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Animal Models of Anxiety and Depression

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Title: Animal Models of Anxiety and Depression


1
Animal Models of Anxiety and Depression
  • György Lévay Ph.D.
  • 04.25.2008

2
Central Nervous System Disorders
  • Diseases of the autonomous nervous system
  • Neuroendocrine disorders
  • Movement disorders
  • Anxiety disorders
  • Depression
  • Addiction, drug abuse
  • Psychosis, schizophrenia
  • Learning and memory disorders
  • Dementias
  • Neurodegenerative disorders (Alzheimers disease,
    Parkinson disease, prion diseases, etc)
  • Sleep diturbances
  • Attention deficit
  • Pain
  • Migraine
  • Epilepsy
  • Stroke, ischaemia, oedema
  • Tumours

3
Drugs Acting on the Central Nervous System
  • Hypnotics and sedatives)
  • Anesthetics (general and local)
  • Anxiolytics
  • Antidepressants
  • Antipsychotics
  • Pain medications
  • Antiepileptics
  • Antimigrain agents
  • Antiemetics
  • Antiparkinsons
  • Nootropics, cognitive enhancers
  • Neuroprotectíve, antiischaemic agents
  • Psychostimulants, drugs of abuse
  • Drugs effective in the treatment of addiction

4
Major Neurotransmitters of the Central Nervous
System
  • Glutamate (Glu)
  • GABA
  • Glycine (Gly)
  • Dopamine (DA)
  • Noradrenaline (norepinephrine) (NA, NE)
  • Serotonin (5-HT)
  • Histamine (H)
  • Acetylcholine (Ach)
  • Opiates (endorphines, encephalines, dynorphines)
  • Cannabinoides
  • Neuropeptides (CRF, NPY, CCK, ACTH, stb.)
  • Purines
  • Steroides and neurosteroides
  • Neurotrophic factors (Neurotrophine, BDNF, GDNF,
    cytokines, stb)

5
Typical Connections in the CNS
6
Physiological and Pathological Anxiety
NORMAL PATHOLOGICAL
Jitter
Panic attacks
Obsessions, compulsions
Stage-fright
Flashbacks, nightmares
Nervousness
Pathological fear
Worrying
7
Anxiety Disorders (DSM-IV)
  • Panic disorder (PD)
  • Unexpected panic attacks associated with
    physiological symptoms of the autonomous nervous
    system
  • Intensive fear
  • Phobias
  • Avoidance of places and situations where panic
    attacks occurred
  • Often comorbide with depression and alcohol abuse
  • 2 of the population, beginning in teens and
    early 20s
  • Twice as common in women than men
  • Current therapies
  • Cognitive behavioral therapy
  • Chronic antidepressant therapy( TCA, SSRI, MAOI)
  • Occasionally (and acutely) alprazolam,
    clonazepam)

8
Reduction in Mean Number of Panic Attacks for
Patients (n78) with Panic Disorder Treated with
Paroxetine or Placebo


p lt0.019 vs. placebo. J Clin Psychiatry 199960
(suppl 18)
9
Reduction in Mean Hamilton Rating Scale for
Anxiety Score from Baseline for Patients with
Panic Disorder Treated with Paroxetine,
Clomipramine, or Placebo for 36 Weeks
J Clin Psychiatry 199960 (suppl 18)
10
Anxiety Disorders (DSM-IV)
  • Obsessive-compulsive disorder (OCD)
  • Obsessions (recurrent, intrusive and generally
    distressing thoughts, images or feelings
  • Compulsions (repetitive, ritualistic behaviors
    aimed to alleviate obsessions)
  • Obsessions and compulsions occupy at least 1 h
    daily causing significant distress and disability
  • Often comorbid with depression
  • 2 , early adolescence, or young adulthood
  • Femalesmales
  • Current therapy
  • Cognitive behavioral therapy
  • SSRI antidepressants

11
Anxiety Disorders (DSM-IV)
  • Social phobia (SA or SP)
  • Excessive fear of negative evaluations by others
  • Extreme discomfort where patients feel people are
    watching or evaluating their performance
  • Avoidance of such situations, occasional panic
    attacks
  • Often comorbide with depression and alcohol abuse
  • Late childhood, early adolescence
  • Occurs more often in women although men are more
    likely to seek treatment
  • Current therapy
  • Behavioral therapy
  • SSRI, MAOI
  • Clonazepam, acutely

12
Pharmacotherapy for Social Anxiety Disorder
Percentage of responders to Paroxetine who
relapsed within 12 weeks after randomisation to
continued Paroxetine or placebo J Clin Psychiatry
199960 (suppl 9)
13
Mean Total Score on Liebowitz Social Anxiety
Scale (LSAS) for Paroxetine-treated and
Placebo-treated Patients






p 0.001 vs. placebo. J Clin Psychiatry 199960
(suppl 18)
14
Anxiety Disorders (DSM-IV)
  • Post-traumatic stress disorder (PTSD)
  • Develops subsequent to experiencing or witnessing
    a traumatic event
  • Precipitating event life treatening assault
  • Symptoms (lasting at least 4-6 weeks)
    reexperiencing the trauma, (flash-backs,
    memories, nightmares), avoidance of trauma
    associated sitiations numbing of emotions,
    arousal (not habituated)
  • 7-8, twice as much women than men
  • Current therapy
  • Cognitive behavioral therapy
  • Chronic antidepressant therapy( TCA, SSRI, MAOI)

15
Time Course of PTSD Symptom Improvement in
Responders to Paroxetine (N10)



_at_

_at_
_at_ _at_
_at_
_at_ _at_

Significant between 4-week intervals (plt 0.05).

_at_ Significant between weeks 0 and 8
(plt 0.001).
_at__at_ Significant
between weeks 4 and 12 (plt 0.001). J Clin
Psychiatry 199960 (suppl 18)
16
Anxiety Disorders (DSM-IV)
  • Generalized anxiety syndrome (GAD)
  • Excessive and uncontrollable worries about normal
    life events
  • Symptoms of motor tension, autonomic reactivity
    or hypervigilance
  • Minimum duration of 6 months
  • Comorbide with depression and other mood
    disorders
  • 3-4 , more women than men, any ages, familial
    association
  • Current therapy
  • Benzodiazepines
  • Limited extent to antidepressants

17
Comparison of Diazepam, Imipramine and Trazodone
Efficacy in GAD










Adjusted postreatment means decreasing
(visitwise) sample size and 2-week end point
(n210) (in drug-placebo differences, asterisk
indicates plt0.05, double asterisks,
plt0.01) Rickels et al, 1993
18
Anxiety in Different Age-Groups
  • Childhood
  • Usually not hereditary (except special phobias)
  • Often transient (family environment, early
    events)
  • Behavioral inhibition (in unfamiliar situation
    or after meeting with unfamiliar person) born to
    be anxious (low arousal threshold in the amygdala
    and hypothalamus)
  • PD is 2-3 times more frequent in adolescent girls
    than boys correlation with sexual maturation
  • Separation Anxiety Disorder (SAD) occuring in
    childhood, only

19
Anxiety in Different Age-Groups (cont.)
  • Youth, adult age
  • 14.6 of the population is affected
  • Tipicaly comorbid with depression (MD especially
    with PTSD) and drug abuse
  • Dramatically decreased work performance (except
    simple phobias)
  • Annual cost in the US only 50 billion USD
  • Old age
  • Prevalence is not decreasing significantly with
    age (approx. 10 )
  • 48 of MD patient suffer from anxiety disorders
  • Special anxiety of the old age developing after
    stroke, thyroid diseases, pulmonary diseases,
    dementias, etc.

20
Pharmacotherapy of Anxiety Disorders
  • History
  • Sedative drugs
  • Ethanol
  • Chloral hydrate
  • Meprobamate
  • Glutethimide
  • Barbiturates

21
Pharmacotherapy of Anxiety Disorders (cont.)
  • Current therapies
  • Benzodiazepines

Lorazepam
Oxazepam
Diazepam
Chlordiazepoxide
Flumazenil
Tofizopam
Zolpidem
Alprazolam
Triazolam
22
Typical doses of benzodiazepines
23
Receptors for Benzodiazepines
  • Binding site on the GABA-Cl--ion channel receptor
    commplex
  • BZ1, (?1) high affinity to ?1 subunits and low
    affinity to ?5 subunits of GABAA receptors
  • BZ2, (?2)

24
Genetic Dissection of Benzodiazepine-Induced
Behavior
25
Therapeutic indications of benzodiazepines
  • Anxiety disorders (GAD, phobia, panic disorder-
    high potecy benzodiazepines)
  • Anxiety accompanying other psychiatric or
    neurodegenerative disorders
  • Alcohol and drug abuse
  • Anxiety accompanying somatic disorders
  • Insomnia
  • Status epilepticus
  • Anxiety generated by certain antipsychotic,
    antidepressant or antiemetic agents
  • Muscular spazms
  • Preoperative sedation

26
Side effects of benzodiazepines
  • Limited clinical efficacy in certain diseases
  • Sedation
  • Muscle relaxant effect
  • Anticonvulsant effect
  • Tolerance
  • Dependence
  • Significant withdrawal reactions
  • Deleterious impact on memory, particularly in the
    elderly
  • Interaction with ethanol

27
Pharmacotherapy of Anxiety Disorders New
Mechanisms and Perspectives
  • Glutamate receptor ligands
  • mGluR2 agonists (LY-354740)
  • AMPA allosteric modulators (negative and
    positive)
  • NMDA antagonists
  • CRF (corticotropin releasing factor) receptor
    antagonists
  • Non-peptide CRF1 antagonists anxiolytic,
    antidepressant efficacy (CP-142635, CRA0165)
  • CRF2 antagonists
  • CCK (cholecistokinin) receptor antagonists
  • CCKB antagonist CI-988 antipanic effect
  • Other neuropeptides (NPY, Substance P, CART,
    Orexin, stb) receptor ligands
  • Serotonergic compounds
  • 5-HT2C antagonists
  • 5-HT7 ligands

28
Pharmacotherapy of Anxiety Disorders (cont.)
  • Current therapies
  • Selective serotonin reuptake inhibitors (SSRI)

Fluoxetine
Citalopram
Sertraline
Paroxetine
Fluvoxamine
29
Usual doses of SSRI drugs
Overdosing and/or combination with MAOI
antidepressantsmight result in serotonin syndrome
(severe hyperthermia, muscle rigidity,
myoclonus, rapid changes in mental status and
vital signs)
30
Therapeutic indications of SSRI compounds
  • Depression
  • Bulimia (fluoxetine)
  • Panic disorder
  • Post-traumatic stress disorder
  • Obsessive compulsive disorder
  • Social anxiety disorder
  • Alcohol and drug abuse
  • Anxiety accompanying other psychiatric or
    neurodegenerative disorders

31
Side effects of SSRIs
  • Slowly developing effect (minimum of 2 weeks)
  • Acute anxiogenic effect
  • Nausea, vomiting
  • Diarrhoea
  • Insomnia
  • Decreased libido
  • Sexual disfunction such as anorgasmia
  • Agitation
  • Aggressivity

32
Animal models of anxiety
  • Methods based on unconditioned (spontaneous)
    response
  • Exploratory activity
  • elevated plus-maze
  • light-dark (two compartment box)
  • open field, closed field, etc.
  • Social behavior
  • social interaction
  • maternal separation, ultrasonic distress calls
  • Predator
  • mouse defense test battery
  • human threat (primates)
  • predators call, odor associated avoidance
    response

33
Animal models of anxiety (cont.)
  • Methods based on conditioned (learned) response
  • Conflict models
  • Vogel punished drinking
  • Geller-Seifter conflict
  • marmoset, pigeon conflict models
  • Other
  • four plate test
  • active/passive avoidance learning
  • conditioned ultrasonic vocalization (adult rats),
    etc.

34
Animal models of anxiety 1.
  • Methods based on unconditioned (spontaneous)
    response
  • Exploratory activity
  • elevated plus-maze
  • light-dark (two compartment box)
  • open field, closed field, etc.
  • Social behavior
  • social interaction
  • maternal separation, ultrasonic distress calls
  • Predator
  • mouse defense test battery
  • human threat (primates)
  • predators call, odor associated avoidance
    response
  • Methods based on conditioned (learned) response
  • Conflict models
  • Vogel punished drinking
  • Geller-Seifter conflict
  • marmoset, pigeon conflict models
  • Other
  • four plate test

35
Animal models of anxiety 2.
  • Normal (adaptive) anxiety
  • Elevated plus-maze
  • Ultrasonic distress calls
  • Light-dark
  • Marble burying
  • Social interaction
  • Stress-induced anxiety
  • Stress-induced hyperthermia
  • Vogel lick conflct
  • Novelty-induced stressz
  • Pathological anxiety
  • Nneurochemically-induced anxiety
  • mCPP, CCK4 or pentagastrine, CRF, etc.
  • transgenicc models
  • CRF overexpression
  • 5-HT1A knock-out, etc.

36
Elevated plus-maze
  • Source of anxiety open space, height, new
  • environment
  • Parameters measured time spent in the open arms
  • entries into the open arms
  • time spent in the closed arms
  • entries into the closed arms
  • total entries
  • central time
  • Anxiolytic effect statistically significant
    increase in open time or open
    entries
  • Pelow, S, Chopin, P., File, S.E. and Briley, M.
    Validation of openclosed arm entries in an
    elevated plus-maze as a measure of anxiety in the
    rat. J. Neurosci. Methods, 1985, 14 149-167

37
Elevated plus-maze
38
Light-dark model
  • Source of anxiety light, novelty,
  • Parameters measuredtime spent in both area
  • (horizontal, vertical activity)
  • movement time in both area
  • number of transitions
  • Anxiolytic effect statistically significant
    increase in light (movement) time or
    number of transition
  • Costall,B., Jones,B.J., Kelly,M.E., Naylor,R.J.
    and Tomkins,D.M. Exploration of mice in a black
    and white test box Validation as a model of
    anxiety. Pharm.Biochem.Behav., 1989, 32 777-785

39
Light-dark model
40
Ultrasonic distress calls
  • Source of anxiety maternal separation
  • Parameters measured time spent with ultrasonic
  • vocalization
  • total number of ultrasonic
  • vocalization
  • Anxiolytic effect statistically significant
    increase in either parameters
  • measured
  • WINSLOW J.T.and INSEL T.R. (1991) Serotonergic
    modulation of the rat pup ultrasonic isolation
    call studies with 5HT1 and 5HT2
    subtype-selective agonists and antagonists.
    Psychopharmacology 105513-520

41
Effect of EGIS-xxxxx on ultra- sonic distress
calls in rat pups
42
Social interaction
  • Source of anxiety presence of an unfamiliar
  • social partner
  • Parameters measured exploration, ambulation,
  • sniffing, rearing, grooming
  • following, social contacts,
  • allogrooming, sexual behavior,
  • attack, fighting, biting
  • defensive posture, immobility, etc
  • Anxiolytic effect statistically significant
    increase in the number of
  • social interactions,
  • and decrease in aggression
  • FILE,S.E. and HYDE,J.R.G.Can social interaction
    be used to measure anxiety?. Br.J.Pharmacol.
    1978, 62, 19-24

43
Effect of EGIS-xxxxx on social interactions under
stressful conditions
44
Marble burying
  • Source of anxiety presence of an unfamiliar
  • objects (potential source
  • of danger)
  • Parameters measured number of buried marbles
  • Anxiolytic effect statistically significant
    decrease in the number of
  • buried marbles
  • BROEKKAMP, C.L.E., JOLY-GELOUIN, D., LLOYD, K.L.,
    and RIJK, H.W.Major tranquilizers can be
    distinguished from minor tranquilizers on the
    basis of effects on marble burying and
    swim-induced grooming in mice. Eur.J.Pharmacol.
    126223, 1986

45
Stress-induced hyperthermia (Handling order)
  • Source of anxiety anticipatory anxiety,
  • handling, new environment
  • Parameters measured core temperature in the
  • first three and last three
  • animals in each group
  • of 15 mice
  • Anxiolytic effect body temperature of the last
  • three animals are not significantly
  • different from the first three
  • BORSINI,F, LECCI,A, VOLTERRA,G and MELI,A, A
    model to measure anticipatory
  • anxiety in mice? Psychopharmacology, 1989, 98
    207-211

46
Effect of EGIS-xxxx on stress- induced
hyperthermia
47
Vogel lick-conflict
  • Source of anxiety stressful situation
  • (48 h water depr.)
  • conflict between thirst
  • and punishment after drinking
  • Parameters measured number of accepted
    punishment
  • (electric shock)
  • Anxiolytic effect statistically significant
    increase in the accepted shocks
  • VOGEL, J.R., BEER, B. and CLODY, D.E. A simple
    and reliable conflict procedure for testing anti
    anxiety agents. Psychopharmacologia (Berl.),
    1971, 21 1-6

48
Vogel lick-conflict
49
mCPP-induced anxiety
  • Source of anxiety chemically induced anxiety
  • Parameters measured time spent in both side
  • (horizontal, vertical activity)
  • frequency of motion
  • number of transition
  • Anxiolytic effect statistically significant
    increase parameters
  • measured in the lit compartment or
  • in number of transition
  • BILKEI-GORZO,A, GYERTYAN,I and LEVAY,G,
    mCPP-induced anxiety in the light-dark box in
    rats - a new method for screening anxiolytic
    activity, Psychopharmacol., 1998, 136 291-298

50
mCPP-induced anxiety
51
Mood disorders (DSM-IV)
  • Major (unipolar) depression, episode
  • Major (unipolar) depression, relapsing
  • Dysthymia
  • Other minor depression (recurrent short,
    ultradian)
  • Hypomanic episode
  • Manic episode
  • Bipolar I. and II. disorder
  • Psychotic depression or mania

52
Etiology of depression
  • Genetic factors
  • 8-18 times higher incidence among close relatives
  • Relevant gens are not yet identified (various
    loci on chromosomes 4, 16, 18, 21 and X )
  • Psychosocial factors
  • Premorbid personality
  • Life events
  • Social support, social relations
  • Age
  • Childhood events
  • Usually starts at young adulthood
  • First episode in old age is very rare
  • Prevalence women 18-34, men 10-19

53
Neurochemical-biochemical background of
depression
  • Neurotransmitters and amino acids
  • Norepinephrine
  • Serotonin
  • Dopamine
  • GABA
  • Glutamate
  • Adetylcholine
  • Neuropeptides
  • Signal transduction, second messengers
  • Presynaptic NaK-ATPase
  • Postsynaptic second messengers
  • Proteinkinases
  • Transcription factors
  • Neurotrophic factors
  • Neuroendocrine alterations
  • HPA-axis cortisol ?, CRF-induced ACTH-release ?,
    CRF ?
  • HPT-axis TRH-induced TSH response is abnormal
    (30-40), liquor TRH ?

54
Neuroanatomical and functional alterations in
depression
  • Decreased hippocampal volume, reduced dendritic
    arborisation
  • The lymbic system and basal ganglia are both
    affected
  • Reduced bloodflow in the frontal cortex and basal
    ganglia (PET)
  • Membrane phospholipid metabolism is disturbed
    (fMRI)
  • LTP ?

55
Symptoms of depression
  • Depressed mood, intense dispair and lack of
    happiness
  • Physical dispair, decreased energy, reduced
    activity
  • Decreased attention and loss of concentration,
    memory impairments, mental slowing
  • Reduced self-confidence, intensive feeling of
    guilt, self-deprecation
  • Pessimistic worry, hopelessness
  • Suicide, thoughts of self-destruction
  • Psychomotor agitation or reduced motion
  • Disruption of the normal circadian rhytm, sleep
    disturbances, loss of apetite, anorexia

56
Therapy of depression
  • Depression
  • Pharmacotherapy
  • Tri- and tetracyclic antidepressants
  • MAO-A inhibitors
  • SSRI
  • Mixed SSRI and SNRI
  • Psychotherapy
  • Supportive psychotherapy,
  • Cognitive behavioral therapy
  • Interpersonal therapy
  • Family therapy
  • Drama therapy
  • Other
  • Sleep deprivation, light therapy
  • Electroconvulsive therapy
  • Mania
  • Pharmacotherapy
  • Lithium, Carbamazepine, valproate
  • Supplementary 1,4-benzodiazepines, antipsychotics

57
Requirement for animal models of depression
(McKinney and Bunney)
  • It is reasonanly analogous to the human disorder
    inits manifestation or symptomatology
  • There is a biological change that can be
    monitored
  • The biological changes could be reversed by
    treatment effective in zhe human disease
  • Widely reproducible

58
Animal models of depression
  • Situation models
  • Porsolt forced swimming
  • Learned helplessness
  • Tail suspension
  • Inhibition of muricide activity
  • Anatomical pathophisiological models
  • Olfactory bulbectomy
  • Chronic mild stress
  • Biochemical (interaction) models
  • Inhibition of tetrabenazine-induced ptosis
  • Inhibition of apomorphine-induce hypothermia
  • Inhibition of yohimbine-induced toxicity
  • Widely reproducible

59
Porsolt forced swimming
  • Symptoms of depression hopelessness,
  • immobility,
  • behavioral dispair
  • abandoning
  • of escape behavior,
  • Parameters measured time spent with escape
  • oriented movement,
  • immobility
  • (swimming, climbing)
  • Antidepressant effect statistically significant
    decrease in immobility
  • Weakness Effects of SSRI is not consequently
    detected
  • PORSOLT,RD et al, (1977) Depression a new animal
    model sensitive to antidepressant treaments.
    Nature, 266730-732

60
Porsolt forced swimming
61
Porsolt forced swimming
62
Tail suspension
  • Symptoms of depression hopelessness,
  • immobility,
  • behavioral dispair
  • reduction in
  • escape behavior,
  • Parameters measured time spent with escape
  • oriented movement,
  • immobility
  • (hangigg)
  • Antidepressant effect statistically significant
    decrease in immobility
  • Weakness Effects of SSRI is not consequently
    detected, better than Porsolt

63
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65
Learned helplessness
  • Symptoms of depression unavoidable shock,
  • hopelessness,
  • decreased reactivity
  • Parameters measured escape failure
  • Antidepressant effect statistically significant
    increase in number of escapes
  • Weakness Symptoms are ceased 2-3 days after
  • shocks
  • WEISS, JM and KILTS, D (1998) Animal models of
    depression and schizophrenia. In Textbook of
    Psychopharmacology eds Nemeroff, CB and
    Schatzberg, H pp88-123

66
LEARNED HELPLESSNESS TEST IN THE RAT
plt0.05 plt0.001
67
Olfactory bulbectomy
  • Symptoms of depression irritability,
    hyperactivity,
  • decreased cognitive functions,
  • aggressivity,
  • neurochemical, neuroendocrine changes
  • Parameters measured motor activity
  • learning and memory parameters
  • Antidepressant effect decreased hyperactivity
    increased cognitive functions
  • increased habituation to new environment
  • Weakness time consuming
  • validity is questioned
  • KELLY et al (1997) The olfactory bulbectomized
    rats as model of depression an update.
    Pharmacol.Ther. 74 299-316

68
Knock-out depression models
69
Models of learning and memory
  • Classical conditioning
  • Active avoidance tasks
  • One way
  • Two way
  • Passive avoidance tasks
  • Step through
  • Step down
  • Operant conditioning
  • Skinner box
  • Maze models
  • Y-maze
  • Morris water-maze
  • T-maze
  • Radial maze

70
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