Animal Models of Depression Flashcards
What are the criteria for an animal model of depression?
be reasonably analogous i symptomatology to the human disorder
cause behavioral changes that can be objectively monitored
produce behavioral changes that are sensitive to the same treatment modalities as are effective in humans
should be reproducible between investigators
What is construct validity in animal models?
similarity between the methods by which the models is induced and the etiology of disease as compared to humans
genetic and environmental factors
What is predictive validity in animal models?
utility of the model to predict drug effects
assumes similarities in effect are based on shared mechanism
What is face validity in animal models?
ability of the model to recreate key features of a disease
anatomical, behavioral, and neurochemical features of diseases
What is a model?
methods used to induce a depressive state in subjects
What is a test?
analysis used to evaluate or quantify the depressive state
What is the relationship between models and tests?
a model is dependent on the validity of tests to validate the depressive phenotype
What are the measurable endophenotypes of depression in rodents?
anhedonia
anxiety-related behaviors
neuroendocrine disturbances
behavioral despair
appetite or weight changes
altered sleep architecture
cognitive changes
cognitive affective bias
neuroanatomical changes
How is despair measured in rodents?
despair-based tests are one of the oldest models currently in use
based on the time an animal spends struggling to escape an inescapable situation
behavioral correlates are speculative with the human condition
sensitive to antidepressants with or without an inducible model (e.g. chronic stress)
What is the forced swimming test (FST)?
in a 5 minute period measure time spent immobile
immobility is presumed to be an indicator of despair
sensitive to MAOI and TCA antidepressants
mixed findings with SSRI
What is the tail suspension test?
similar to FST
limited to mouse models due to behavioral differences
sensitive to a range of antidepressants
What are the strengths of despair models?
FST and TST have high reproducibility
simple and inexpensive
high predictive validity to antidepressants
TST is amenable to high throughput
What are the limitations of despair models?
can be measured against a baseline that is non-depressed (face validity?)
sensitive to confounds: hypothermia (FST), locomotion, motivation, stimulation/fatigue
sensitive to acute AD treatments: time course in FST/TST does not match clinical observations
validity with non-monoamine treatments is unknown
construct validity not demonstrable (ethics)
How is anhedonia measured in animal models of depression?
as a major component of depressive disorders in humans anhedonia is a promising model
used in conjunction with a model that induces a depressed state - higher face validity
What is the sucrose preference test?
provide animals with a choice of water sweetened with sucrose vs unsweetened
preference for sweetened water diminished with induction of depressive model
What is intracranial self-administration/stimulation?
implanted electrode in various locations to activate reward circuitry
depressive models lead to decrease in self-stimulation
sensitive to antidepressants
What are the strengths of anhedonia measures?
high face validity when used with an appropriate induction model of depression
sensitive to chronic but not acute AD treatment (good predictive validity)
measures affective state and motivation
What are the limitations of anhedonia measures?
cost and complexity (e.g., ICS)
invasive (i.e., ICS)
not well elevated in all models of depression
What are the models of depression?
coupled with testing paradigms to assess treatment efficacy
models with high construct and face validity are used to evaluate mechanisms underlying depressive disorders
lesion-based, pharmacological, stress-based, genetic
What are the pharmacological models of depression?
used primarily to test antidepressants affecting monoamine neurotransmitters
have high predictive validity but very low face validity
have been key in development of monoamine-based pharmacotherapies
What is reserpine?
reserpine treatment blocks monoamine uptake into vesicles by VMAT (vesicular monoamine transporter)
decreased vesicular uptake increases monoamine metabolism by MAO and COMT leading to depletion of monoamines: induces mood changes in healthy volunteers
syndrome characterized by locomotor hypomotility and reduced body temperature, reversed by acute AD treatments
What is 5-hydroxytryptophan?
treatment with 5-hydroxytryptophan (5-HTP, precursor to 5-HT) leads to elevated serotonin and a behavioral syndrome
AD effects measured as an increase in behavioral syndrome above baseline 5-HTP
sensitive to acute AD treatments
does not model depressive behaviors
How is psychostimulant withdrawal used as a model of depression?
withdrawal from cocaine or amphetamine produces depressive-like symptoms including anhedonia, immobility, etc
reversed by antidepressant treatments
What are stress-based depression models?
consistent with the HPA axis model of depression
rely on behavioral conditioning to induce depressive behaviors
have high face validity and generally show consistent endocrine and biochemical changes as in human depression
What is the learned helplessness model?
animal exposed to repeated and unavoidable electric shock
subjects show deficits such as decreased escape in FST/TST, cognitive and reward behaviors (sucrose preference)
acute model - stress effects last only a few days
responds to acute antidepressant treatment
limited in practice by ethical considerations
limited construct validity
What is the chronic mild model?
uses a range of mild stressors to induce a depressive state over days - weeks
results in long-lasting changes in behavior and neurochemistry including decreased sucrose preference and intracranial self-stimulation, stress-induced grooming deficits, changes in corticosterone levels
has high inter-lab variability and is very labor intensive
high construct validity
What is the social stress model?
dyadic models use resident-intruder paradigms involving repeat exposure to an aggressive dominant animal
group social paradigms use social instability (mixing a stable social group) or social disruption (high aggressive male introduced)
social stressors lead to anhedonia, neuroendocrine changes that are reversed by long-term antidepressant treatment
high construct validity
What is the maternal deprivation model?
pups are separated from dam for 1 to 24 hours during the first two postnatal weeks
separation increases depressive behaviors including anxiety, anhedonia, and HPA axis activation that persists into adulthood
use of mice allows high throughput
behavioral changes are affected by chronic antidepressant treatment
What are genetic models of depression?
emerging models using genetic approaches to identify and model genetic determinants of depression
these can include analyses of polymorphisms found in depressed patients, genetic screens for changes that are coincident with depressive behaviors, or selective breeding for depressive traits
What is the forward genetics approach?
blinded approach used to randomly mutagenize genomic DNA
offspring are characterized for depressive behaviors
genetic changes are mapped
What is the reverse genetics approach?
inserting targeted changes in genomic DNA to produce a depressive behavior: polymorphisms identified in humans, targeting components of biological hypothesis
reconstitute genetic risks observed in humans: good construct validity
can be used to model gene x environment interactions
How was selective breeding used to create the Rouen mouse?
tests such as the TST have inter-animal variability
researchers crossed mice in high-response TST and low-response TST groups for 5 generations
developed TST-sensitive and TST-resistant groups with measurable changes in neurotransmitter levels and activity
likely coincident rather than causal changes
most differences were in dopaminergic systems, and the TST-resistant group was more susceptible to stresses outside of the TST (electric shocks)
