Transcript Pharmacological Models - Advantages and Challenges

Animal Models of Schizophrenia
Pharmacological Models
- Advantages and Challenges Thomas Steckler
Pharmacological Models
Dopamine
Glutamate
CB
5-HT
Manipulation
Acute
(Sub-)chronic/Sensitization
Withdrawal/Abstinence
Neurodevelopmental
(pre-/postnatal)
Test
Measure
•
•
•
•
Does the model impair cognitive function in domains relevant to SZ?
Does the model resemble some of the pathophysiological constructs thought to contribute to
SZ?
Do we see relevant effects of therapeutic intervention in the model?
Can the effects seen in the model be reproduced (within/across labs) and is the model reliable?
Publications on Pharmacological Models of
Schizophrenia 2009
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ACh DA
5-HT
Glut
CB
DA
Glut
DA
Glut
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Mouse
Series2
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Rat
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acute
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chronic
neonatal
Medline search
• 584 hits
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94 articles selected
• 125 models published
Challenge Models – General Features
• In general based on face validity
– Drugs like amphetamine, lysergic acid diethylamide (LSD), phencyclidine
(PCP), or ketamine produce schizophrenia-like symptoms in humans
and/or exacerbate symptoms in schizophrenic patients
– Used to mimic aspects of schizophrenia in animals, almost exclusively
originate from attempts to model positive symptoms
• High degree of practicability
– Flexibility in choice of test, not limited to species-specific model (construct
validity)
– Allow for high throughput (esp. acute challenge models)
– Duration of test rather than model generation may become the timecritical step
• Good validity to predict efficacy of antipsychotics to treat positive
symptoms
– Effective screening tools
Challenge Models – General Features
• In general, reports of activity in a wide variety of preclinical
tests relevant for cognitive domains affected in schizophrenia
– Speed of processing, attention, working memory, visual learning and
memory, problem solving/executive control, social cognition, gating
• Good sensitivity to established and novel mechanisms of
action, also in tests of cognition
– E.g., atypical antipsychotics, D1, 5-HT6, AMPA, mGlu2/3, mGlu5,
PDE10, nic. α7,…
– Sensitivity depends on response window, which varies as a function of
model and test
• Small window may lead to difficulties in detecting effects of test compounds
Challenge Models – General Features
• Allow for fine-tuning of the models according to the need
– Dose-response and time-response pilot studies help to optimize the
model for the specific test condition and to the compounds under
investigation
– High variability in methodological details across labs, also in
seemingly similar models
• Dose, route of administration, time of administration, duration and treatment
regime in case of repeated dosing
– Different dosing risks undesired effects (esp. in acute and chronic
models)
PCP
desired
unreliable
irreversibility
non-specific
toxic
dose
• NMDA channel blocker
• Sigma receptor
• Other ion channel
receptors
• Transporters
• GPCRs
Challenge Models – General Features
• Effects of challenge may depend on exact compound employed
– Seemingly the same mechanism of action may result into differed behavioural
profile
Effects of NMDA antagonists on biconditional
VI30/VI30
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•
NMDA antagonists tested in various VI
schedules of reinforcement
Biconditional VI 30/VI 30:
–
–
–
•
•
•
Gilmour et al., Psychopharmacology 205, 2009
Two-lever operant chamber
CS presentation: rats were rewarded under VI 30
schedule at the appropriate lever conditional on
the presentation of a conditional stimulus (clicks
or light)
ISI: No stimuli presented, both levers present but
inactive
PCP decreased lever press rate and
response accuracy at highest dose during
CS presentation
MK-801 had biphasic effects
Ketamine and memantine decreased
responding
Acute Challenge Models – Advantages and
Disadvantages
• Good cross-species neural homology
– From invertebrate to man, translational model
– Some notable exceptions, e.g. PCP (neurotoxicity, abuse liability prevent
human testing)
Acute ketamine increases RCGU in HV
NMDA antagonism increases 2-DG
brain uptake in mice
Saline IP
Frontomedial cortex
Frontolateral cortex
Anterior cingulate cortex
Posterior cingulate
cortex
Parietal cortex
Somatosensory cortex
Motor cortex
Temporlateral cortex
Temporomedial cortex
Occipitomedial cortex
Occipitolateral cortex
Caudate nucleus
Putamen
Thalamus
Cerebellum
Vollenweider et al., Eur Neuropsychopharmacology 7, 1997
Ketamine 30 mg/kg IP
MK-801 0.5 mg/kg IP
Miyamoto et al., Neuropsychopharmacology 22, 2000
Acute Challenge Models – Advantages and
Disadvantages
• Allow for deconstruction of the cognitive processes involved
– E.g., effects on acquisition vs. consolidation vs. retrieval vs. extinction
– No risk of carry-over effects
•
Allow for deconstruction of the neural processes involved
– E.g., local infusions into selected brain areas
• May represent mechanistic rather than disease models
Increased prefrontal dopamine release following acute
amphetamine in rats
Cognitive symptoms in schizophrenia
associated with prefrontal DA
hypofunction
1.5 mg/kg s.c.
2.5 mg/kg s.c.
Hertel et al., Behav Brain Res 72, 1995
Abi-Dargham and Moore, Neuroscientist 9, 2003
Acute Challenge Models – Advantages and
Disadvantages
• Gained popularity due to high sensitivity to detect clinically used
drugs
– Risks to detect more of the same
PCP increases peripheral and
central AMPH levels
• Potential drug/drug interactions
• Time-dependent effects
– Pharmacokinetics determine behavioural response
• Need for time-limited cognitive tests
– Pharmacodynamics may determine behavioural response
PCP-induced DA peak followed by sustained glutamate efflux
Prefrontal Dopamine
Sershen et al., Neurochem Int 52, 2008
Prefrontal Glutamate
Adams and Moghaddam, J Neurosci 15, 1998
Acute Amphetamine
Effects on Cognitive Function in Animals
Reduced 5-CSRRT reaction time / increased impulsivity in rats
Higgins et al., Behav Brain Res 185, 2007
Reduced stop-signal reaction time in rats with slow baseline
Feola et al., Behav Neurosci 114, 2000
Impaired conditional discrimination in rats
Dunn et al., Psychopharmacology 177, 2005
Impaired reversal learning in rats
Idris et al., Psychopharmacology 179, 2005
Amphetamine Effects Aren’t Necessarily
Disruptive, but Depend on Task Difficulty
Increasing attentional load improves accuracy and shortens correct response
latency in rats on 5-CSRRT
total trials
total trials
Grottick and Higgins, Psychopharmacology 164, 2002
•
Extended number of trials (100 → 250), beneficial effects seen during later stages
•
Shorter stimulus duration (0.5 s → 0.25 s)
Antipsychotics Reverse Effects of Acute
Amphetamine
Haloperidol, but not clozapine, reverses the amphetamine-induced impairment in
reversal learning
Idris et al., Psychopharmacology 179, 2005
Clozapine, but not haloperidol or eticlopride, reverses the
amphetamine-induced impairment in conditional
discrimination
• Validity to predict cognitive
enhancing effects in
patients limited ?
Dunn and Killcross, Psychopharmacology 188, 2006
Acute PCP – Impairments Across Multiple
Cognitive Domains
Speed of
processing,
attention
Problem
solving,
flexibility
Visual
learning and
memory
Working
memory
Social
cognition
Antipsychotics Reverse Effects of Acute PCP
Task
Species
Attenuation of PCP Deficit
Reference
5-CSRTT
Rat
• Clozapine (acute)
• Clozapine (chronic)
• Risperidone
Exacerbates
NO
Exacerbates
Amitai et al., Psychopharmacology
193, 2007
Reversal learning
Rat
• Clozapine
• Lamotrigine
YES
YES
Idris et al., Psychopharmacology 179,
2005
Radial arm maze
Rat
• Quetiapine (chronic)
YES
He et al., Behav Brain Res 168, 2006
Social recognition
Rat
• Clozapine
• Amisulpride
• Haloperidol
YES (partially)
YES
NO
Terranova et al., Psychopharmacology
181, 2005
Attenuation of PCP effects on prefrontal rCBF
•
•
Gozzi et al., Neuropsychopharmacology 33, 2008
Acute PCP model seems more
sensitive to atypical than to typical
antipsychotics
Limited validity to predict cognitive
enhancing effects in patients ?
Repeated Challenge Models
• Suggested to better model the behavioural and metabolic
dysfunction of schizophrenia
• Translational value: comparison with e.g. amphetamine, PCP
or ketamine abusers (etiological validity)
• (Sub-)chronic models allow for testing at steady state
(osmotic minipump)
• Abstinence models
– Enable testing without challenge drug on board
– Reduce some pharmacokinetic issues (e.g., drug/drug interactions,
dependency on T½)
– At least in part based on finding that dug-induced psychosis can last
for weeks despite abstinence (e.g. PCP)
Effects of Amphetamine Abstinence in Man
• The effects of repeated exposure to amphetamine reproduce the main
features of paranoid schizophrenia, cognitive and negative symptoms
• Following discontinuation of drug use, subjects remain more sensitive to
the psychotogenic effects of amphetamine
• There is an increased sensitivity of the mesolimbic dopamine system to
the effects of amphetamine, which resembles the hyper-responsiveness
seen in the system in schizophrenic patients
Reviewed in Sarter et al., Psychopharmacology 202, 2009
Repeated Amphetamine – Neurobiological Effects in Rodents
Index
Dopamine
Brain area
Prefrontal cortex
GABA
Glucose utilization
NGF
Prefrontal cortex
Accumbens
Hippocampus, occ
cortex, hypothals
Occipital cortex,
hypothalamus
BDNF
CaMKII
Striatum
Effect
- basal utilization
↑ stress-induced utilization
↓ parvalbumin immunoreactivity
↓ basal utilization
↓ level
Reference
↓ level
Angelucci et al., Eur Neuropsychopharmacol 17, 2007
↑ expression
Greenstein et al., Synapse 61, 2007
Hamamura and Fibiger, Eur J Pharmacol 237, 1993
Morshedi and Meredith, Neuroscience 149, 2007
Tsai et al., Psychiat Res 57, 1995
Angelucci et al., Eur Neuropsychopharmacol 17, 2007
Effects of Amphetamine Sensitization,
Withdrawal and Abstinence
Altered prefrontal DA levels in sensitized
animals under withdrawal
Long-lasting 5-CSRTT deficit
Naive
Sensitized
sensitization weeks
Hedou et al., Neuropharmacology 40, 2001
Amphetamine 1.5 mg/kg IP 5 days
Withdrawal 2 days, followed by microdialysis
withdrawal weeks
Fletcher et al., Neuropsychopharmacology 32, 2007
Amphetamine 1 - 5 mg/kg 3x/week, 5 weeks
Attenuation of Impaired Performance in
Amphetamine Abstinent Rats by D1 Agonism
Increased impairment with increased
attentional load
Stimulation of prefrontal D1 with SKF38393 improves
performance in sensitized rats
SKF 0.06 µg
Testing during weeks
11 + 12 of withdrawal
Fletcher et al., Neuropsychopharmacology 32, 2007
Testing during weeks 6 + 7 of withdrawal
Cognitive Effects of Amphetamine Sensitization
Sarter et al., Psychopharmacology 202, 2009
Antipsychotics Attenuate the Effects of
Amphetamine Pre-treatment
Attenuation of impaired attention by
haloperidol and clozapine
Sustained attention task
Pre-treatment regimen
VI: Vigilance Index
Haloperidol 0.025 mg/kg SC, 10 days
Clozapine 2.5 mg/kg SC, 10 days
All rats received amphetamine (1.0 mg/kg) challenge
Martinez and Sarter, Neuropsychopharmacology 33, 2008
Effects of Subchronic PCP on DA Utilization
and Metabolic Activity
Subchronic PCP reduces basal DA utilization in
prefrontal cortex in rats
Subchronic PCP reduces LCGU in
prefrontal cortex in rats
Vehicle
PCP (2.58 mg/kg chronic intermittend)
Jentsch et al., Neuropsychopharmacology 17, 1997
Cochran et al., Neuropsychopharmacology 28, 2003
PCP Abstinence – Neurochemical and
Neuroanatomical Effects Suggest Decent Etiological
Validity vis-a-vis Schizophrenic Patients
Index
Brain area
Effect
Reference
Dopamine
Prefrontal cortex
↓ basal utilization
Jetsch et al., Science 277, 1997
↓ stress-induced utilization
Jentsch et al., Neuropsychopharmacology 17, 1997;
Noda et al., Neuropsychopharmacology 23, 2000
Glutamate
Prefrontal cortex
↓ extracellular basal level
Murai et al., Behav Brain Res 180, 2007
GABA
Frontal cortex,
hippocampus
↓ parvalbumin expression
Cochran et al., Neuropsychopharmacology 28, 2003;
Reynolds et al., Neurotox Res 6, 2004; Abdul-Monim et
al., Behav Brain Res 169, 2006
Glucose utilization
Prefrontal cortex
↓ basal utilization
Cochran et al., Neuropsychopharmacology 28, 2003*
NAA and NAAG
Temporal cortex
↓ level
Reynolds et al., Schizophr Res 73, 2005
CaMKII
Prefrontal cortex
↓ learning-associated
phosphorylation
Enomoto et al., Mol Pharmacol 68, 2005
↓ swim-stress-induced
phosphorylation
Murai et al., Behav Brain Res 180, 2007
ERK
Hippocampus, amygdala
↓ learning-associated
phosphorylation
Enomoto et al., Mol Pharmacol 68, 2005
Neurodegeneration
Cingulate cortex
Neuronal vacuolization
Olney et al., Science 244, 1989
Cingulate, entorhinal,
retrospl cx, hippocampus
Altered morphology
Ellison and Switzer, Neuroreport 5, 1993
Prefrontal cortex
↓ number of spine synapses
↑ astroglial process density
Hajszan et al., Biol Psychiatry 60, 2006
*chronic intermittent
Modified from Mouri et al., Neurochem Int 51, 2007
Cognitive Effects Acute versus Chronic PCP
Acute PCP
Chronic PCP
Comment
5-CSRRT
Mild impairment (Amitai et al.,
Psychopharmacology 193, 2007)
Impairment (Amitai et al.,
Psychopharmacology 193, 2007; Amitai
& Markou, Psychopharmacology 202,
2009)
Tested over 5 days
repeated treatment
Set shifting
Impairment (Eggerton et al.,
Psychopharmacology 179, 2005)
No impairment (Deschenes et al., Behav
Brain Res 167, 2006)
Test 1 day after 33
days treatment
Novel object
recognition
Novelty preference intact (Pichat et
al., Neuropsychopharmacology 32,
2007)
Impairment (Mandillo et al., Behav
Pharmacol 14, 2003)
Test 1 day after 5
days treatment
Delayed
alternation
Water maze
Delay-dep. impairment (Jentsch et al.,
Neuropsychopharmacology 17, 1997)
Impaired acquisition (Podhorna &
Didriksen, Behav Pharmacol 16, 2005;
Wass et al., Behav Brain Res 174,
2006)
Impaired acquisition, intact
consolidation (Didriksen et al.,
Psychopharmacology 193, 2007;
Podhorna & Didriksen, Behav Pharmacol
16, 2005))
• High degree of heterogeneity of treatment regimes (number, frequency,
duration, dose)
• Testing w/o PCP challenge dose
Cognitive Effects Acute versus Abstinence
from Chronic PCP
Set shifting
Acute
Wihdrawal/Abstinence
↓ ED shift (Eggerton et al.,
Psychopharmacology 179, 2005)
↓ ED shift (Rodefer et al., Eur J Neurosci 21, 2005;
McLean et al., Behav Brain Res 189, 2008;
Goetghebeur and Dias, Psychopharmacology 202,
2009; Broberg et al., Psychopharmacology 206,
2009)
- (Fletcher et al., Psychopharmacology 183, 2005)
Reversal learning
↓ (Idris et al., Psychopharmacology
179, 2005)
↓ (Abdul-Monim et al., J Psychopharmacol 21, 2006;
Abdul-Monim et al., Behav Brain Res 169, 2006)
Novel object
recognition
- Novelty preference (Pichat et al.,
Neuropsychopharmacology 32,
2007)
↓ Novelty preference (Hashimoto et al., Eur J
Pharmacol 519, 2005; Harte et al., Behav Brain Res
184, 2007; Nagai et al., Psychopharmacology 202,
2009)
↓ Novelty preference following additional acute PCP
challenge (Pichat et al., Neuropsychopharmacology
32, 2007)
Delayed alternation,
T-maze
↓(Stefani and Moghaddam, Behav
Brain Res 134, 2002)
↓ Delay-dependent (Seillier and Giuffrida, Behav
Brain Res 204, 2009)
- (Stefani and Moghaddam, Behav Brain Res 134,
2002)
Reference memory,
radial maze
- (Li et al., Pharmacol Biochem Behav 75, 2003)
Antipsychotics Reverse Effects of Repeated PCP
Task
Species Attenuation of PCP deficit
Reference
5-CSRTT
Rat
• Clozapine (chronic)
YES
Amitai et al., Psychopharmacology 193, 2007
Set shifting
Rat
• Clozapine
• Risperidone
• Haloperidol
YES
YES
NO
McLean et al., Behav Brain Res 189, 2008
• Sertindole
• Risperidone
• Haloperidol
• (Modafinil)
YES
NO
NO
YES
Goetgebheur and Dias, Psychopharmacology 202,
2009
• Sertindole
YES
Broberg et al., Psychopharmacology 206, 2009
Object retrieval
Monkey
• Clozapine (3 days)
YES
Jentsch et al., Science 277, 1997
Novel object
recognition
Rat
• Clozapine
• Risperidone
• Haloperidol
YES
YES
NO
Grayson et al., Behav Brain Res 187, 2007
Mouse
• Clozapine
• Haloperidol
YES
NO
Hashimoto et al., Eur J Pharmacol 519, 2005
• Aripiprazole
• Haloperidol
YES
NO
Nagai et al., Psychopharmacology 202, 2009
• Clozapine
• Risperidone
• Sertindole
• Haloperidol
YES
YES
YES
NO
Didiriksen et al., Psychopharmacology 193, 2007
Water maze
•
Rat
Data support suggestion that repeated PCP model is more sensitive to atypical
than to typical antipsychotics – but limited use of typical antipsychotics
Conclusion I
Acute DA and NMDA Challenge Models
• Generally considered to be of predictive utility for models of positive
symptoms
• High degree of cross-species neural homology
– Comparable biological substrates affected across species
• Translational model: can be used to challenge healthy volunteers under
well controlled experimental conditions
• Limited utility as disease model of cognitive symptoms
•
Limited etiological validity vis-a-vis schizophrenia
• Useful for screening purposes, to increase the response window (testing
of impaired rather than normal animals)
• Strong mechanistic aspect, risks detection of compounds with effects
analogous to current antipsychotics and false positives; no reports of
superiority of novel mechanisms of action
Conclusion II
Repeated DA and NMDA Challenge Models
• Activity in a wide variety of preclinical test relevant for cognitive domains
impaired in schizophrenia
• High degree of cross-species homology/etiological validity
– Comparable biological substrates affected across species
– Neurochemical and –anatomical features resembling schizophrenia more closely
• Translational model: can be used to compare with certain nonschizophrenic human populations (e.g., amphetamine abusers) to bridge
the gap
• Highly variable treatment and test protocols
– Difficulty to compare results across labs and to evaluate reliability and
reproducibility
• Atypical antipsychotics more efficacious than typical antipsychotics
• Some novel mechanisms of action show activity – but definitive clinical
proof of concept missing
Flipping the Coin
• Do effects of atypical antipsychotics in pharmacological
models of schizophrenia translate into effects on
cognitive function in schizophrenic patients?
• Are these clinical effects statistically significant or
clinically relevant?
• Answer determines utility of pharmacological models to
predict therapeutic effects