Behavioral Indices in Antipsychotic Drug Discovery

Abstract

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-HT 2 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 an...

Animal models for predicting the efficacy and side effects of antipsychotic drugs

“…This model, contrary to the others mentioned above, may be able to distinguish the effects promoted by atypical vs. typical antipsychotics. 16,47 This profile is similar to that observed after administration of NMDA receptor antagonists to humans. 10,36 In humans, the startle reflex can be measured as a contraction of the skeletal and facial muscles, such as an eye-blink reflex.…”

“…Interesting, the data have been more consistent with atypical antipsychotics. [14][15][16][17] Nonetheless, this activity is not specific for this class of drugs, since anxiolytic compounds also increase social interaction in rats. In any case, this test is relevant, since current antipsychotic drugs have very limited efficacy against negative symptoms.…”

“…42 NMDA receptor antagonists also produce stereotypies, and the disturbance produced by these compounds, whether acutely or chronically administered, can also be prevented by treatment with antipsychotic drugs. 16,43 The advantage of this test is that stereotypies can be easily quantified by a trained observer, at minimal cost and yielding rapid results. The reversion of this behavior by antipsychotic drugs demonstrates its predictive validity.…”

“…[14][15][16][17] Other tests include those relevant to studying the attention process, such as the 5-Choice Serial Reaction Time Task. [14][15][16][17] Tests that predict the side effects of antipsychotic drugs As mentioned in the introduction, the short-term side effects of first-generation antipsychotic drugs include parkinsonian syndrome, dystonia and akathisia, whereas chronic treatment leads to tardive dyskinesia, which comprises abnormal, excessive, and involuntary movements. 51 Despite a large number of investigations, the mechanisms through which these effects occur remain to be elucidated.…”

“…Generally, these models consist of certain responses exhibited by rodents (mice and rats) after pharmacological, genetic or developmental interventions. 10,11,[14][15][16][17] In this review, we focus specifically on the pharmacological models and related behavioral tests relevant for the study of schizophrenia and antipsychotic drugs. First, the pharmacological models of schizophrenia will be briefly described.…”