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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 25 ACh DA 5-HT Glut CB DA Glut DA Glut 20 % 15 Mouse Series2 10 Rat Series1 5 0 1 2 3 4 5 6 7 acute 8 9 10 11 12 13 14 15 16 17 18 19 20 chronic neonatal Medline search • 584 hits • 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 • • 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