- Email: [email protected]
Preclinical tests that predict clozapine-like atypical antipsychotic actions
145
Controls CLOZAPINE TYP-APD
Age (years)
Impulsiveness Scores
Platelet 5-HT (ng/ml/lO9 platelet)
33.9+2.7 36 + 1.9 41+__1.6
0+0 3.8 + 0.6 6.8+0.5*
1773+106 2818 _ 297t 1172+284"
Means±SE of means, *P<0.05 independent t-test compared to clozapine group, tP<0.05 independent t-test compared to controls. These results indicate that clozapine may increase platelet 5-HT levels and, via a similar effect in brain, reduce impulsiveness in schizophrenia. The clinical implication of these results is that priority should be given to clozapine in impulsive schizophrenic patients.
VI.B.4 EFFECT OF TYPICAL AND ATYPICAL NEUROLEPTICS ON FOS PROTEIN EXPRESSION IN THE RAT FOREBRAIN A. Fink-Jensen, T. Specht Ludvigsen, N. Korsgaard and P. Kristensen
Endocrinology, Health Care Discovery, Novo Nordisk A/S, DK-2760 Mdlov, Denmark The cellular synthesis of the transcription factor protein Fos, is regarded a biochemical marker of neuronal activity and previous studies suggest that the effect of the atypical neuroleptic clozapine on Fos protein expression in the medial prefrontal cortex (PFC) may be related to its unique effects on negative symptoms in schizophrenia (Neuroscience (1992) 46:315-328). In order to investigate if the Fos protein expression pattern induced by clozapine applies to other compounds with an atypical profile in preclinical or clinical trials we investigated the acute effect of the atypical neuroleptics clozapine, risperidone, sertindole and NNC 22-0031 (4(6-fluoro-l,2-benzisoxazol-3-yl) -1- (3- (3,4-methylenedioxy-phenylcarboyloxy) propyl)piperidine) as well as the prototypical neuroleptic haloperidol. The Fos protein expression was assessed in PFC and nucleus accumbens (NAc) as well as in the dorsoslateral striatum (DLSt) by use of immunohistochemistry. The present results show that atypical and prototypical neuroleptics can be differentiated on the basis of their ability to induce Fos protein since the ratio between Fos protein expression in PFC and in DLSt was much higher for the atypical neuroleptics than observed with the prototypical neuroleptic, haloperidol. In addition, the involvement of ctl-adrenergic or 5HT2-receptor blockade in the atypical profile of clozapine was investigated. The cd-adrenergic receptor antagonist, prazosin and the 5HT2-receptor antagonist, ritanserin did not
increase Fos protein immunoreactivity by themselves and did not mimic the clozapine response when co-administered with haloperidol. Consequently, our results indicate that neither ctl-, 5HT2-, 5HT2/D2 nor cd/D2 receptor blockade can explain the Fos protein induction pattern of clozapine in the rat forebrain.
VI.B.5 PRECLINICAL TESTS THAT PREDICT CLOZAPINE-LIKE ATYPICAL ANTIPSYCHOTIC ACTIONS J.M. Goldstein
Zeneca Pharmaceuticals, 1800 ConcordPike, Wilmington, DE 19850 U.S.A. The success of clozapine has stimulated widespread efforts to develop new agents that share clozapine's enhanced therapeutic effects and relative lack of extrapyramidal side effects compared to standard antipsychotics, eg, haloperidol, but that have better safety profiles, eg, less cardiovascular, seizure, and agranulocytotic liability. Identifying clozapine-like agents on the basis of laboratory tests has proven elusive because we still don't understand the pharmacologic basis for clozapine's unique clinical effects. Recently, research efforts have led to additional preclinical tests or models that may further distinguish clozapine-like from haloperidol-like agents; these include drug discrimination in clozapine-trained monkeys, regional expression of early gene products, prepulse inhibition, the paw test, and a monkey model for the negative symptoms of schizophrenia. These tests may help reveal the mechanism underpinning clozapine's unique effects, as well as help differentiate among the new generation of putative atypical agents, including 'Seroquel' (ICI 204636), risperidone, olanzapine, sertindole, and ziprasidone. Not all of the newer agents have features that match the unique preclinical features of clozapine. 'Seroquel' is a trademark, the property of ZENECA Limited.
VI.B.7 DIRECT EVIDENCE THAT REDUCED ACCUMBENS DOPAMINE FUNCTION POTENTIATES LATENT INHIBITION: A MODEL OF ANTIPSYCHOTIC ACTION WITH CONSTRUCT VALIDITY M.H. Joseph, S.L. Peters, G.A. Grigoryan, P. Boulenguez and J.A. Gray
MRC Behavioural Neurochemistry Group, Dept of Psychology, lnst of Psychiatry, London, U.K. Indirect dopamine (DA) agonists disrupt, and antagonists potentiate, latent inhibition (LI), an attentional phenomenon
Controls CLOZAPINE TYP-APD
Age (years)
Impulsiveness Scores
Platelet 5-HT (ng/ml/lO9 platelet)
33.9+2.7 36 + 1.9 41+__1.6
0+0 3.8 + 0.6 6.8+0.5*
1773+106 2818 _ 297t 1172+284"
Means±SE of means, *P<0.05 independent t-test compared to clozapine group, tP<0.05 independent t-test compared to controls. These results indicate that clozapine may increase platelet 5-HT levels and, via a similar effect in brain, reduce impulsiveness in schizophrenia. The clinical implication of these results is that priority should be given to clozapine in impulsive schizophrenic patients.
VI.B.4 EFFECT OF TYPICAL AND ATYPICAL NEUROLEPTICS ON FOS PROTEIN EXPRESSION IN THE RAT FOREBRAIN A. Fink-Jensen, T. Specht Ludvigsen, N. Korsgaard and P. Kristensen
Endocrinology, Health Care Discovery, Novo Nordisk A/S, DK-2760 Mdlov, Denmark The cellular synthesis of the transcription factor protein Fos, is regarded a biochemical marker of neuronal activity and previous studies suggest that the effect of the atypical neuroleptic clozapine on Fos protein expression in the medial prefrontal cortex (PFC) may be related to its unique effects on negative symptoms in schizophrenia (Neuroscience (1992) 46:315-328). In order to investigate if the Fos protein expression pattern induced by clozapine applies to other compounds with an atypical profile in preclinical or clinical trials we investigated the acute effect of the atypical neuroleptics clozapine, risperidone, sertindole and NNC 22-0031 (4(6-fluoro-l,2-benzisoxazol-3-yl) -1- (3- (3,4-methylenedioxy-phenylcarboyloxy) propyl)piperidine) as well as the prototypical neuroleptic haloperidol. The Fos protein expression was assessed in PFC and nucleus accumbens (NAc) as well as in the dorsoslateral striatum (DLSt) by use of immunohistochemistry. The present results show that atypical and prototypical neuroleptics can be differentiated on the basis of their ability to induce Fos protein since the ratio between Fos protein expression in PFC and in DLSt was much higher for the atypical neuroleptics than observed with the prototypical neuroleptic, haloperidol. In addition, the involvement of ctl-adrenergic or 5HT2-receptor blockade in the atypical profile of clozapine was investigated. The cd-adrenergic receptor antagonist, prazosin and the 5HT2-receptor antagonist, ritanserin did not
increase Fos protein immunoreactivity by themselves and did not mimic the clozapine response when co-administered with haloperidol. Consequently, our results indicate that neither ctl-, 5HT2-, 5HT2/D2 nor cd/D2 receptor blockade can explain the Fos protein induction pattern of clozapine in the rat forebrain.
VI.B.5 PRECLINICAL TESTS THAT PREDICT CLOZAPINE-LIKE ATYPICAL ANTIPSYCHOTIC ACTIONS J.M. Goldstein
Zeneca Pharmaceuticals, 1800 ConcordPike, Wilmington, DE 19850 U.S.A. The success of clozapine has stimulated widespread efforts to develop new agents that share clozapine's enhanced therapeutic effects and relative lack of extrapyramidal side effects compared to standard antipsychotics, eg, haloperidol, but that have better safety profiles, eg, less cardiovascular, seizure, and agranulocytotic liability. Identifying clozapine-like agents on the basis of laboratory tests has proven elusive because we still don't understand the pharmacologic basis for clozapine's unique clinical effects. Recently, research efforts have led to additional preclinical tests or models that may further distinguish clozapine-like from haloperidol-like agents; these include drug discrimination in clozapine-trained monkeys, regional expression of early gene products, prepulse inhibition, the paw test, and a monkey model for the negative symptoms of schizophrenia. These tests may help reveal the mechanism underpinning clozapine's unique effects, as well as help differentiate among the new generation of putative atypical agents, including 'Seroquel' (ICI 204636), risperidone, olanzapine, sertindole, and ziprasidone. Not all of the newer agents have features that match the unique preclinical features of clozapine. 'Seroquel' is a trademark, the property of ZENECA Limited.
VI.B.7 DIRECT EVIDENCE THAT REDUCED ACCUMBENS DOPAMINE FUNCTION POTENTIATES LATENT INHIBITION: A MODEL OF ANTIPSYCHOTIC ACTION WITH CONSTRUCT VALIDITY M.H. Joseph, S.L. Peters, G.A. Grigoryan, P. Boulenguez and J.A. Gray
MRC Behavioural Neurochemistry Group, Dept of Psychology, lnst of Psychiatry, London, U.K. Indirect dopamine (DA) agonists disrupt, and antagonists potentiate, latent inhibition (LI), an attentional phenomenon