if animal models are new , and reflect the disease state better , then they may allow different compounds to be selected if final compound selection is performed in the disease model .
thus very different , compounds will be chosen for drug development . the disease state may change the kinetics of receptor interactions or the multiple states of a receptor , meaning that screening in normal conditions may not be appropriate . from thermodynamics , changing affinity by 100- to 1000-fold ( ie , a enormous change in structure - activity )
may reflect a change in only one hydrogen bond between ligand and receptor , which is very difficult to predict , on a molecular level .
thus , it is likely that conformational modifications in a disease state - if the target is really a causative agent in the disease process - would involve changes of such a magnitude . indeed , switching the conformation of a receptor between agonist or antagonist states can change the affinity by more than a 1000-fold , entirely changing the structure - activity , because of changes in different binding pockets .
thus , differences between receptor  states  can be more important , than differences between types of receptor . 
 
it , is thus clear then that screening in appropriate disease models , rather than on putative receptor targets under normal conditions , would lead to drugs better targeted toward the pathological events , and thus toward better treatment , of the patient .
it is also important to ensure that the same measures can be made in animals as in clinical testing .
this may be easily accessible in the cardiovascular system , but studies in the central nervous system ( cns ) may require more indirect comparisons . however , some end points are amenable
. we have studied electroencephalographic ( eeg ) techniques and extensively characterized means of transferring preclinical effects in conscious animals toward the same effects in man , as clinical erg is a powerful means of defining the effects of drugs .
abnormalities in the neural circuits in the prefrontal cortex , which are involved in working memory , are the basis of the model of schizophrenia proposed by goldman - rakic , and have been seen in imaging studies . a robust reduction ( > 3.5 million ) in the number of thalamic
thus , the prefrontal cortex is a key area and the hippocampus is also important because the ncurodcvelopmcnt model of schizophrenia indicates changes in its development .
phencyclidine ( pcp ) is an iv - methyl - d - aspartate ( nmda ) antagonist that induces hallucinations in man .
pcp and the structurally related molecule ketamine have been shown to exacerbate existing psychotic disorders in schizophrenics and to reactivate symptoms in remittance .
use of pcp in animals and of ketamine in man has been claimed to be the most valid model for schizophrenia today . 

the effects of pcp were not well characterized in the rrg of animals , and so we set up an animal model of the rrg effects of pcp .
we had previously characterized more than 50 drug - induced changes in a model of rrg of prefrontal cortex , using the somatosensori - motor region as a control for effects on motor functions . 
  chronically implanted
eeg leads in the prefrontal cortex of conscious rats are used to obtain  fingerprints  of drug profiles over the range of 1 to 30 hz by subtracting the control eeg from the eeg spectrum in the presence of the test drug 24 hours later .
we reported that activation of noradrenergic and dopaminergic receptors causes a decrease in rrg power ( desynchronization ) , whereas inhibition of these two systems increases reg power ( synchronization ) .
decreases in eeg power in this model are induced by agents which increase vigilance , such as modafinil .
interestingly , nearly all the antipsychotic agents that we tested ( clozapine , haloperidol , and risperidone ) increased theta / alphal power ( peaks between 7 and 8 hz ) , indicating an impact , on cortical processes in the prefrontal cortex , as theta rhythm is involved in memory processes and neuronal plasticity .
we found that antipsychotic agents ( haloperidone , chlorpromazine , risperidone , clozapine , and olanzepine ) increased theta frequencies ( about 8 hz ) in the rat prefrontal cortex .
theta rhythm is 4 to 7 hz in man and 3 to 12 in rats ( usually 72 hz ) , and is increased by movement , implying a role in motor function : the faster a rat runs , the faster the theta rhythm .
theta rhythm is used to create a unit of cell assemblies , across the brain , in phase , working on a common problem .
thus , theta also has the capacity to separate assemblies that are working on different problems .
thus , the fact , that antipsychotic agents increase the probability of theta rhythm in the prefrontal cortex indicates direct effects in cognitive processes .
in contrast , while studying the effects of the propsychotic nmda antagonist pcp , to our surprise , we found massive increases in rrg spectral power at low frequencies ( < 4 hz ) and a powerful reduction in power ( desynchronization ) at 6 to 30 hz .
the model was simple : implantation of transcortical electrodes in the prefrontal and sensorimotor cortices with analysis of rrg power spectra between 1 and 30 hz over 3 hours .
the effects of the vehicle , administered on the first day , was subtracted from the effects of the drugs , administered on the second day , allowing an rrg power spectrum of the effects of the drugs .
the results were published by sebban et al in 2001 , and are summarized here : the eeg effects of the propsychotic agent pcp showed that pcp ( 0.1 - 3 mg.kg , subcutaneous ) ( figure 2 . ) caused a marked dose - dependent increase in rrg power in the frontal cortex at 1 to 3 hz , with decreases in power at higher frequencies ( 9 - 30 hz ) .
mk801 ( 0.050.1 mg.kg , intraperitoneal [ ip ] ) caused similar effects , but , with lesser changes in power .
in contrast , the noncompetitive ampa ( amino-3hydroxy-5-methyl-4-isoxazole propionic acid ) antagonists gyki 52466 and gyki 53655 increased rrg power over the whole power spectrum ( 1 - 10 mg.kg , ip ) .
clozapine , an atypical antipsychotic agent ( 0.2 mg.kg , subcutaneous ) synchronized the rrg ( peak 8 hz ) ( figure 3 . ) the 5-ht2a antagonist m100907 specifically increased rrg power at 2 to 3 hz at low doses ( 10 and 50 ug.kg subcutaneous ) , whereas at higher doses ( 0.1 mg.kg , subcutaneous ) the profile resembled that of clozapine .
clozapine ( 0.2 mg.kg , subcutaneous ) , gyki 53655 ( 5 mg.kg , ip ) , prazosin ( 0.05 and 0.1 mg.kg , ip ) , and m100907 ( 0.01 and 0.05 mg.kg , subcutaneous ) antagonized the decrease in power between 5 and 30 hz caused by pcp ( 1 mg.kg , subcutaneous ) , but not the increase in power at 1 to 3 hz in prefrontal cortex ( figure 4 . )
thus , clozapine , supposedly the best antipsychotic agent , available , apart from its limiting side effects , clearly increased theta rhythm in prefrontal cortex , indicating beneficial effects on cognition .
clozapine also partially antagonized the effects of pcp on rrg , but only the desynchronization .
these results clearly show that the effects of pcp on rrg can be used a model for schizophrenia , which may be transposable to man .
the profiles of compounds screened for activity in this model are allowing new therapies for schizophrenia to be developed , particularly if all the effects of pcp may be antagonized .
 although many new potential drug targets have been discovered subsequent to the cloning of the human genome and the discovery of most of the relevant receptors , the role of these receptors in psychiatric disease is still not clear . 
 we argue that research into the disease process leading to new animal models that can be transposed to man is critical to drug discovery , and present an example of an animal model for schizophrenia using electroencephalography . 
Drug screening in vivo
Which models may be used for schizophrenia?
Drug-induced changes in EEG
Conclusion