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Animal Models of Schizophrenia Pharmacological Models - Advantages and Challenges -

Animal Models of Schizophrenia Pharmacological Models - Advantages and Challenges -. Thomas Steckler. Pharmacological Models. Dopamine Glutamate CB 5-HT. Acute (Sub-)chronic/Sensitization Withdrawal/Abstinence Neurodevelopmental

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Animal Models of Schizophrenia Pharmacological Models - Advantages and Challenges -

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  1. Animal Models of SchizophreniaPharmacological Models- Advantages and Challenges - Thomas Steckler

  2. Pharmacological Models Dopamine Glutamate CB 5-HT Acute (Sub-)chronic/Sensitization Withdrawal/Abstinence Neurodevelopmental (pre-/postnatal) • 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? Manipulation Test Measure

  3. Publications on Pharmacological Models of Schizophrenia 2009 ACh DA Glut DA 5-HT Glut DA Medline search • 584 hits • 94 articles selected • 125 models published CB Glut Mouse % Rat methamphetamine amphetamine apomorphine SKF-83566 PCP MK-801 ketamine memantine quipazine DOI scopolamine THC amphetamine PCP MK-801 ketamine kynurenic acid quinpirole PCP MK-801 acute chronic neonatal

  4. 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 time-critical step • Good validity to predict efficacy of antipsychotics to treat positive symptoms • Effective screening tools

  5. 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

  6. 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 • NMDA channel blocker • Sigma receptor • Other ion channel • receptors • Transporters • GPCRs desired irreversibility non-specific toxic unreliable dose

  7. 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 • NMDA antagonists tested in various VI schedules of reinforcement • Biconditional VI 30/VI 30: • 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 Gilmour et al., Psychopharmacology 205, 2009

  8. 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 Ketamine 30 mg/kg IP MK-801 0.5 mg/kg IP Vollenweider et al., Eur Neuropsychopharmacology 7, 1997 Miyamoto et al., Neuropsychopharmacology 22, 2000

  9. 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 1.5 mg/kg s.c. 2.5 mg/kg s.c. Increased prefrontal dopamine release following acute amphetamine in rats Cognitive symptoms in schizophrenia associated with prefrontal DA hypofunction Hertel et al., Behav Brain Res 72, 1995 Abi-Dargham and Moore, Neuroscientist 9, 2003

  10. Acute Challenge Models – Advantages and Disadvantages • Gained popularity due to high sensitivity to detect clinically used drugs • Risks to detect more of the same • Potential drug/drug interactions • Time-dependent effects • Pharmacokinetics determine behavioural response • Need for time-limited cognitive tests • Pharmacodynamics may determine behavioural response PCP increases peripheral and central AMPH levels Sershen et al., Neurochem Int 52, 2008 PCP-induced DA peak followed by sustained glutamate efflux Prefrontal Glutamate Prefrontal Dopamine Adams and Moghaddam, J Neurosci 15, 1998

  11. Acute AmphetamineEffects on Cognitive Function in Animals Reduced 5-CSRRT reaction time / increased impulsivity in rats Impaired conditional discrimination in rats Higgins et al., Behav Brain Res 185, 2007 Dunn et al., Psychopharmacology 177, 2005 Reduced stop-signal reaction time in rats with slow baseline Impaired reversal learning in rats Feola et al., Behav Neurosci 114, 2000 Idris et al., Psychopharmacology 179, 2005

  12. 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)

  13. 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

  14. Acute PCP – Impairments Across Multiple Cognitive Domains Speed of processing, attention Problem solving, flexibility Visual learning and memory Working memory Social cognition

  15. Antipsychotics Reverse Effects of Acute PCP Attenuation of PCP effects on prefrontal rCBF • Acute PCP model seems more sensitive to atypical than to typical antipsychotics • Limited validity to predict cognitive enhancing effects in patients ? Gozzi et al., Neuropsychopharmacology 33, 2008

  16. 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)

  17. 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

  18. Effects of Amphetamine Sensitization, Withdrawal and Abstinence Long-lasting 5-CSRTT deficit Altered prefrontal DA levels in sensitized animals under withdrawal Naive Sensitized sensitization weeks withdrawal weeks Hedou et al., Neuropharmacology 40, 2001 Fletcher et al., Neuropsychopharmacology 32, 2007 Amphetamine 1.5 mg/kg IP 5 days Withdrawal 2 days, followed by microdialysis Amphetamine 1 - 5 mg/kg 3x/week, 5 weeks

  19. 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

  20. Cognitive Effects of Amphetamine Sensitization Sarter et al., Psychopharmacology 202, 2009

  21. Antipsychotics Attenuate the Effects of Amphetamine Pre-treatment Sustained attention task Attenuation of impaired attention by haloperidol and clozapine 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

  22. Effects of Subchronic PCP on DA Utilization and Metabolic Activity Subchronic PCP reduces LCGU in prefrontal cortex in rats Subchronic PCP reduces basal DA utilization 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

  23. PCP Abstinence – Neurochemical and Neuroanatomical Effects Suggest Decent Etiological Validity vis-a-vis Schizophrenic Patients *chronic intermittent Modified from Mouri et al., Neurochem Int 51, 2007

  24. Cognitive Effects Acute versus Chronic PCP • High degree of heterogeneity of treatment regimes (number, frequency, duration, dose) • Testing w/o PCP challenge dose

  25. Cognitive Effects Acute versus Abstinence from Chronic PCP

  26. Antipsychotics Reverse Effects of Repeated PCP • Data support suggestion that repeated PCP model is more sensitive to atypical than to typical antipsychotics – but limited use of typical antipsychotics

  27. Conclusion IAcute 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

  28. Conclusion IIRepeated 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 non-schizophrenic 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

  29. 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

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