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Neurobiology of Disease > Exam 3 > Flashcards

Exam 3 Flashcards

1
Q

Two competing theories of depression

A

Monoamine Depletion Theory and the receptor sensitivity hypothesis

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2
Q

Due to the widespread nature of mood disorders, many studies focus on the role of these pathwasy

A

Diffuse modulatory systems

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3
Q

Bipolar disorder is also called

A

manic-depressive disorder

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4
Q

Depression is the leading cause of

A

suicide

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5
Q

This is the Milder form of depression

A

dysthymia

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6
Q

Mood v emotion

A

Mood = predominant emotional state over time

Emotion- transient response

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7
Q

Mood disorders are characterized by

A

1) feeling emotional state is no longer under control

2) fluctuates spontaneously with no link to stressful events

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8
Q

Mood disorders have a general tendency

A

towards progression

early episodes precipitated by psychosocial stress, but later ones happening spontaneously

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9
Q

Key evidence supporting monoamine depletion theory f depression:

A

1) Reserpine– block VMAT2 transporter and depletes serotonin levels, which causes depression
2) Tricyclic Antidepressants– inhibit SERT/NET, thus increasing amount of NT in the synapse and prolonging its effect
3) MAOI (monoamine oxidase inhibitors)– inhibit a degradation enzyme for monoamine

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10
Q

How to increase 5-HT in brain?

A

Eat more tryptophan!

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11
Q

How to increase NE in the brain?

A

administer L-Dopa

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12
Q

Evidence against monoamine depletion hypothesis (3):

A

1) Administering 5-HT via a high tryptophan diet and administering NE via L-Dopa does not improve depression
2) Depletion of 5-HT or NE does not lead to depression
3) Time lag between antidepressant treatment and relief– while these drugs act quickly to increase monoamine levels, therapeutic effects are only seen after several week

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13
Q

How to reduce 5-HT in brain?

A

remove tryptophan from diet

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14
Q

How to reduce NeE in brain

A

low doses of TH (tyrosine hydroxylase) inhibitor– rate limiting step

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15
Q

Monoamines are involved in the maintenance of antidepressant response

A

when patients are successfully treated with either 5-HT or NE selective reuptake inhibitors, they become vulnerable to depletion of the corresponding monoamine

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16
Q

a2 adrenergic receptor

A

Is an inhibitory autoreceptor (presynaptic)

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17
Q

Treatment of 5-HT1A agonist

A

-autoreceptor on soma of serotonin neurons

reduces the response time to SSRIs

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18
Q

Sustained elevation of monoamine levels by chronic anti-dep treatment leads to

A

continued activation of postsynaptic monoamine receptors and eventua down-regulation of postsynaptic receptors

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19
Q

Chronic antidepressant treatment ______ beta adrenergic receptors *leads to what hypothesis?

A

down regulates

This leads to hypothesis that b-AR upregulation leads to depression

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20
Q

Problems with b-AR hypothesis (3)

A

1) Not all antidepressants lead to upregulation of b-AR
2) Timedelay of down-regulation effect is fast (so doesn’t explain why antideps take weeks)
3) b-AR antagonists are not good antideps

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21
Q

Conflciting evidence of b-AR receptors

A

b-AR antagonists are not good anti-depressants and b-AR agonists sometimes have antidepressant effects

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22
Q

Chronic antidep treeatment induces _______ of 5-HT2A receptors

*leads to what hypothesis?

A

down-regulation

5HT2A upreguilation leads t o depression

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23
Q

Problems with 5HT2A receptor hypothesis

A

1) Not all antideps increase 5-HT2A
2) Time delay of down regulation is faster than effect on antidep
3) Electroconvulsive seizure therapy which is effective for depression, actually upregulates 5-HT2A
3) 5-HT2A antagonists are not good anti-depressants

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24
Q

____________ are the substrats of second messenger-dependent protein kinases. What causes an alteration in activity of these?

A

transcription factors

phosphorylation by kinases (like PkA)

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25
Q

What is CREB?

A

a transcription factor that when phosphorylated, binds to the CRE and initiates transcription

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26
Q

Gs pathway

A

Activation of Gs-coupled receptors

Stimulation of adenylyl cyclase

Elevation of intracellular cAMP

Activation of PKA

Increased transcriptional activity of CREB

Regulation of target genes (like BDNF and TrkB)

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27
Q

Chronic antidepressant treatment leads to upregulation of ________ via CREB

A

BDNF and TrkB

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28
Q

Antidep treatment leads to downregulation of (_ and _), which demonstrates

A

5HT7 and b1-AR

supports the idea that sustained activation of these receptors leads to a sustained activation of cAMP cascade

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29
Q

Gq coupled 5-HT and NE receptors

A

5-HT2A, 2C

a1-AR

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30
Q

Gq pathway

A 
Activation of Gq-coupled 
5-HT and NE receptors 
(5-HT2A,2C, a1-AR)
	
Release of Ca2+ from intracellular stores
	
Activation of CaMK
	
Increased transcriptional activity of CREB
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31
Q

Up-regulation of the CREB cascade suggests that genes containing ______ can be targets for antidepressant treatment.

A

Cre (cAMP response element)

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32
Q

Role of neurotrophic factors (like BDNF)

A
  • critical to differentiation and development of immature neurons
  • required for the survival and functioning of neurons in the adult nervous system
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33
Q

activation of glucocorticoid
receptors leads to suppression of
_____________.

A

CREB mediated gene transcription and thus levels of BDNF in the brain

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34
Q

chronic stress and glucocorticoid administration causes

A

down regulation of BDNF in hippocampus and atrophy of hippocampal pyramidal neurons

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35
Q

Findings that support the idea that BDNF is the target for antidepressant treatment (3)

hc, stress, time course

A

1) Chronic treatment of antidepressants upregulates BDNF in HC
2) antidep treatment blcoks stress-induced downregulation of BDNF in HC
3) time course and regional distribution of BDNF corrsponds to that of CREB by antidepressant treatment

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36
Q

Antidepressant treatment leads to increase in BDNF which leads to

A

1) increased arborization
2) increased synaptic efficiency
3) decrease depression in animal models where BDNF is injected
4) increased neurogenesis

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37
Q

Pathways of stress in BDNF

A

 Elevation of glucocorticoids

 Down-regulation of BDNF

 Atrophy and damage of hippocampal neurons

 Reduction of the hippocampal feedback inhibition of the HPA axis (leads back to 1 in a vicious cycle)

 Depression

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38
Q

Pathway of Antidepressant action (BDNF)

A

Increased 50HT and Ne transmission

Upregulation of CREB cascade

increased BDNF and TrkB

growth and survival of HC neurons

increase in HC inhibition of HPA axis

nless depression

39
Q

Treatments for Mood disorders (5)

A

1) electroconvulsive therapy– most effective (increases BDNF)
2) psychotherapy– not sure if this one increases BDNF)
3) Exercise– increases BDNF
4) Antidepressants
5) Lithium

40
Q

How does lithium work?

A

dsmpen action of Gq coupled receptors (but don’t know how it affects mood)

41
Q

Novel Targets for the treatment of depression

A

1) specific agonists for Gs coupled 5-HT and NE receptors
2) Agents that could directly stimulate cAMP cascade (like PDE inhibitors)
3) NMDA-antagonists (like ketamine)
4) BDNF or BDNF like things that can cross BBB
5) CRF receptor antagonists

42
Q

Skinnerian view of cognition

A

the nervours system is a stimulus-response machine

43
Q

What is cognition? Cognitive processes?

A

the process in the brain that heps us understand and respond to stimuli

Cognitive process intervenes to modulate a response to environmental stimulus

44
Q

brain area that is involved in cognition

A

called the association cortex– area of cerebral cortex that is not involved in sensory or motor processing

45
Q

Working memory

A

temporary storage of information whcih allows an internal “image” based on recent sensory inputs, integrate it with other information to guide future behavior

46
Q

Site of working memory

A

prefrontal cortex

47
Q

Tests of working memory in prefrontal

A

Delayed-response task in animals

Wisconsin Card Sorting Task for humans

48
Q

People with prefrontal lesions have great difficulty recognizing and adopting a new sorting rule; they continue to sort according to a rule that no longer applies

A

Perseveration

49
Q

_____________ individuals perform poorly on WSTC and are disorganized- relates this to __________ ______.

A

SZ,

working memory

50
Q

What is the most common cause of chronic psychosis?

A

SZ

51
Q

Three categories of SZ symptoms

A

1) positive symptoms– psychosis
2) negative symptoms– fla affect, social withdrawal, poverty of speech
3) disorganized– formal thought disorder, inappropriate affect, incoherence, word salad

52
Q

Schizophrenia is associated with what morphological feature

A

larger ventrcles

53
Q

What is LSD?

A

a hallucinogenic drug that acts as a potent 5-HT agonist

54
Q

What are psychostimulants functionally?

A

cocaine and amphetamine

dopamine uptake inhibitors

55
Q

What is PCP functionally?

A

an open channel blocker of NMDA

56
Q

Three competing models of psychosis

A

Serotonergic (evidence: LSD), dopaminergic (evidence: psychostimulants), glutamatergic (PCP)

57
Q

SZ is supposed to associated with a ___________ state because ____________ are so good at suppressing symptons

A

hyperdopaminergic state

dopamine receptor antagonists

58
Q

Which brain regions receive input from PFC? What does this do?

A

Striatum, VTA, SNc, Limbic Areas

regulate DA release

59
Q

Why is serotonergic model weak?

A

There are differences between LSD psychosis and SZ

  • auditory instead of visual hallucination in SZ
  • NO delusions as in SZ
  • No thought disorder as is in SZ
  • Presrervation of affect
60
Q

hallucinations as in LSD are though to be due to _________ receptors

A

5HT2A agonism

61
Q

LSD is a potent agonist of autoreceptors such as ____ in soma and ____ in presynaptic terminal. Why is 5-HT2A still considered the mechanism?

A

5HT-1A

5hT 1b/D

hallucinogenic effect correlates with affinity for 5HT2A

62
Q

Hallucinogenic activation of 5HT2A modules frontal cortex via these 2 mechanism

A

1) Stimulation o 5-HT receptors on pyramidal neurons
2) Stimulation of interneurons that inhibit GABA-ergic projects on pyramidal neurons

Leads to increase in pyramidal neuron activity in frontal cortex

63
Q

Pyramidal neurons are glutamatergic true or fals

A

true

64
Q

Hallucinogenic pathway

A

hallucinogen

Increase in glutamaterigic output in pyramidal neurons

Hyperdopamiergic state in VTA

65
Q

New anti-psychotics are potent _______

A

5HT2A antagonists

66
Q

psychostimulant psychosis best models _________

A

paranoid SZ

67
Q

Psychostimulant psychosss is thought to arise from ________

A

sensitization due to repeated exposure (this may be irreversible– i.e. people who have not abused meth for years will take it and have psychosis after years of abstinence

68
Q

Sensitization happens with this drug schedule while this drug schedule leads to tolerance

A

intermittent, continuous

69
Q

Sensitization due to psychostimulants associated with (2)

A

1) is linked with increased stimulant-induced dopamine release in axonal terminal fields
2) dependent on glutamate input to VTA

70
Q

Repeated treatment with psychostimualnts enances ______ receptor expression in ________

A

AMPA, VTA

71
Q

Evidence that hyperdopaminergic state in SZ

A

1) psychostimulant-naive SZs show an increased response to amphetamines
2) brain imaging confirms that SZs have increase dopamine release from amphetamines

72
Q

Phencyclidine model of SZ

A

subanesthetic doses of PCP leads to Sz-like symptoms (very similar so PCP abusers are often misdagnosed as having SZ)

73
Q

Anti NMDA receptor encephalitis

A

autoimmune disorder against NMDA receptors, which causes psychosis

74
Q

NMDA antagonists psychosis symptoms

A

disorganized thought and behavior, impaired cog function, negative symptoms

75
Q

NMDA antagonist psychosis is resistant to _____ but is senstive to ____________

A

typical antipsych (bc they are d2 receptor antagonists)

atypical antpsych

76
Q

Mice with fewer NMDA receptors

A

display SZ behavior, reduced sociality, repetitive movements, and can be treated with atypical antipsychotics

77
Q

Original vs. revised dopamine hypothesis

A

SZ results simply from hyperdopaminergia

Revised– hyperdop in striatum/subcortical (positive symptoms), hypodop in cortical areas (hypofrontality)

78
Q

Limitations of original dopamine hypothesis

A

1) D2 antagonists don’t always treat SZ
2) Da metabolite studies in CSF contradict (you would expect to see a lot but don’t)
3) Psychostimulants that increase dopaminergic activity don’t increase all symptoms

79
Q

SZs show _______ levels of HVA (________ metabolite) suggesting

A

lower, dopamine, which suggests hypodopaminergia in cortex

80
Q

Da receptors that are predominat in PFC

A

Dopamine D1 receptors

81
Q

Evidence supporting hypodopaminerogia in cortex (4)

A

1) lower CSF levels of HVA metabolite
2) TH immunolabeling is decreased (TH is the enzyme that makes dopamine)
3) increase in D1 receptors in PFC, consistent with compensatory upregulation due to lack of endogenous activation
4) high activity COMT alleles lead to lower cognition– COMT leads to DA degradation

82
Q

SZ patients with _______ have selective deficits in PFC, is often observed in patients with lots of )_________

A

hypofrontality

negative symptoms

83
Q

Decreased PFC activity is related to ___________, which means that ______ activity of ________ DA neurons might be at play

A

decreased HVA concentration in CSF

reduced, mesocorticolimbic

84
Q

Action potential in phasic release causres

A

Ca inflyx through voltage gated channels

sudden/transient incease in Ca in cytosol

85
Q

How is tonic Da release regulated

A

by glutamatergic input at Da axon terminals (axoaxonic)

86
Q

depolarization blockade of ______ in implcated in antipsychotic effect, while blockade of SNc leads to ____

A

VTA

EPS

87
Q

Postsynaptic receptors of mesocortical DA system are mainly. Therefore D1 _______ may help treat negative symptoms

A

D1-like

agonists

88
Q

To promote NMDA receptor function, use ______

A

glycine transporter inhibitors

89
Q

Postmortem brain studies in SZ show that there is an increase in ________ in the striatum

A

D2 receptors

striatum

90
Q

Atypical antipsychotics have a lower affinity for ______ than for ____/______, meaning that the latter might have stronger link to antipsychotic effect (and the former to _____)

A

D2

D4/5-HT2A

EPS

91
Q

_____ _________ reduce the psychotomimetic effects of ketamine

A

AMPA antagonists

92
Q

Pathway of glutamatergic mdoel

A

NMDA receptor blockade

 Reduction of the activity of
GABAergic interneurons

 Disinhibition of cortical
glutamatergic neurons

 Increased cortical
glutamatergic output

 Excessive activation of
AMPA receptors

93
Q

Psychostimulants lead to increased __________ expression in VTA DA neurons

A

AMPA receptor expression

Neurobiology of Disease (2 decks)

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