Mood Disorders Flashcards
How does ketamine exert its antidepressant actions and who said this?
Ketamine is an NMAR antagonist on the GABA interneurone leading to more inhibition of GABA- less GABA release causing less inhibition of the main neurone and so increase in glutamaterelease leading to anti-depressant effects
Aleksanra et al 2017
How else apart from NMDAR antagonism does ketamine exert its anti-depressant effects
Zanos et al showed least amount of escape failures in mouse model with the ketamine metabolite HNK
It is seen to enhance hippocampal fEPSP
Describe the antidepressant actions of tianeptine
In the force swim test samuels et al 2017 found that mouse administered with tianpetine compared to saline spent the lest amount of time immobile
Apart from antiepressant actions what else does tianeptine do?
enhances place recognition memory in mice
enhances hippocampal AMPA receptor dependent synaptic transmission and enhances hippocampal long term potentiation of synaptic strength
What does the tianeptine work on?
the mu and delta opiod receptors and particularly its actions of the delta opiod receptors may underlie its AMPA-modulating properties
Name the different inputs to the nucleus accumbens
medial pre-frontal cortex
basolateral amygdala
ventral tegmentum
hippocampus
Discuss D1and D2 expressing medium spiny neurons
D1 MSN activation reinforces behaviour an is rewarding
D2 MSN- activation inhibits behaviour an is aversive
What does Francis et al say about D1 MSN?
repeated d1 MSN activation reverses the social interaction imapirement
What does covington et al say?
Says that IEG(immediate early genes) markers of neuronal activity are reduced in post mortem brain tissue from depressed patients
Reduced in mouse social defeat stress model of depression
Rescuing depressant affects?
optogenetic burst activation of the mPFC has antidepressant effects
What does Johnston et al say?
Hippocampal activity is abnormally high during loss events in treatment resistant depression
Talk about the optogenetic dissection of the roles of hippocampal versus prefrontal inputs
optogeneti depression of synaptic strength in the hippocampal —-Nac pathway reverses chronic social defeat stress induced depressive symptoms
optogenetic stimulation of vHPC–NAc increases depressive symptoms
optogeneti stimulation of mPFC—NAc decreases the depressive symptoms
Induction of LTD at vHIP—NAc synapses reverses depressive symptoms
Bagot et al 2015
Stats on depression stuff
Whitford et al 2010 says that mental and substance use disorders are the leading cause of years lived with disability
Chang C et al 2011- according to a london based study 32,000 people - 8-15years lost for men and 10-18 lost for women
What is the ICD-10 criteria for depression?
2 out of - depressed mood - loss of interest/anhydonia - anergia \+
3 out of
- reduced concentration
- decreased self esteem
- guilt/unworthiness
- disturbed sleep/appetite
For atleast 2 weeks
Talk about RDoc and the National Institue of Mental Health
RDoc- framework of priorities that the NIMH will fund
the domains are
- negative valence- fear, anxiety, loss etc
- positive valence- reward, habituation, values
- cognitive system- attention, memory
- social system- attachment, communication
-arousal/modulatory- circadian rhythm, sleep/wake cycle
Discuss the disordered appetitive with relation to depression and mania?
previously neutral stimuli becomes rewarding- mania
difficulty identifiying rewarding stimuli , reduced sontact with previously rewarding stimuli and increased aversive stimuli contact—low mood
what does porter et al 2003 say?
severity of depression correlates with impairement in learning and memory
What did the study by johnston et al 2015 show?
failure of hippocampal deactivation during loss events in depression
abnormal hippocampal activity correlates well with severity of cognitive features of depression
Dorsal raphe nucleus- overactive
median raphe nucleus- underactive resulting in overactive hippocampus during loss events
success/reward gan events- blunted striatal pathway
Who talks about increased amygdala activation in depression?
Drevets 1997
What does schmall et al say?
meta analysis - of roughly 9,000 participants , enigma group using neuroimaging showed robust reduction in hippocampal volume
how is the ventral striatum affected in depression?
blunted striatal reward link activation - blunted positive valance system
What did devinski 1999 say?
regions implicated in depression- anterior cingulate and used to be a long establishe treatment only for severe highly resistant depression, involves small bilateral lesions placed in cingulate bundle
What did steele 2008 discover?
basically anterior cingulate gyrus has been implicated in depression especially the more rostral parts
placing a lesion there will help with depression
Discuss the median raphe nucleus and dorsal raphe nucleus
Median raphe nucleus- inhibits consolidation of aversive memories via hippocampus and this is underactive in depression thus causing ruminations
talk about neuroimaging and depression
overlap between patient and control groups
aim- apply same technique to making predictions in clinical situations where its currently impossible - e.g. very early diagnosis of dementia
what did mwangi et al 2012 say?
multi center study in edinburgh and aberdeen- tructural brain scan t1 weighted
90% accuracy using wihin study replication
Talk about BDNF and depression?
reduced in depressed suicide victims and increased in patients on treatment for depression
Discuss the effects of dorsal raphe nucleus on amygdala?
distant threats activates the amygdala by 5-HT2C receptors
activates the PAG outputs for resp/autonomic BUT the flight/fight component of PAG is inhibited
Discuss effects of dorsal raphe nucleus on PAG?
promixal threats activates the PAG which mediates he flight/fight behaviour
What are pharmacological approaches to treatment of depression?
monoamine oxidase inhibitors
tricyclic antidepressants
selective seratonin re-uptake inhibitors
How do anti-depressants work?
increase seraonin levels but also seconary neuroplastic changes involving transcription and translation are involved
SSRIs increase neurogenesis in the rodent hippocampus
stimulate brain erived neurotrophic factor (BDNF) activity that promotes neuronal growth and survival
dsm criteria for bipolar disorder
mania requires atleast three of the following for atleast a week
little need for sleep, inflated self-esteem, pressure of speech, flight of ideas,
What are the concepts of validity?
face validity- symptoms
construct validity-pathophysiology/eiiology
predicitive validity- tretaments effective in humans
examples of tests of depression like behaviour
anhedonia- sucrose preference test and reduced intra cranial self stimulation
lack of motivation - decrease grooming and decrease nest building
resignation/despair- forces swim test and tail suspension
describe the tests of anhedonia
intra cranial self stimulation
rodents with chronically implanted hypothalamic electrodes find self-stimulation rewarding and will work (e.g. lever press ) for reward
what are the tests for anxiety?
light/dark box- number of time spent in light area is recorded
open field test- time in center vs periphery
social interaction through a barrier
elevatedplus maze with two open and two closed arms
What does shirayama et al show?
when BDNF doses are administered the number of failures and escape latency in a learned helplesnness shuttle box task DECREASES
Instead of acute models what is the chronic mild stress model of depression?
aims to model the onset of a depressive like state that develops gradually over time
stresses include over a period of atleast 2 weeks - temp changes, change of cage mates, periods of foo/water deprivation
very good face, construct and predictive value and probably the best
pros and cons of the resignation/despair tests
pro- cheap and good predictive value an so usually used for drug trial
cons- bad face and construct value cause its a very acute inducement
what are the early life stress model?
maternal seperation where pups are seperated from the dam for 1-24h per day for the first 2 postnatal weeks resulting in increase anxiety and depression like behaviours
what does the early life stress model result in?
anhedonia in rats in later life as measured by reduced intracranial self stimulation
goo construct validity
what is the early life stress reduce being model?
reduced bedding available from P2-P9
depressive symptoms are evident in adulthood and it has good construct validity
what does yu et al show?
LF-3-88 which is a nicotinic partial agonist dose dependently decreases the total time spent immobile
name another chronic stress based model
mice/rats are repeatedly exposed to another dominant animal leading to social aversion in subsequent interactions
good predictive, face and construct validity however very time consuming and can only be used with male mice as females are less aggressive
describe the olfactory bulbectomy
bulbectomy causes chronic stress cause of sensory deprivation
model- poor construct but good preicitive validity
