position
by a medium
-chain fatty acid
(octanoic acid)

48
Q

Ghrelin is modified at the S3 position
by a medium
-chain fatty acid
(octanoic acid) Enzyme responsible for acylation is

A

O
-acyltransferase (GOAT).

49
Q

GOAT activity

A

increases after intake of
medium
-chain fatty acids in the diet
–
leading to increased acylation of
ghrelin and increasing huger stimuli.

50
Q

Ghrelin and sleep Ghrelin release follows a

A

circadian rhythm

51
Q

Ghrelin release follows a circadian rhythm Increases near

A

expected meal times

52
Q

Ghrelin release follows a circadian rhythm Slow, steady increase from

A

midnight to dawn

53
Q

Ghrelin is co-expressed with

A

circadian clock proteins in the gut

54
Q

Ghrelin expression has a

A

negative correlation with sleep time

55
Q

Decreased sleep leads to

A

elevated ghrelin

56
Q

ncreased sleep leads to

A

decreased ghrelin

57
Q

Sleep disruption can

A

disrupt ghrelin rhythms leading to increased ghrelin levels

58
Q

Sleep disruption can disrupt ghrelin rhythms leading to increased ghrelin levels

A

Sensitive to light levels during sleep phase (lights, light pollution, possibly backlit screens)

59
Q

Long-term changes in ghrelin Ghrelin release is also inversely proportional to

A

body weight

60
Q

Weight loss leads to

A

increased ghrelin release

61
Q

Weight gain leads to

A

decreased ghrelin release

62
Q

Ghrelin release is also inversely proportional to body weight Proposed to be an endogenous mediator of

A

weight and
energy stores

63
Q

stress eating

A

Ghrelin release increases with stress

64
Q

Ghrelin as a potential therapeutic target

A
  • Ghrelin is interesting as a target for obesity treatment
65
Q

obesity vaccine’ has been demonstrated in pigs

A

mmune reaction against GHSR

66
Q

Increased ghrelin levels correlate with antidepressant
and

A

anxiolytic effects

67
Q

Increased ghrelin levels correlate with antidepressant
and anxiolytic effects

A
  • High potential for side effects on mood
68
Q

GHRL and addictions

A

Ghrelin is involved in reinforcing aspects of food

69
Q

Ghrelin also involved in signalling reinforcing aspects of

A

alcohol

70
Q

Ghrelin also involved in signalling reinforcing aspects of alcohol

A

Expected as alcohol is also a high calorie vice

71
Q
  • Ghrelin has been shown to modulate
A

addictive behaviours in response to
non-caloric substances

72
Q

Ghrelin administration increases motivation to

A

self-administer heroin

73
Q

Ghrelin antagonists reduce the behavioural response to

A

cocaine and nicotine

74
Q

Measuring motivation
Progressive ratio schedule

A

an increasing response requirement for reinforcer delivery over successive sessions

75
Q

Measuring motivation Breaking point

A

The highest completed ratio of demand to response
is termed the break point

76
Q

Break point reflects motivation

A

amount of work
willing to perform to achieve reward

77
Q

Ghrelin and break point

A

Ghrelin administration increases the break point of
heroin self-administration

78
Q

Ghrelin and conditioned place preference

A

Ghrelin administration alone can induce a CPP in
animal models

79
Q

Orexin / hypocretin Two peptides

A

(orexin A/B or hypocretin 1/2) formed from a
single prepropeptide off the HCRT gene

80
Q

Orexin-secreting neurons are
found in the

A

lateral
hypothalamus but extensively
innervate the brain and spinal
cord.

81
Q

Orexin functions Orexigenic

A

Orexin neurons are downstream of ghrelin and leptin sensitive neurons of the arcuate nucleus

82
Q

Ghrelin & NPY stimulate

A

orexin release

83
Q

Leptin & CART inhibit

A

orexin release

84
Q

Orexin k/o mice show no

A

orexigenic effects of ghrelin administration

85
Q

Orexin functions Sleep

A

Proposed to link sleep and metabolism

86
Q

Long-term sleep deprivation (in rodents) increases

A

s food intake and energy metabolism (with
eventual lethal consequences)

87
Q

Orexin administration stimulates

A

wakefulness

88
Q

Orexin and narcolepsy Orexin receptors were identified as a common cause of

A

canine
narcolepsy

89
Q
  • Orexin receptors were identified as a common cause of canine
    narcolepsy
A

Receptor loss-of-function mutation leads to decreased function of
orexin

90
Q

Orexin and narcolepsy * A common cause of narcolepsy is a mutation in the

A

HLA antigen
leading to autoimmune disease against orexin neurons

91
Q

Knockout mice for orexin develop

A

narcolepsy

92
Q

Orexins and wakefulness

A

Orexinergic neurons receive indirect input from suprachiasmic nucleus (SCN) – important in
circadian rhythms

93
Q

Orexin projects to systems involved in wakefulness (4)

A
  • Locus ceruleus norepinephrine systems
  • Dorsal raphe seratonin systems
  • Tuberomamillary histamine systems
  • Basal forebrain cholinergic system (BFCS)
94
Q

Locus ceruleus

A

norepinephrine systems

95
Q

Dorsal raphe

A

seratonin systems

96
Q

Tuberomamillary

A

y histamine systems

97
Q

Orexin activity increases just before

A

e waking, orexin neurons are more active during wake period
than sleep

98
Q

In mouse models optogenetic stimulation of orexin neurons cause

A

waking within several second

99
Q

Pharmacological target for sleep disorder Suvorexant

A

an OX receptor antagonist (dual orexin receptor
antagonists, DORA) for insomnia treatment
- contraindicated in patients with narcolepsy

100
Q

Almorexant

A

a DORA developed by GlaxoSmithKline –
discontinued in 2011 during phase III trials for unspecified reasons (likely
adverse side effects)

101
Q

Orexins and addictions

A

As with the other orexigenic peptides, orexin is implicated in addictions

102
Q

As with the other orexigenic peptides, orexin is implicated in addictions - Expected as the systems interact in the

A

ARC of hypothalamus

103
Q

As with the other orexigenic peptides, orexin is implicated in addictions Interactions with the

A

dopaminergic reward pathways in VTA

104
Q
  • OX receptor antagonists decrease
A

self-administration of alcohol, opiates,
nicotine

105
Q

Administration of orexin into the lateral hypothalamus results in

A

increased
alcohol consumption or reinstatement of extinguished alcohol or nicotine
seeking

106
Q

Orexins and emotional memory Orexinergic neurons receive inputs from the

A

limbic system

107
Q

Orexinergic neurons receive inputs from the limbic system

A

Modulate physiological responses to emotional stimuli

108
Q
  • Orexin k/o mice show
A

decreased responses to intruder mice, air-jet stress

109
Q

OX receptor antagonists

A

decrease cue-conditioned fear responses

110
Q

Human narcolepsy patients show

A

diminished autonomic responses to emotional
stimuli, esp. aversive

111
Q
  • Altered orexin levels observed in patients with
A

anxiety or PTSD

112
Q

Orexins and emotional memory Proposed to maintain

A

n wakefulness in response to emotional arousal via limbic
inputs

113
Q

Orexins in motivational activation

A

Orexins interact with systems involved in both wakefulness/arousal and reward, motivation, and
salience (dopamine!)

114
Q

Roles of orexin in food intake and wakefulness suggest

A

involvement in motivational activation

115
Q

Phasic orexin activity increases during

A

adaptive behaviour

116
Q

During food deprivation orexin stimulates

A

food seeking behaviour

117
Q

Orexins facilitate reward seeking only when

A

motivated by an underlying physiological (e.g. hunger)
or psychological need (e.g. cues, stressors)

Neuro-pharmacology (26 decks)

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