Exam 3 Flashcards
Two competing theories of depression
Monoamine Depletion Theory and the receptor sensitivity hypothesis
Due to the widespread nature of mood disorders, many studies focus on the role of these pathwasy
Diffuse modulatory systems
Bipolar disorder is also called
manic-depressive disorder
Depression is the leading cause of
suicide
This is the Milder form of depression
dysthymia
Mood v emotion
Mood = predominant emotional state over time
Emotion- transient response
Mood disorders are characterized by
1) feeling emotional state is no longer under control
2) fluctuates spontaneously with no link to stressful events
Mood disorders have a general tendency
towards progression
early episodes precipitated by psychosocial stress, but later ones happening spontaneously
Key evidence supporting monoamine depletion theory f depression:
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
How to increase 5-HT in brain?
Eat more tryptophan!
How to increase NE in the brain?
administer L-Dopa
Evidence against monoamine depletion hypothesis (3):
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
How to reduce 5-HT in brain?
remove tryptophan from diet
How to reduce NeE in brain
low doses of TH (tyrosine hydroxylase) inhibitor– rate limiting step
Monoamines are involved in the maintenance of antidepressant response
when patients are successfully treated with either 5-HT or NE selective reuptake inhibitors, they become vulnerable to depletion of the corresponding monoamine
a2 adrenergic receptor
Is an inhibitory autoreceptor (presynaptic)
Treatment of 5-HT1A agonist
-autoreceptor on soma of serotonin neurons
reduces the response time to SSRIs
Sustained elevation of monoamine levels by chronic anti-dep treatment leads to
continued activation of postsynaptic monoamine receptors and eventua down-regulation of postsynaptic receptors
Chronic antidepressant treatment ______ beta adrenergic receptors *leads to what hypothesis?
down regulates
This leads to hypothesis that b-AR upregulation leads to depression
Problems with b-AR hypothesis (3)
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
Conflciting evidence of b-AR receptors
b-AR antagonists are not good anti-depressants and b-AR agonists sometimes have antidepressant effects
Chronic antidep treeatment induces _______ of 5-HT2A receptors
*leads to what hypothesis?
down-regulation
5HT2A upreguilation leads t o depression
Problems with 5HT2A receptor hypothesis
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
____________ are the substrats of second messenger-dependent protein kinases. What causes an alteration in activity of these?
transcription factors
phosphorylation by kinases (like PkA)
What is CREB?
a transcription factor that when phosphorylated, binds to the CRE and initiates transcription
Gs pathway
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)
Chronic antidepressant treatment leads to upregulation of ________ via CREB
BDNF and TrkB
Antidep treatment leads to downregulation of (_ and _), which demonstrates
5HT7 and b1-AR
supports the idea that sustained activation of these receptors leads to a sustained activation of cAMP cascade
Gq coupled 5-HT and NE receptors
5-HT2A, 2C
a1-AR
Gq pathway
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
Up-regulation of the CREB cascade suggests that genes containing ______ can be targets for antidepressant treatment.
Cre (cAMP response element)
Role of neurotrophic factors (like BDNF)
- critical to differentiation and development of immature neurons
- required for the survival and functioning of neurons in the adult nervous system
activation of glucocorticoid
receptors leads to suppression of
_____________.
CREB mediated gene transcription and thus levels of BDNF in the brain
chronic stress and glucocorticoid administration causes
down regulation of BDNF in hippocampus and atrophy of hippocampal pyramidal neurons
Findings that support the idea that BDNF is the target for antidepressant treatment (3)
hc, stress, time course
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
Antidepressant treatment leads to increase in BDNF which leads to
1) increased arborization
2) increased synaptic efficiency
3) decrease depression in animal models where BDNF is injected
4) increased neurogenesis
Pathways of stress in BDNF
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
Pathway of Antidepressant action (BDNF)
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
Treatments for Mood disorders (5)
1) electroconvulsive therapy– most effective (increases BDNF)
2) psychotherapy– not sure if this one increases BDNF)
3) Exercise– increases BDNF
4) Antidepressants
5) Lithium
How does lithium work?
dsmpen action of Gq coupled receptors (but don’t know how it affects mood)
Novel Targets for the treatment of depression
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
Skinnerian view of cognition
the nervours system is a stimulus-response machine
What is cognition? Cognitive processes?
the process in the brain that heps us understand and respond to stimuli
Cognitive process intervenes to modulate a response to environmental stimulus
brain area that is involved in cognition
called the association cortex– area of cerebral cortex that is not involved in sensory or motor processing
Working memory
temporary storage of information whcih allows an internal “image” based on recent sensory inputs, integrate it with other information to guide future behavior
Site of working memory
prefrontal cortex
Tests of working memory in prefrontal
Delayed-response task in animals
Wisconsin Card Sorting Task for humans
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
Perseveration
_____________ individuals perform poorly on WSTC and are disorganized- relates this to __________ ______.
SZ,
working memory
What is the most common cause of chronic psychosis?
SZ
Three categories of SZ symptoms
1) positive symptoms– psychosis
2) negative symptoms– fla affect, social withdrawal, poverty of speech
3) disorganized– formal thought disorder, inappropriate affect, incoherence, word salad
Schizophrenia is associated with what morphological feature
larger ventrcles
What is LSD?
a hallucinogenic drug that acts as a potent 5-HT agonist
What are psychostimulants functionally?
cocaine and amphetamine
dopamine uptake inhibitors
What is PCP functionally?
an open channel blocker of NMDA
Three competing models of psychosis
Serotonergic (evidence: LSD), dopaminergic (evidence: psychostimulants), glutamatergic (PCP)
SZ is supposed to associated with a ___________ state because ____________ are so good at suppressing symptons
hyperdopaminergic state
dopamine receptor antagonists
Which brain regions receive input from PFC? What does this do?
Striatum, VTA, SNc, Limbic Areas
regulate DA release
Why is serotonergic model weak?
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
hallucinations as in LSD are though to be due to _________ receptors
5HT2A agonism
LSD is a potent agonist of autoreceptors such as ____ in soma and ____ in presynaptic terminal. Why is 5-HT2A still considered the mechanism?
5HT-1A
5hT 1b/D
hallucinogenic effect correlates with affinity for 5HT2A
Hallucinogenic activation of 5HT2A modules frontal cortex via these 2 mechanism
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
Pyramidal neurons are glutamatergic true or fals
true
Hallucinogenic pathway
hallucinogen
Increase in glutamaterigic output in pyramidal neurons
Hyperdopamiergic state in VTA
New anti-psychotics are potent _______
5HT2A antagonists
psychostimulant psychosis best models _________
paranoid SZ
Psychostimulant psychosss is thought to arise from ________
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
Sensitization happens with this drug schedule while this drug schedule leads to tolerance
intermittent, continuous
Sensitization due to psychostimulants associated with (2)
1) is linked with increased stimulant-induced dopamine release in axonal terminal fields
2) dependent on glutamate input to VTA
Repeated treatment with psychostimualnts enances ______ receptor expression in ________
AMPA, VTA
Evidence that hyperdopaminergic state in SZ
1) psychostimulant-naive SZs show an increased response to amphetamines
2) brain imaging confirms that SZs have increase dopamine release from amphetamines
Phencyclidine model of SZ
subanesthetic doses of PCP leads to Sz-like symptoms (very similar so PCP abusers are often misdagnosed as having SZ)
Anti NMDA receptor encephalitis
autoimmune disorder against NMDA receptors, which causes psychosis
NMDA antagonists psychosis symptoms
disorganized thought and behavior, impaired cog function, negative symptoms
NMDA antagonist psychosis is resistant to _____ but is senstive to ____________
typical antipsych (bc they are d2 receptor antagonists)
atypical antpsych
Mice with fewer NMDA receptors
display SZ behavior, reduced sociality, repetitive movements, and can be treated with atypical antipsychotics
Original vs. revised dopamine hypothesis
SZ results simply from hyperdopaminergia
Revised– hyperdop in striatum/subcortical (positive symptoms), hypodop in cortical areas (hypofrontality)
Limitations of original dopamine hypothesis
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
SZs show _______ levels of HVA (________ metabolite) suggesting
lower, dopamine, which suggests hypodopaminergia in cortex
Da receptors that are predominat in PFC
Dopamine D1 receptors
Evidence supporting hypodopaminerogia in cortex (4)
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
SZ patients with _______ have selective deficits in PFC, is often observed in patients with lots of )_________
hypofrontality
negative symptoms
Decreased PFC activity is related to ___________, which means that ______ activity of ________ DA neurons might be at play
decreased HVA concentration in CSF
reduced, mesocorticolimbic
Action potential in phasic release causres
Ca inflyx through voltage gated channels
sudden/transient incease in Ca in cytosol
How is tonic Da release regulated
by glutamatergic input at Da axon terminals (axoaxonic)
depolarization blockade of ______ in implcated in antipsychotic effect, while blockade of SNc leads to ____
VTA
EPS
Postsynaptic receptors of mesocortical DA system are mainly. Therefore D1 _______ may help treat negative symptoms
D1-like
agonists
To promote NMDA receptor function, use ______
glycine transporter inhibitors
Postmortem brain studies in SZ show that there is an increase in ________ in the striatum
D2 receptors
striatum
Atypical antipsychotics have a lower affinity for ______ than for ____/______, meaning that the latter might have stronger link to antipsychotic effect (and the former to _____)
D2
D4/5-HT2A
EPS
_____ _________ reduce the psychotomimetic effects of ketamine
AMPA antagonists
Pathway of glutamatergic mdoel
NMDA receptor blockade
Reduction of the activity of
GABAergic interneurons
Disinhibition of cortical
glutamatergic neurons
Increased cortical
glutamatergic output
Excessive activation of
AMPA receptors
Psychostimulants lead to increased __________ expression in VTA DA neurons
AMPA receptor expression
