Methods and Findings in Experimental and Clinical Pharmacology
Vol. 25, Suppl. A, 2003
ISSN 0379-0355
Copyright 2003 Prous Science, S.A.
CCC: 0379-0355/2003
http://www.prous.com

Developmental Pharmacology. Behavioral Assays in Antipsychotics

A. Brasó, M. Princep, M. Schmid, A. Tabernero, C. Perez and A. Guglietta

Centro de Investigación y Desarrollo Farmacéutico, Grupo Ferrer, Barcelona, Spain

Schizophrenia is a heterogeneous syndrome characterized by perturbations of language, perception, social activity, affection and volition. Schizophrenic patients may present positive symptoms (such as conceptual disorganization, delusions and hallucinations) and/or negative symptoms (loss of function, anhedonia, decreased emotional expression, impaired concentration and diminished social engagement) and should have at least two of these symptoms for a 1-month period and continuous signs for at least 6 months to meet the diagnostic criteria for schizophrenia.

Antipsychotic drugs (APDs) remain the cornerstone of acute and maintenance treatment of schizophrenia. New antipsychotic drugs are defined as "atypical" APDs to differentiate them from the classic or "typical" APDs. Available evidence indicates that new APDs can be differentiated from typical APDs, particularly on the basis of fewer extrapyramidal effects (EPS) and improvement of negative and cognitive symptoms.

The most widely accepted hypothesis to explain the effect of APDs is the inhibition of dopaminergic (DA) function in limbic and/or cortical brain regions. On the other hand, it is generally accepted that EPS are mediated by inhibition of nigrostriatal DA function. The different limbic and/or cortical selectivity is probably due to a corrected balanced inhibition of several neurotransmitter receptors, particularly D₂ and 5-HT₂ receptor, as well as alpha₁-adrenoceptors and muscarinic receptors, which leads to a selective inhibition of limbic/cortical DA function.

In development pharmacology, the study of the pharmacological properties of APDs focus mainly on in vitro multireceptorial profiles and in vivo behavioral animal models predictive of both antipsychotic activity and EPS.

Herein, we describe some behavioral pharmacology animal models to evaluate the antipsychotic activity and EPS and to relate these effects with the symptoms of schizophrenia and the interaction with receptors.

Behavioral assays to predict in vivo activity include: (D₂) Inhibition of amphetamine-induced hyperactivity in mice; inhibition of apomorphine-induced climbing in mice; conditioned-avoidance responses in rats; inhibition of apomorphine-induced loss of startle response in rats; (5-HT_2A) inhibition of the DOI (or quipazine) induced head twitches in mice; inhibition of the central hyperactivity induced by quipazine; (alpha₁) protection against noradrenaline-induced lethality in mice; antagonism of the discriminative stimulus properties of the alpha₁ against St 587 in rats; (NMDA) inhibition of dizocilpine-induced hyperactivity in mice; and protection to dizocilpine-induced deficit in social interaction in rats.

Behavioral assays of extrapyramidal symptoms and anticolinergic effects include: Induction of catalepsy in rats; (D₂) inhibition of apomorphine-induced stereotypy in rats; inhibition of amphetamine-induced stereotypy in rats; (D₁) inhibition of SKF 38393-induced grooming in mice; (Muscarinic) protection to physostigmine-induced lethality in mice; and inhibition of oxotremorine-induced tremors.

Behavioral assays of safety in S.N.C include: the Irwin test; spontaneous motor activity; motor coordination; effect on pentylenetetrazol-induced proconvulsivant activity.

Taking into account that each APD has its own pharmacological profile, it is difficult to select an antipsychotic drug for clinical development based only on the basis of results from a few behavioral pharmacology animal models. On the other hand, it is very encouraging that accumulated clinical evidence largely confirms the predictions of animal studies: that atypical APDs are effective antipsychotics with fewer EPS effects than typical APDs.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 25, Suppl. A, 2003
ISSN 0379-0355 Copyright 2003 Prous Science, S.A. CCC: 0379-0355/2003 http://www.prous.com