Schizophrenia is characterized by three major symptom classes: positive symptoms, negative symptoms, and cognitive deficits. Classical antipsychotics (phenothiazines, thioxanthenes, and butyrophenones) are effective against positive symptoms but induce major side effects, in particular, extrapyramidal symptoms (EPS). The discovery of clozapine, which does not induce EPS and is thought effective against all three classes of symptom, has driven research for novel antipsychotics with a wider activity spectrum and lower EPS liability. To increase predictiveness, current efforts aim to develop translational models where direct parallels can be drawn between the processes studied in animals and in humans. The present article reviews existing procedures in animals for their ability to predict compound efficacy and EPS liability in relation to their translational validity. Rodent models of positive symptoms include procedures related to dysfunction in central dopamine and glutamatergic (N-methyl-d-aspartate) and serotonin (5-hydroxytryptamine) neurotransmission. Procedures for evaluating negative symptoms include rodent models of anhedonia, affective flattening, and diminished social interaction. Cognitive deficits can be assessed in rodent models of attention (prepulse inhibition) and of learning/memory (object and social recognition, Morris water maze and operant-delayed alternation). The relevance of the conditioned avoidance response is also discussed. A final section reviews procedures for assessing EPS liability, in particular, parkinsonism (catalepsy in rodents), acute dystonia (purposeless chewing in rodents, dystonia in monkeys), akathisia (defecation in rodents), and tardive dyskinesia (long-term antipsychotic treatment in rodents and monkeys). It is concluded that, with notable exceptions (attention, learning/memory, EPS liability), current predictive models for antipsychotics fall short of clear translational validity.
Schizophrenia is characterized by three major classes of symptom: positive symptoms (delusions, hallucinations, bizarre speech and thought, paranoia); negative symptoms (anhedonia, affective flattening, impoverishment of speech and thought, social withdrawal); and cognitive deficits (impairments in attention, learning, and memory).
Despite intensive research, the etiology of schizophrenia remains far from understood. Most hypotheses have evolved from the actions of drugs in clinical use or as a result of similarities between the symptoms of schizophrenia and the effects of certain drugs of abuse, notably the indirect dopamine (DA) receptor agonist amphetamine, the glutamate receptor antagonist phencyclidine (PCP), and the 5-HT2 receptor agonist lysergic acid diethylamide. The major hypothesis has centered around central DA neurotransmission because all classical antipsychotics (phenothiazines, thioxanthenes, and butyrophenones) have as principal mechanism the blockade of central DA receptors (Carlsson, 1988).
The introduction of the atypical antipsychotic clozapine in the early 1970s and its revival in the late 1980s (Meltzer, 1989) has stimulated the search for other hypotheses because clozapine is clearly active as an antipsychotic, does not induce EPS, and has been claimed effective even against negative symptoms and cognitive deficits (Meltzer, 1989). Clozapine is less potent than classical antipsychotics in blocking central D2 receptors but has affinity for a wide range of other receptors, including D1, D4, 5-HT2A, 5-HT6, NAα1, H1, and M1 (Jones et al., 2008). Discovery strategies for novel antipsychotics for the past 30 years have therefore been dominated by attempts to reproduce the advantages of clozapine.
Validity is an essential requirement for any animal procedure used in drug discovery and traditionally has been divided into predictive validity, face validity, and construct validity (Willner, 1991). For predictive validity, the procedure must be capable of predicting therapeutic effects in humans. For face validity, the procedure must mimic clinical symptomatology. For construct validity, the procedure must reproduce etiological factors of the disease. Drug discovery programs aim principally to achieve predictive validity. Important in this respect are the notions of sensitivity (absence of false negatives) and selectivity (absence of false positives). Decreasing the number of false positives would seem to represent the major challenge for the discovery of antipsychotics.
In recent years, psychopharmacologists have made considerable efforts to develop translational procedures that seek a direct parallelism between the dependent measures used in animals and in human disease, with the aim to increase the pertinence of the animal procedures employed and thereby improve predictions of therapeutic efficacy (Markou et al., 2009). The prevalence of the translational approach has been highlighted by two recent research initiatives, the National Institute of Mental Health, National Institutes of Health-funded MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) battery and the European Commission initiative NEWMEDS (Novel Methods Leading to New Medications in Depression and Schizophrenia).
The present article will review currently used behavioral procedures in animals for their translational validity and their capacity to predict clinical efficacy and side effect liability, concentrating on the three primary symptom classes in schizophrenia (positive symptoms, negative symptoms, and cognitive deficits) and the principal side effects of antipsychotic drug treatment (EPS). A more detailed treatment can be found in Castagné et al. (2009).
Procedures for Evaluating Positive Symptoms
Agitation, hallucinations, delusions, and paranoia represent the main positive symptoms described in patients with schizophrenia. Although delusions, paranoia, and hallucinations are difficult to model in rodents, agitation is more easily amenable to behavioral testing. Indeed, the majority of tests relevant to agitation use different reagents to reproduce a behavioral abnormality that is assumed to be present in patients suffering from psychosis (Geyer and Ellenbroek, 2003). Although caution must be used in drawing parallels between animal and human behavior, stereotyped behavior in animals has been generally accepted as a model for the stereotyped behavior observed in patients with psychosis, whereas hyperactivity would seem to translate more closely psychotic agitation.
Hyperactivity and Stereotypies Induced by DA Agonists
Direct and indirect DA agonists, such as apomorphine, cocaine, and amphetamine, induce hyperactivity at moderate doses and stereotypies at higher doses when administered to rodents. This suggests a certain translational validity since direct or indirect activation of DA receptors can exacerbate florid psychotic symptoms in patients with schizophrenia. Activation of dopamine D2 receptors located in the nucleus accumbens induces hyperactivity, whereas stereotypies seem to involve D2 receptors in the striatum (Costall et al., 1982). Although all classical antipsychotics inhibit amphetamine-induced locomotion and stereotypies, clozapine has been found to be less effective against stereotypies (O'Neill and Shaw, 1999; Castagné et al., 2009). This finding could reflect clozapine's supposed preferential action on D2 receptors in the limbic system (Leite et al., 2008). Because EPS are thought to result from decreased DA activity in the striatum, a preferential action of a novel substance against DA-agonist-induced hyperactivity thus might represent a first indicator of a lower propensity to induce EPS in patients.
Behavioral tests using DA agonists would seem exclusively linked to the DA hypothesis. Nonetheless, other potential antipsychotics with minimal affinity for DA receptors, for example, the 5-HT2A antagonist MDL 100-907 [R-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol], or the 5-HT2C agonist WAY 163909 [(7bR,10aR)-1,2,3,4,8,9,10,1a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], and diverse client substances that we have evaluated in our own laboratory, also antagonize DA-agonist effects, suggesting that these procedures are not exclusive to the DA system. On the other hand, substances, such as lithium and diverse substances used for mood control, also attenuate DA agonist-induced hyperactivity but are devoid of antipsychotic activity (false positives).
Hyperactivity and Stereotypies Induced by NMDA Antagonists
Similarly to DA agonists, stereotypies and hyperactivity are induced in rodents by noncompetitive antagonists acting at the ion channel associated with the NMDA subtype of the glutamate receptor, such as PCP, ketamine, and dizocilpine (MK-801). PCP and ketamine are known to induce psychotic hallucinations and delusions in humans (Coyle et al., 2003).
NMDA antagonist-induced hyperactivity and stereotypies in the rat can be reversed by both classical and atypical antipsychotics. Atypical antipsychotics, such as clozapine, aripiprazole, and olanzapine, have been reported to be more effective than classical antipsychotics (Leite et al., 2008). Thus, the situation is different from that observed with DA agonists. On the other hand, the doses required to antagonize NMDA antagonist-induced stereotypies are sometimes considerably higher than those antagonizing DA-agonist effects (Castagné et al., 2009). It is noteworthy that the efficacy of antipsychotics (haloperidol, clozapine, and olanzapine) against PCP-induced hyperactivity has been reported to become more robust after repeated treatment and testing, whereas their efficacy against amphetamine-induced hyperactivity tends to wane (Sun et al., 2009). Repeated administration studies of potential antipsychotics against NMDA antagonists might therefore represent a promising approach for the use of NMDA antagonist models for the prediction of antipsychotic efficacy.
Behaviors Induced by 5-HT Agonists
Hallucinogens acting on 5-HT receptors, e.g., lysergic acid diethylamide, psilocybin, and mescaline, induce visual hallucinations in humans and cause characteristic behavioral signs in animals, suggesting an animal marker for 5-HT agonist-induced hallucinations in humans. For example, administration of mescaline to specific strains of mice induces episodes of paroxysmic scratching. Mescaline-induced scratching is inhibited by classical and atypical antipsychotics, in particular, those that directly or indirectly antagonize 5-HT2 receptors (Cook et al., 1992; Castagné et al., 2009).
On the other hand, a wide range of indirectly or directly acting 5-HT receptor agonists without known hallucinogenic properties also induce clear behavioral effects in rodents, for example, the forepaw treading, head twitches and lower lip retraction induced by 5-HT1A agonists, or the head twitches and wet-dog shakes induced by the 5-HT2 agonist 5-HTP. These effects are also clearly antagonized by numerous 5-HT antagonists, including antipsychotics with affinity for 5-HT2 receptors (Gardell et al., 2007).
Therefore, it is not clearly established that tests using 5-HT agonists are predictors of antipsychotic activity. Indeed, they might reflect more of the anti-5-HT activity of some of the substances tested. Furthermore, whereas 5-HT agonist-induced hallucinations in humans are primarily visual, hallucinations occurring in schizophrenia are usually auditory.
Procedures for Evaluating Negative Symptoms
Negative symptoms include anhedonia, emotional blunting, affective flattening, impoverishment of speech and thought, and social withdrawal. Even in clinical terms, these symptoms are more difficult to characterize than the more florid positive symptoms discussed above and, furthermore, are not specific to schizophrenia. Some of them (impoverished speech and thought) are unique to humans and therefore not amenable to modeling in animals. Other symptoms lend themselves more readily to animal testing and are discussed below.
Anhedonia refers to a decrease in the capacity to feel pleasure and, in addition to representing a negative symptom in schizophrenia, is a core symptom of depression. Anhedonia in animals is usually assessed through measures of sucrose consumption or preference.
In normal rats, classical and atypical antipsychotics decrease sucrose consumption and preference (Muscat and Willner, 1989), suggesting that given alone they induce anhedonia. In contrast, the atypical antipsychotics olanzapine and quetiapine, but not the classical agent haloperidol, reverse stress-induced anhedonia (Orsetti et al., 2007), suggesting the possible relevance of this procedure for assessing novel antipsychotics.
Affective flattening refers to apathy in various situations, including those involving stress. Although there is no animal model for affective flattening, the immobility induced by forced swimming has been suggested to reflect a lowered affective state in the rodent (Porsolt et al., 1977). PCP increases immobility in the forced swim test in the mouse, particularly after repeated treatment (Corbett et al., 1999). PCP-enhanced immobility is attenuated by the atypical antipsychotics clozapine, risperidone, olanzapine, and quetiapine, but not by the classical antipsychotics haloperidol, pimozide, or chlorpromazine (Nagai et al., 2003). The above data suggest that enhanced immobility in the forced swim test induced by PCP might represent a promising model of affective flattening in schizophrenia. In terms of the behaviors involved, forced swimming does not present any clear translational characteristics.
Social interaction in the rat has been widely used as a procedure to evaluate anxiety but has also been proposed as a model for antipsychotic activity using acute or repeated administration of NMDA antagonists to decrease social investigation (Sams-Dodd, 1999).
Classical antipsychotics such as haloperidol do not reverse acute NMDA antagonist-induced deficits in social investigation (Boulay et al., 2004). Conflicting data exist for clozapine, which is either inactive (Boulay et al., 2004) or reverses social investigation deficits (Becker and Grecksch, 2004).
Repeated administration of PCP or MK-801 also decreases social investigation in the rat (Geyer and Ellenbroek, 2003). Acute treatment with the atypical agents ziprasidone and aripiprazole has been reported to reverse subchronic PCP-induced deficits in social investigation, whereas similar treatment with haloperidol or clozapine was without effect (Snigdha and Neill, 2008).
The fact that social interaction is clearly diminished in schizophrenia and by NMDA glutamate antagonists in rodents and improved in the latter by some atypical antipsychotics suggests that NMDA antagonist-reduced social interaction in rodents might represent an interesting translational model for evaluating novel antipsychotics.
Procedures for Evaluating Cognitive Deficits
Cognitive deficits in patients with schizophrenia encompass attentional processes and memory/learning. Both aspects can be investigated in animal models with varying degrees of translational validity.
Cognitive function relies on adequate processes for the treatment of incoming information. The main behavioral paradigm used in preclinical and clinical research is prepulse inhibition (PPI) (Geyer and Ellenbroek, 2003). PPI refers to the decrease in startle reaction to a sudden stimulus by pre-exposure to a weak nonstartling stimulus. The weak and the strong stimuli are termed prepulse and pulse, respectively. PPI is observed in normal humans and is considered an index of sensorimotor gating, i.e., the capacity to filter incoming information. Schizophrenia and several other brain disorders involve PPI deficits that can be modeled in animals with clear translational validity.
The DA agonists apomorphine and amphetamine are widely used to disrupt PPI in the rat. Apomorphine-induced PPI deficits can be reversed by haloperidol (Auclair et al., 2006). Some reports describe reversal of apomorphine-induced PPI deficits by clozapine, although its effects are often limited to a narrow dose range (Martin et al., 2003). Amphetamine-induced PPI deficits are reversed by classical and some atypical antipsychotics (Marquis et al., 2007). Nonetheless, conflicting data exist regarding clozapine (Martin et al., 2003).
Antagonists of NMDA glutamate receptors also disrupt PPI in the rat (Martinez et al., 2000). PCP-induced PPI deficits are resistant to classical and atypical antipsychotics (Pouzet et al., 2002), although reversal by clozapine has been reported (Suemaru et al., 2004). Likewise, deficits in PPI induced by MK-801 are resistant to classical and atypical antipsychotics (Bast et al., 2000), although positive effects have been described for olanzapine and clozapine (see Castagné et al., 2009).
The demonstration of PPI in humans and rodents and the fact that PPI is impaired in patients with schizophrenia and can be disrupted by various means in normal humans and rodents suggest that PPI possesses clear translational validity. On the other hand, the data obtained so far with classical and atypical antipsychotics, although sometimes encouraging, have not yet confirmed its utility for predicting antipsychotic activity.
Learning and Memory
Learning and memory impairments are present in patients with schizophrenia but are difficult to differentiate from symptoms occurring in other central nervous system pathologies. Ketamine, in addition to its hallucinogenic properties, induces clear learning/memory deficits in humans (Morgan and Curran, 2006), suggesting translational relevance of animal models for cognitive deficits induced by glutamate antagonists.
There are a multitude of procedures in animals for investigating learning and memory. The following section will focus on procedures that have been used for developing drugs in schizophrenia and will not attempt to cover the whole range of available procedures in the learning and memory domain.
Object and Social Recognition
Object recognition is impaired in patients with schizophrenia (Gabrovska et al., 2003). This has led to the use of object recognition for evaluating substances aimed to improve cognitive deficits in schizophrenia. The object recognition test, generally performed in the rat, is a two-session procedure where recognition at the second session is indicated by a decrease in investigation of a familiar object compared with a new object. The atypical antipsychotics clozapine and risperidone, but not haloperidol, have been reported to reverse the deficits in object recognition induced by PCP (Grayson et al., 2007). Other substances with different molecular mechanisms intended for the treatment of cognitive deficits in schizophrenia have also been reported active against NMDA antagonist-induced deficits in object recognition (see Castagné et al., 2009).
The social recognition test can be considered a “social version” of the object recognition test. Social recognition at the second session is indicated by a decrease in investigation of an intruder rat previously introduced compared with a new animal. By use of the social recognition test, it has been shown that increasing activity of NMDA receptors via blockade of the glycine transporter with the potential antipsychotic SSR 504734 [[2-chloro-N-S-phenyl 2S-piperidin-2-yl methyl]-3-trifluoromethyl benzamide, monohydrochloride] attenuates the long-term deficits induced by neonatal PCP (Depoortère et al., 2005). Thus, both object and social recognition represent memory models in rodents with potential translational validity to schizophrenia.
Morris Water Maze
The procedure most commonly used for evaluating test substances on learning and memory is the Morris water maze. Rats or mice are placed in a circular water tank and left to find the escape platform just beneath the surface of the water and therefore not visible to the animal. On repeated exposure to the test situation, animals learn to find the escape platform more rapidly. Acute PCP treatment impairs performance in the Morris maze in the rat, and this effect can be reversed by clozapine and other atypical antipsychotics but not by haloperidol (Didriksen et al., 2007). Likewise, acute MK-801-induced impairment of spatial learning in the Morris maze is attenuated by the α7 receptor agonist SSR 180711 [4-bromophenyl-1,4-diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride] (Pichat et al., 2007).
These data are encouraging for the use of the Morris maze as a predictive procedure. On the other hand, the behaviors investigated possess no clear translational validity for schizophrenia.
Another procedure useful for evaluating drug effects on cognition, in particular, short-term memory, is the operant-delayed alternation procedure (delayed nonmatching to sample). Previously trained rats are presented with a lever, either on the right or the left side of the food dispenser. The rat presses on the lever, and the lever is withdrawn. After a delay, two levers are presented and the rat has to press on the lever opposite to that presented previously to obtain a food reward. Data obtained in our laboratory (Castagné et al., 2009) suggest that clozapine can partially correct PCP-induced short-term memory deficits in this task, whereas haloperidol is without effect or even exacerbates them. Although not frequently used in antipsychotic research, the delayed alternation procedure possesses clear translational validity in that analogous procedures can be employed in rodents, primates, and humans.
Conditioned Avoidance Behavior
Blockade of the conditioned avoidance response (CAR) has long been considered a selective and sensitive indicator of antipsychotic activity (Wadenberg and Hicks, 1999). Animals can be trained to prevent the occurrence of an aversive stimulation, usually electric shock, by performing a specific behavior.
In antipsychotic testing, three paradigms have traditionally been used: the pole jump procedure; the shuttle box procedure, both with auditory or visual warning signals (discriminated avoidance); and the Sidman continuous avoidance procedure without any warning signal (nondiscriminated avoidance).
The results obtained, however, have been very different. In an early publication on the effects of antipsychotics on the CAR using the pole jump procedure (Cook and Weidley, 1957), the authors reported a specific blockade of avoidance responding (response to the warning signal) at doses that were without effect on escape responding (response to the shock). These early findings have led to the persistent belief that selective blockade of avoidance behavior is an identifier of antipsychotic activity (Wadenberg and Hicks, 1999). Unfortunately, this principle seems to be procedure-specific. In another early publication, Heise and Boff (1962) showed that neuroleptics blocked escape behavior in a Sidman procedure at doses very close to those blocking the CAR, whereas with benzodiazepines the dose-ratio between escape and avoidance responding was considerably larger, i.e., the opposite of what was described by Cook and Weidley (1957). Using the Sidman procedure in our own laboratory, we have reported observations similar to Heise and Boff (1962) with classic antipsychotics (chlorpromazine, thioridazine, haloperidol), newer agents (sultopride, α-flupenthixol), and the atypical antipsychotic clozapine (see Castagné et al., 2009). All substances inhibited the CAR at doses also impairing escape behavior.
Thus, although drug potency in CAR procedures is clearly correlated both with anti-DA activity and with clinical potency, the notion of selective blockade of the CAR as a specific predictor of antipsychotic efficacy is not generally true or at best is dependent on the procedures employed. Furthermore, the CAR has no apparent translational validity.
Procedures for Evaluating Extrapyramidal Symptoms
EPS were originally viewed as inextricably linked to the therapeutic efficacy of antipsychotics. Classical antipsychotics, before clozapine, induced a variety of symptoms generally grouped under the heading of EPS that occur at different times during antipsychotic treatment. Acute EPS (parkinsonism, dystonia, akathisia) develop early in the course of treatment, whereas tardive dyskinesia occurs only after prolonged antipsychotic therapy (Casey, 1993). Although generally considered to represent different forms of the same underlying drug-induced pathophysiology, EPS syndromes are clinically distinct from one another and may therefore require different animal procedures to assess the liability of novel substances to induce them.
Both antipsychotic-induced parkinsonism and idiopathic parkinsonism are characterized by a triad of symptoms: tremor, rigidity, and akinesia (Casey, 1993). None of these phenomena can be clearly identified in rodent behavior. On the other hand, most classical antipsychotics, but not clozapine, induce catalepsy in rodents. Despite the many different procedures used to assess catalepsy, all involve measures of the time an animal will remain in an unusual position imposed by the experimenter. In contrast to the early days of antipsychotic screening where catalepsy in rats was used as an identifier of antipsychotic activity, modern antipsychotic research seeks to demonstrate a wide difference between the doses showing potential therapeutic activity and those inducing catalepsy.
Although catalepsy bears only a superficial resemblance to parkinsonism, thereby decreasing its translational validity, available data suggest that catalepsy is a good predictor of antipsychotic-induced parkinsonism.
Antipsychotic-induced dystonia is characterized by involuntary muscle spasms, accompanied by briefly sustained or fixed abnormal postures, including bizarre positions of the limbs and trunk, oculogyric crises, tongue protrusion, and torticollis (Casey, 1993).
Nothing resembling the above has been reported in rodents. On the other hand, purposeless chewing movements have been reported in rats that are increased by administration of certain antipsychotics, e.g., haloperidol, cis-flupenthixol, trifluoperazine, fluphenazine, and sulpiride (Stewart et al., 1988), all of which induce dystonia in humans. Clozapine, which is devoid of such effects in clinical use, does not alter chewing behavior, even after chronic administration (Stewart et al., 1988). Furthermore, as in patients, the antipsychotic-induced chewing movements can be attenuated by centrally acting anticholinergic agents, such as scopolamine or atropine, but not by the peripherally acting anticholinergic methylscopolamine, suggesting the central cholinergic origins of the effect. Although purposeless chewing in rats bears no resemblance to the spasmic nature of dystonia in patients, pharmacologically, the model would seem to possess predictive validity.
Clear dystonic phenomena have, however, been reported in different primate species (for details see Castagné et al., 2009). These phenomena are observed with the classical antipsychotics haloperidol and fluphenazine but not with chlorpromazine, thioridazine, and particularly clozapine, thereby resembling the clinical profiles of these substances (Deniker et al., 1980).
The data available suggest that primate dystonia, in contrast to purposeless chewing in the rat, is directly homologous to clinical observations in human and thus can be considered to possess clear translational validity.
Another EPS syndrome associated with antipsychotics is akathisia where subjective feelings of unrest are accompanied by objective signs of restlessness: pacing, rocking, marching on the spot, crossing and uncrossing the legs, and other repetitive nonpurposeful actions (Casey, 1993).
The motor aspect of restlessness would seem difficult to model in the sense that most antipsychotics reduce spontaneous activity. However, it has been suggested that antipsychotic-induced increases in defecation in rats habituated to the test environment may represent a model of the subjective component of akathisia (Sachdev and Brüne, 2000). Indeed, haloperidol and risperidone induce more fecal boli in habituated rats than those treated with clozapine, thioridazine, or chlorpromazine, which would correspond to their clinical profiles. On the other hand, drug-induced anxiety or more local drug effects on gastrointestinal transit could also explain such findings. Indeed, antipsychotic-induced defecation in habituated rats can be attenuated by treatment with anxiolytics that have limited efficacy in treating the subjective restlessness of akathisia.
Overall, the data available are too fragmentary to allow firm conclusions about the usefulness of antipsychotic-induced defecation in rodents for predicting antipsychotic-induced akathisia. In any case, rodent defecation possesses no obvious translational validity.
Tardive dyskinesia is a syndrome of involuntary abnormal movements that occur on reduction or cessation of long-term antipsychotic therapy. The movements include chewing, tongue protrusion, lip smacking, puckering, paroxysms of rapid eye blinking, and choreoathetoid movements of the limbs and trunk (Casey, 1993). Some of the features, for example, the orofacial movements, may resemble or even occur simultaneously with dystonia, making differential diagnosis difficult.
Animal tests for tardive dyskinesia are hindered by the fact that antipsychotic treatment must be continued over considerable periods to model the slowly developing nature of the syndrome. Thus, in the rodent, periods of up to 1 year of antipsychotic treatment have been required to demonstrate an increased behavioral response to DA agonists thought to result from hypersensitivity of central DA receptors (Clow et al., 1979). In contrast to the clinical syndrome, which is thought to be irreversible, these behavioral changes in the rodent disappear spontaneously within a brief period.
More convincing signs of tardive dyskinesia have been induced in monkeys. An early publication (Gunne and Barany, 1976) reported the occurrence of dyskinetic movements persisting for 1 to 6 years in Cebus monkeys after cessation of years of haloperidol treatment. Acute treatment with two putative antipsychotics, the DA autoreceptor receptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-(1-propyl) piperidine] and the benzamide sulpiride suppressed these signs (for details see Castagné et al., 2009).
Although the primate procedures would seem to possess translational validity, they do not lend themselves readily for drug development programs because they are extremely time-consuming. There remains the intriguing possibility that the occurrence of dystonia in humans or monkeys might represent a marker for the propensity of a novel substance to induce tardive dyskinesia after prolonged therapy.
Other Adverse Effects of Antipsychotics
The present article has concentrated on EPS as the major adverse side effect of antipsychotics. This could provide a biased impression of the inconveniences of currently available drugs. Other troublesome side effects include body-weight gain, blood dyscrasias, blood pressure changes, and QT prolongation. In contrast to EPS, these other side effects are not specific to schizophrenia and can occur in conjunction with a wide range of drug treatments. Furthermore, they can all be assessed using procedures with no specific relation to models for schizophrenia. For this reason, they are not reviewed here.
The present article has reviewed the range of behavioral pharmacology procedures for antipsychotics in terms of their predictive and translational validity. The translational approach has received particular attention in recent years in the hope that prediction from animal data will be improved if the processes evaluated are more directly translatable from animals to human.
The major problem with schizophrenia is that the processes involved are still poorly understood. Despite considerable research (not reviewed here), genetic studies have not advanced to the point where a genetically based animal model of schizophrenia could be used for this purpose. Our understanding has to rely on hypothetical disorders in diverse brain neurotransmission systems (DA, NMDA, and 5-HT among other things). To the extent that these hypothesized processes account for schizophrenia, procedures based on them will possess construct validity. The closer such procedures approximate the neurobiological substrates of schizophrenic disease or the symptomatology of schizophrenia, the more such approaches will be considered to possess translational validity. In only a few instances, for example, the induction of dystonia or tardive dyskinesia in monkeys, can the processes be described as homologous to those occurring in humans and thereby truly translational. However, these processes relate to the side effects of antipsychotics and not to their therapeutic efficacy.
The translational approach has been more productive in other areas, in particular, those related to attention and learning/memory deficits, where direct parallels can be drawn between the processes disturbed in schizophrenia and those investigated in animals. On the other hand, the major question posed by such approaches is whether the disturbances investigated are specific to schizophrenia and, much more importantly, whether substances found active in correcting them in animals will be useful in the treatment of schizophrenia. The jury is still out on that question.
We thank Dr. David Sanger for invaluable comments on the manuscript and Nathalie de Cerchio-Dorczynski for expert secretarial assistance.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
- extrapyramidal symptoms
- MDL 100-907
- R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol
- WAY 163909
- SSR 504734
- [2-chloro-N-S-phenyl 2S-piperidin-2-yl methyl]-3-trifluoromethyl benzamide, monohydrochloride
- SSR 180711
- 4-bromophenyl-1,4-diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride
- 3-(3-hydroxyphenyl)-N-(1-propyl) piperidine
- prepulse inhibition
- conditioned avoidance response
- Received January 31, 2010.
- Accepted March 2, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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