2-1 Schizophrenia and Animal Models

Therapeutic drugs for schizophrenia are generally called as "antipsychotics". Once I heard that patients of "neurosis" (anxiety neurosis) but not of "psychosis" (schizophrenia or manic-depressive psychosis) have insight into disease but currently we use words of a mental (or psychiatric) disease or disorder as a name of a disease. Psychosis is not used well as the disease name but remains a drug name as an antipsychotic. Old antipsychotics such as chlorpromazine and haloperidol were also called as neuroleptics but currently novel drugs having different mechanisms from the old antipsychotics were developed and "neuroleptics" have become not to be used as the name of therapeutic drugs for schizophrenia. Characteristic symptoms for schizophrenia are positive and negative symptoms. DSM-IV (Diagnostic and Standard Manual of Mental Disorders Fourth Edition, The American Psychiatric Association) shows 1) delusionA2) hallucination, 3) disorganized conversation, 4) severely disorganized or catatonic behaviors, and 5) negative symptoms as characteristic symptoms of schizophrenia. 1) - 4) such as hallucination and delusion are called as positive symptoms and cured well by antipsychotics. However, the negative symptoms (flattened emotion, poor thinking, and lack of motivation) do not respond well to the drugs and it is a major problem in a schizophrenic therapy.

We cannot establish animal models for hallucination and delusion that similar symptoms are shown in mice and rats as human like anxiety described in "1. Anxiolytics". For example, someone does not eat foods due to his delusion that the foods are poisoned. If we hear him why does he eat the foods, we can know his delusion. However, if mice and rats do not eat foods, we think that they are something ill. If drugs induce to stop eating, we consider that those have anorectic but not hallucinogenic effects. Some schizophrenic patients insist that they hear criminating or directing multiple voices. If they hear such voices where no one is present, it is called as auditory hallucination. If they behave according to directions from auditory hallucination and communicate to the hallucination, we will ask them what happens. If they say that they heard voices, we can know the auditory hallucination. However, we hardly think that rodents behave according to the hallucination and the behaviors in the rodents will be thought to happen by chance in spite of lack of causes. Thus, it is almost impossible that we establish rodent models of hallucination and delusion by similarity to human behaviors.

In such situations behavioral pharmacology can bring a pharmacological solution. It is describe in DSM-IV as discrimination of schizophrenia that schizophrenia-like symptoms are observed in some substance-related disorders. For example delusion and hallucination by a long time use of amphetamine and cocaine or mixture of positive and negative symptoms by phencyclidine abuse are known. If schizophrenia-like symptoms are caused by such drugs, it should be discriminated from schizophrenia. Conversely we can think that intake of these drugs experimentally induces schizophrenia-like symptoms. On these backgrounds behavioral changes in rodents by psychostimulants such as amphetamine and methamphetamine, a dopaminergic agonist, apomorphine, and phencyclidine are widely used to evaluate antipsychotics. Because a major purpose of these models is evaluation of clinically effective drugs in schizophrenia, the models are validated by efficacy of clinically active antipsychotics.

2-1-1 Stereotypy

Observation of increases in locomotion and stereotypy as behavioral changes by acute administrations of the drugs described above is a simple evaluation method for antipsychotics. Spontaneous locomotion in mice and rats is generally measured by automatic measuring devices that can measure it on variety of bases are commercially available. Stereotypy is repeated behaviors and apparently purposeless which is observed clinically in schizophrenic patients. Sniffing is typical stereotypy in rodents and the other behaviors such as biting, gnawing, licking, and rearing are often considered as stereotypy. We observe continuing levels of stereotypy and evaluate by its duration, number, and score of severities. These behaviors are suppressed by antipsychotics but also inhibited by sedative drugs such as anxiolytics. Stereotypy is also observed in other than schizophrenia and the model is not enough in specificity for schizophrenia.

2-1-2 Pre-pulse inhibition

Rat Enclosure and Sensor Plate
A photo cited from Lafayette Instrument

A disorder of a pre-pulse inhibition (PPI) and heredity of the disorder are observed in patients of schizophrenia (1)(2). PPI is a phenomenon that a weak stimulus immediately before a pulse stimulus (pre-pulse) suppresses responses to the pulse stimulus and also measured in mice and rats. The pulse stimulus is usually a short-time tone and the response to the tone (startle response) is measured as actual body movements such as jumping by an automatic measuring device. Although blinks or leg movements are measured by an electromyography (EMG) in humans, in rodents movements of a whole body are detected as movements of a cage containing them. Because sounds other than the tone stimulus are affect the response, the PPI is measured in a sound-attenuating box at a presence of stable background noise. A pre-pulse stimulus is approximately 10 dB more than the background and immediately (ca. 100 msec) after the pre-pulse, a pulse stimulus is given at e.g. 120 dB (background 60 dB). Although durations of pre-pulse and pulse stimuli are a short time such as a couple of 10 msec, pre-pulse is generally shorter. Several trials with and without pre-pulse stimuli are conducted and %PPI is calculated, which means what extents startle responses to the pulse stimuli are inhibited by presence of the pre-pulse stimuli compared to those in absence of the pre-pulse. Dopaminergic agonistic actions by injection of apomorphine etc. induce to impair PPI in rats (3)(4) and mice (5)(6). Impairment by phencyclidine (PCP) of PPI (7) and its amelioration by antipsychotics (8) are observed and measurements of PPI impairment have been a gold standard of an evaluation model for schizophrenia. Because the blocking state of PPI is the model of schizophrenia, it is important that how we impair the PPI in rodents. Administrations of dopaminergic agonists and PCP are easy but only antagonistic effects to these drugs but not antipsychotic effects may be detected. It is important that the PPI impairment is evaluated in multiple models such as knock-out mice (9), brain-injury models (10) and so on. We hope that analyses of different models make clear pathogenesis and pathology of schizophrenia and develop novel drugs having ameliorating effects on a variety of its symptoms, especially negative symptoms.

2-1-3 Phencyclidine Models

Classical (typical) antipsychotics such as haloperidol have antagonistic effects on dopamine D2 receptors and suppress the impairment of PPI by apomorphine. Typical antipsychotics clinically well improve positive but not in negative symptoms in schizophrenia. Current atypical antipsychotics are also called as SDA (Serotonin Dopamine Antagonist) having antagonistic effects on the both serotonergic and dopaminergic nervous systems or a D2 partial agonist, aripiprazole, which have efficacy to negative symptoms as well as positive ones but more potent drugs are needed. Effects on the negative symptoms must be studied in the animal models of the negative symptoms. PCP abuse induces schizophrenia-like symptoms in human and chronic administrations of PCP decrease social interactions in rodents, which is thought to be a good model simulating clinical symptoms.

2-2 Adverse Effects of Antipsychotics (Extrapyramidal Symptoms)

Many antipsychotics suppress the dopaminergic neuronal systems and cause disorders on locomotive functions. The movement disorder is also called as an extrapyramidal syndrome includes parkinsonism such as tremor and rigidity and dyskinesia. Tardive dyskinesia may be observed after a long-term intake of antipsychotics, which is a very severe adverse effect.

Rodents are used for evaluation of such extrapyramidal symptoms. A long-time continuing unnatural posture is one of them and called as catalepsy and can be evaluated by a simple model. If the both forepaws of rodents are hooked on a horizontal wire at the appropriate height, they promptly get down their forepaws. However, they continue this unnatural posture for a long time (a couple of 10 sec) when catalepsy is occurred and we can evaluate catalepsy by measuring its duration in mice and rats.

Atypical antipsychotics recently used are less in the extrapyramidal symptoms but induce obesity which is a novel problem. Of cause, the behavioral pharmacology such as measuring increase in food intake is used for evaluation of obesity.

2-3 Closing

Interestingly, McDannald and Schoenbaum reported that they considered hallucination as confused reality and discussed Pavlovian conditioning as an animal model of hallucination (11). If tone is conditioned to rewards (foods) by classical Pavlovian conditioning, the animals hope by tone alone that foods will be given. If rodents become sick by LiCl after a food intake, they will not eat foods, which is conditioning called as taste aversion learning. If tone is conditioned to LiCl after conditioned to foods in rats by these combinations, the rats will not eat the foods (12). Because LiCl is not directly conditioned to foods, we easily understand that rats confuse to assess reality if rats think to become sick by eating foods and decrease the food intake. However, it is difficult to instinctive feel that associate such confused reality in rat experiments to visual and acoustic hallucinations which we see and hear no existence, respectively. These discussions are also psychologically interested but further studies are needed.