lecture 18 LOs

Question 1

what is the NT adenosine a key modulator of

Answer 1

drowsiness

Question 2

what type of NT is adenosine

Answer 2

primarily an inhibitory NT, can act on both postsynaptic neurons and on presynaptic glutamate terminals
adenosine levels in the brain tend to be lowest after waking from sleep, increase over the day that may serve as a type of sleep time clock

Question 3

where does extracellular adenosine come from

Answer 3

ATP released from inside cells and is then broken down to adenosine, which stimulates extracellular receptors

Question 4

at typical doses what does caffeine act as

Answer 4

an adenosine receptor antagonist
caffeine has other neural effects but at higher doses than typically ingested
four adenosine receptors have been identified and stimulant effects of caffeine are primarily on the alpha2A subtype

Question 5

where are the adenosine alpha2A receptors found, and what do they form

Answer 5

found on GABA output neurons in the dorsal/vental striatum
form heteromers with the D2 receptors

Question 6

what can activation of the alpha2A receptors do

Answer 6

reduce affinity of D2 receptors for DA, decreasing arousing/behaviourally activating effects of DA

Question 7

what can caffeine do by blocking adenosine receptors

Answer 7

1. enhance D2 signalling, leading to mild arousal and psychomotor activation
2. reduce inhibitory effect of adenosine on other post-synaptic neurons and presynaptic glutamate terminals, increasing neural activity

Question 8

what is major unipolar depression characterized by

Answer 8

unhappy mood (more an absence of happiness than increased sadness), worthlessness, guilt, desperation
loss of interest, energy/motivation, appetite, pleasure (anhedonia)
difficulty in concentration, restless agitation

Question 9

what can trigger unipolar depression episodes

Answer 9

external events (reactive), or occur with no apparent cause (endogenous)

Question 10

when is depression considered pathological

Answer 10

when symptoms are disproportionate/prolonged
high comorbidity of depression with other medical conditions.metnal disorders (anxiety, alcohol dependence)
symptom clusters vary with individuals (there may be depression subtypes associated with distinct causes and pathophysiologies)

Question 11

what are the costs to individuals and societies with depression

Answer 11

dramatically increased risk of suicide
impact on relatives/friends of the individual with depression
lost productivity costs

Question 12

how does unipolar depression ebb and flow

Answer 12

alternates with normal states, episodes can last up to 6-9 months
episodes can recur through life, often increasing in frequency and intensity
sometimes depressive episodes can end on their own

Question 13

what is the prevalence of unipolar depression

Answer 13

15-20% of the population may be afflicted at any one time

Question 14

sex differences of depression

Answer 14

women are more likely to be diagnosed and incidence often coincides with major hormonal changes (postpartum or menopause)

Question 15

how do stress and anxiety play into depression

Answer 15

depression is viewed as a stress-related disorder and is closely related with anxiety
intense stress and anxiety often precede depression

Question 16

how do alterations in the HPA axis and in CRF levels affect depression

Answer 16

some forms of depression may be linked to alterations in the HPA axis and higher CORT levels as well as CRF levels
CRF is a stress-related peptide transmitter in brain that affects numerous limbic brain regions and stimulates cortisol release

Question 17

if you have cushings syndrome, what are you at a higher risk for and why

Answer 17

depression because of high levels of glucocorticoids

Question 18

what is the test that can show excessive CORT release

Answer 18

the dexamethasone suppression test
dexamethasone is a synthetic glucocorticoid that can suppress CORT release in normal people but not in depressed patients

Question 19

where in the brain is there increased blood flow in depressed people

Answer 19

in the amygdala and the ventral medial prefrontal cortex
amygdala: increased anxiety

Question 20

where has reduced volume been seen in the brain to correlate with depression

Answer 20

in the hippocampus

Question 21

what is the glucocorticoid hypothesis for depression

Answer 21

focuses on the stress-related neuro-endocrine abnormalities of depression
hypothalamic CRF neurons are regulated by other nuclei (the amygdala stimulates and the hippocampus inhibits)
early life stress can increase CRF expression in the hypothalamus, increases amygdala sensitivity to stress and decrease glucocorticoid receptors in the hippocampus

Question 22

what do glucocorticoids do

Answer 22

increase hippocampal excitability
high, sustained levels can cause atrophy oh hippocampal/PFC neurons

Question 23

what does impaired hippocampal function lead to

Answer 23

loss of inhibitory regulation of HPA axis
may also contribute to behavioural syndrome in depression where patients often report being unable to remember a time where they were happy
antidepressant drugs reduce CRF levels and reverse loss of hippocampal dendrites in animal studies

Question 24

what does chronic mild stress do to animal models

Answer 24

rodent exposed to multiple different types of stressors (cold temps, wet bedding, restraint, sudden loud noises) over 1-3 weeks (so that the animal cannot habituate to one form of stress)

Question 25

what does chronic social defeat do to animal models

Answer 25

have an intruder rat/mouse fight a more dominant conspecific-repeated experiences with defeat can induce depression

Question 26

what does early maternal separation do to animal models

Answer 26

young animals are separated from their mothers for brief periods daily during the first few weeks of life

Question 27

what does the forced swim test show in animal models

Answer 27

models behavioural despair, immobility is thought to reflect a passive coping strategy
acute antidepressant treatment reduces immobility and increases active coping strategy (swimming, climbing) in normal animals

Question 28

what does social avoidance do in animal models

Answer 28

typically used with social defeat model
rodents avoid conspecifics after repeated defeats

Question 29

what does sucrose preference do to animal models

Answer 29

models anhedonia
depression models reduce preference for sucrose solution vs water
chronic antidepressants can reverse this effect

Question 30

what can early life stressors do to brain regions to cause depression

Answer 30

can make HPA axis over responsive and increase the risk for depression

Question 31

what is seen in adult rats who are subjected to early life trauma

Answer 31

higher stress induced cortisol and CRF release as adults
greater depressed like behavious

Question 32

what does antidepressant treatment prevent in animals

Answer 32

prevents cortisol/CRF increase in adults
reduced depressed like behaviour
when treatment was terminated all the abnormalities returned

Question 33

what are some key drugs in the monoamine hypothesis of depression

Answer 33

reserpine: drug that reduce monoamine levels induces depression
monoamine oxidase inhibitor: blocks metabolism of monoamines and increase brain levels alleviated depression
impramine: first tricyclic antidepressant, blocks monoamine reuptake, effective in alleviating depression
fluoxetine (SSRI, Prozac): found to be effective at treating depression
***depression is the result of abnormal reductions in brain monoamine (mostly serotonin and noradrenaline) levels

Question 34

what are four limitations of the monoamine hypothesis

Answer 34

• antidepressants increase monoamine levels quickly yet there is a long lag between drug treatment and reduction of symptoms
• not all depressed patients respond to drugs that increase monoamine levels
• depletion of serotonin or NE does not cause a depressive-phenotype in animal models
• tryptophan depletion induce symptoms of depression in unmedicated depressed patients (in remission) or health subjects with family history of depression but NOT IN SUBJECTS WITHOUT FAMILY HISTORY OF DEPRESSION