Schizophrenia animal models

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

Specific animal models are discussed in some detail in the appropriate chapters on epilepsy, depression, schizophrenia, etc. 

Altered startle reactivity and attenuation of the inhibition of the startle reflex by an acoustic prepulse has been observed in psychiatric patients, e.g. in schizophrenia (Braff et al. 1978). Disrupted prepulse inhibition in rats can be normalized by antipsychotics and this paradigm is being used as an animal model for drug development. Interestingly, a2c-KO mice had enhanced startle responses, diminished prepulse inhibition, and shortened attack... 

Braff DL, Geyer MA Sensorimotor gating and schizophrenia human and animal model studies. Arch Gen Psychiatry 47 181-188, 1990 Bramanti P, Bianchi L, Benedetto M, et al Study of the hypnic effect of amineptine evaluation by polygraphy and tests. Prog Neuropsychopharmacol Biol Psychiatry 9 157-165, 1985... 

NON-GENETICALLY-BASED ANIMAL MODELS Models of Schizophrenia... 

Among the animal models of schizophrenia a distinction can be made between pharmacological, lesion-induced and neurodevelopmental models. As is the case with models of depression and anxiety, it will be inappropriate to describe an animal with unusual behavior as suffering from schizophrenia however, it is possible in animals to mirror at least some of the symptoms or parameters known to be predominant and aberrant, respectively, in schizophrenic patients. 

Ellenbroek, BA., Gever, MA., Cools, A.R. The behavior of APO-SUS rats in animal models with construct validity for schizophrenia. J. Neurosci. 15, 7604-7611, 1995. 

Kilts, C.D. The changing roles and taigets for animal models of schizophrenia. Biol. Psychiatry 50, 845-855, 2001. 

Sams-Dodd, F. Phencyclidine-induced stereotyped behaviour and social isolation in rats a possible animal model of schizophrenia. Behav. Pharmacol. 7 3-23. 1996. 

Ampakines are drugs that potentiate currents mediated by AMPA-type glutamate receptors. In behavioral tests, ampakines are effective in correcting behaviors in various animal models of schizophrenia and depression. They protect neurons against neurotoxic insults, in part by mobilizing growth factors such as brain-derived neurotrophic factor (BDNF). 

Cannabinoid antagonists. Cannabinoid receptors are discussed in further detail in Chapter 13 on drug abuse. An antagonist to cannabinoid 1 (CB1) receptors, SR141716A, reduces the activity of mesolimbic dopamine neurons in animal models, suggesting possible antipsychotic actions in schizophrenia and leading to testing in schizophrenic patients. 

Jacobson KA, Hoffmann C, Cattabeni F, Abbracchio MP (1999) Adenosine-induced cell death evidence for receptor-mediated signalling. Apoptosis 4(3) 197—211 Kafka SH, Corbett R (1996) Selective adenosine A2A receptor/dopamine D2 receptor interactions in animal models of schizophrenia. Eur J Pharmacol 295(2-3) 147-154 Latini S, Bordoni F, Corradetti R, Pepeu G, Pedata F (1998) Temporal correlation between adenosine outflow and synaptic potential inhibition in rat hippocampal slices during ischemia-like conditions. Brain Res., 794, (2) 325-328. 

Key Words 5-HT6 receptors Alzheimer disease animal models cognition schizophrenia. 

Moser PC, Hitchcock JM, Lister S, Moran PM. The pharmacology of latent inhibition as an animal model of schizophrenia. Brain Res Rev 2000 33 275-307. 

Castner SA, Goldman-Rakic PS, Williams GV. Animal models of working memory insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology 2004 174 111-125. 

Pouzet B, Didriksen M, Amt J. Effects of the 5-HT(7) receptor antagonist SB-258741 in animal models for schizophrenia. Pharmacol Biochem Behav 2002 71 655-665. 

The synthesis and discovery of the antipsychotic effects of the piperazinyl-dibenzoazepine, clozapine (Fig. 13.1) and its launch in 1972 was an important turning point in the drug treatment of schizophrenia [1-3]. Clozapine was called an atypical antipsychotic as it did not produce side effects characteristic for compounds of the chlorpromazine- or haloperidol-type (i.e., extrapyramidal symptoms) either in animal models or in the clinic. Its use, however, became very limited when it was recognized that clozapine might cause a severe, and sometimes fatal, form of agranulocytosis. 

The aim of this study was to determine, as a proof of concept, if DMXB-A significantly improves neurocognition and to assess, by effects on P50 inhibition, whether its actions are consistent with activation of oc7-nicotinic receptors. Because the proposed effect is agonism at a ligand-gated ion channel, biological effects were expected immediately, consistent with the results from animal models (Stevens et al., 1998). Twelve persons with schizophrenia consented to the study. They were concurrently treated with neuroleptic medications. Subjects who had not used nicotine or tobacco within the last month were selected to avoid possible interaction with chronic nicotine exposure. DMXB-A was administered orally (150 or 75 mg) followed 2 h later by a half dose (75 or 37.5 mg). The half dose, administered at the predicted half-life of the... 

Lipska BK. 2004. Using animal models to test a neurodeve-lopmental hypothesis of schizophrenia. J Psychiatry Neurosci 29 282-286. 

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