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PSYCH 478 > Orexigenic Peptides > Flashcards

Orexigenic Peptides Flashcards

1
Q

Peptides having an orexigenic effect do what

A

Stimulates appetite or increases food intake

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2
Q

Where are most orexigenic peptides identified and what do they function as in the CNS

A
  • most originally identified in the periphery-> esp as GI hormones
  • functions as both peptide hormones and as neuromodualtors-> neuropeptide Y, Ghrelin, Orexins
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3
Q

What is responsible for the control of energy homeostasis

A

Gut-brain axis

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4
Q

True or false: leptin is a neuropeptide

A

false

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5
Q

true or false: leptin is 16kDa (167 amino acids) protein hormone released from adipose tissue to reduce appetite

A

true

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6
Q

where are the leptin receptors found

A

in the arcuate nucleus of the hypothalamus (main site of action)

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7
Q

what does the inability to signal satiety in mice with a mutation to the leptin gene (ob/ob) lead to?

A

constant hunger

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8
Q

where was neuropeptide y (NPY) identified and is expressed from the NPY gene as _______

A

-in the porcine hypothalamus
- preproNPY

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9
Q

where is NPY highly expressed in

A

in the arcuate nucleus of the hypothalamus

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10
Q

what does IV administration of NPY do to rodents

A

increases food intake

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11
Q

_________ has increased permeability of the BBB from monitoring of blood-borne hormones and release of hypothalamic hormones

A

hypothalamus

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12
Q

true or false: agonists of NPY decrease food intake

A

false: increase

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13
Q

what are the receptors of NPY

A

5 types of NPY GPCRs

  • NPYR 1,5 are orexigenic (most important ones)
  • NPYR 2,4 are autoreceptors (selective agonists decrease food intake)
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14
Q

where do genetically obese mice tend to have high levels of NPY in

A

the hypothalamus

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15
Q

true or false: NPY interacts with environmental stress

A

true

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16
Q

______ ______ and __ _____ ______ _____ leads to an increase in abdominal adipose deposits (trunk obesity)

A

Chronic stress; a high calorie diet

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17
Q

True or false: just like other neuropeptides, NPY has good pharmacodynamic

A

false; poor

short half-life circulation

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18
Q

what is required for NPY

A

IV administration since peptides are both highly hydrophilic and sensitive to acid hydrolysis

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19
Q

what does NPY receptor antagonism lead to

A

transient effects on NPY signalling and has pharmacodynamic tolerance

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20
Q

what is meant by short-term efficacy only

A

NPY levels readily compensate for changes

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21
Q

Gherlin (GHRL) gene expresses what

A

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

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22
Q

what does GHRL function as, when does it release, and what does the release result in

A
  • functions as a classic gastrointestinal hormone and is released from the GI to stimulate hunger
  • is released constitutively but inhibited by a mechanosensitive process when the stomach is stretched/ full
  • release stimulates hunger and inhibition attenuates hunger
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23
Q

what does GHRL act at and what is identified as

A
  • acts at the growth hormone secretagogue type 1A receptor (GHSR)
  • identified as an endogenous agonist for the GHSR
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24
Q

GHSR is widely expressed in the _________ (esp the vagus nerve) and in the ________ on ______ ___________ ______ of the arcuate nucleus

A
  • periphery
  • CNS
  • NPY secreting cells
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25
Q

what activation leads to secretion of NPY

A

GHSR

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26
Q

what kind of administration of ghrelin increases food intake and what does gastric bypass surgery do

A
  • systematic

-decreases ghrelin levels in obese patients

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27
Q

what does ghrelin also interact with and what does ghrelin increase

A
  • interacts with numerous aspects of mood, stress, and diet to affect food intake
  • increases hedonic aspects of food intake

hedonic- emotional eating/ comfort food

28
Q

in addition to the hypothalamus, where else is Gherlun expressed in and what area does it have pronounced effects on

A
  • ventral tegmental area, substantia nigra, raphe nuclei, hippocampus (dentate gyrus)
  • mesolimbic cholinergic-dopaminergic reward network
29
Q

what is the natural role of gherlin

A

the signal reinforces aspects of food reward

30
Q

What is the enzyme responsible for acylation of ghrelin? Where does it occur?

A

GOAT; at S3 position by a medium-chain fatty acid

31
Q

GOAT actigvity _______ after intake of medium-cahin fatty acids in the diet - leading to _____________ acylation of ghrellin and _____________ hunger stimuli.

A

increases; increased; increasing

32
Q

Describe the circadian rhythm of ghrelin.

A
  • increase near expected meal times
  • slow, steady increase from midnight to dawn
  • co-expressed with circadian clock proteins in the gut
33
Q

Ghrelin expression has a ___________ correlation with sleep time. Decreased sleep leads to __________ ghrelin. Increased sleep leads to ___________ ghrelin.

A

negative; elevated; decreased

34
Q

Sleep disruption can disrupt ghrelin rhythms leading to ____________ ghrelin levels.

A

increased

35
Q

TRUE or FALSE: if you are exposed to light during sleep phase, ghrelin will decrease

A

FALSE: it will spike/increase

36
Q

TRUE or FALSE: ghrelin release is proportional to body weight

A

FALSE: inversely proportional

i.e. lose weight = increased ghrelin
i.e. gain weight = decrease ghrelin

37
Q

Which hormone is proposed to be an endogenous mediator of weight and energy stores?

A

ghrelin

38
Q

TRUE or FALSE: ghrelin release increases with stress

A

TRUE

39
Q

What is a potential therapeutic target for obesity? What are the side effects? What animal was it demonstrated in?

A
  • ghrelin
  • if we decrease ghrelin, could lead to depression and anxiety
  • pigs –> immune reaction against GHSR
40
Q

How is GHRL implicated in addictions?

A
  • ghrelin signals reinforcing aspect of alcohol (high calorie)
  • ghrelin administration increases motivation to self-administer heroin
  • ghrelin antagonists reduce the behavioural response to cocaine and nicotine
41
Q

Describe the operant conditioning apparatus. What is it used to study?

A
  • modified Skinner box
  • IV or oral self-administration
  • operant training for drug/substance reward
  • animals have catheter implanted into jugular and affixed to infusion pump
  • lever press results in dose of drug of choice
  • used to study MOTIVATION to self-administer
42
Q

How do you measure motivation?

A
  • progressive ratio schedule –> response demand is increased progressively starting from 1
  • determine breaking point (highest completed ratio of demand to response)
  • break point reflects motivation - amount of work willing to perform to achieve reward
43
Q

How does ghrelin affect break point of heroin self-administration?

A

increases break point

44
Q

Describe the conditioned place preference.

A
  • Pavlovian conditioning paradigm
  • drug injection paired with neutral envvironemtnal stimulus to create conditioned stimulus
  • 2-3 chamber conditioning box
  • 3 phase CPP protocol (pre-, conditiong, post-)

(see slide 23)

45
Q

How does ghrelin affect CPP in animal models?

A

ghrelin administration alone can induce a CPP in animal models

46
Q

Orexin A/B are formed from a single __________ off the ________ gene.

A

prepropeptide; HCRT

47
Q

Where are orexin-secreting neurons found?

A

lateral hypothalamus (but extensively innervate brain and spinal cord)

(see diagram on slide 25 for details on input and output areas)

48
Q

What are the functions of orexin?

A
  • orexigenic (food)
  • sleep
49
Q

How doe ghrelin, NPY, leptin, and CART affect orexin?

A
  • ghrelin and NPY stimulate orexin release
  • leptin and CART inhibit orexin release
50
Q

How do we know that ghrelin and NPY do not directly lead to increased eating?

A
  • orexin K/O mice show no orexigenic effects of ghrelin administration
  • i.e. need to active orexin to increase eating
51
Q

How does orexin affect sleep?

A
  • link sleep and metabolism
  • orexin adminstration stimulates wakefulness
52
Q

How does long-term sleep deprivation affect food intake and metabolsim?

A

increase food intake and energy metabolism

53
Q

Receptor ______________ mutation leads to decreased funtion of orexin, leading to __________.

A

loss-of-function; narcolepsy

54
Q

A common cause of narcolepsy is a mutation in the ___________leading to ___________________ against ________.

A

HLA antigen; autoimmune disease; orexin neurons

55
Q

where does oreixigenic neurons receive indirect input from?

A

SCN

56
Q

Where does oreixn project to for wakefulness?

A
  • Locus ceruleus norepinephrine systems
  • Dorsal raphe seratonin systems
  • Tuberomamillary histamine systems
  • Basal forebrain cholinergic system (BFCS)
57
Q

When does orexin activity increae? When is it more active?

A
  • increase just before waking
  • active during wake (vs. sleep)
58
Q

What is suvorexant?

A

dual OX receptor antagonist (DORA) for insomnia treatment

59
Q

What is almorexant?

A

dual OX receptor antagonist (DORA) discontinued in 2011 during phase III trials

60
Q

How are orexins implicated in addiction?

A
  • orexin increases consumption in animals that are already addicted, but not creation of new addiction
  • intreact with dopaminergic reward paths in VTA
  • OX receptor ANTAGONSITS decrease self-administration of alcohol, opiates, nicotine
61
Q

Administration of orexin into the lateral hypothalamus results in _____ alcohol consumption or _________ of extinguished alcohol or nicotine seeking

A

increased; reinstatement

62
Q

How are orexins implicated in emotional memory? (reword this question)

A
  • orexinergic neurons receive inputs from limbic system
  • orexin K/O mice show decreased response to stress/fear stimuli
  • human narcolepsy patients show diminished autonomic responses to emotional stimuli
  • altered orexin levels with anxiety/PTSD
  • KEY: proposed to maintain wakefulness in response to emotional arousal via limbic inputs
63
Q

How are orexins implicated in motivational activation?

A

ghrelin act on motivation itself; orexin is not a motivator itself, but it play a role during food intake and wakefulness

64
Q

phasic orexin activity increases during ________________ ___________.

A

adaptive behaviour

65
Q

orexins facilitate reward seeking only when motivated by _____________.

A

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

PSYCH 478 (28 decks)

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