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DA stabilisers — fourth generation antipsychotic drugs
10. Neurochemistry, Animal
119 weeks, the ketamine-associated disruption in social memory was blocked and memory was normalized. This study supports the use of a hippocampally-dependent animal learning model in development of new antipsychotic drugs.
DA STABILISERS - FOURTH GENERATION ANTIPSYCHOTIC DRUGS S. Waters,* J. Kullingsj6, C. Sonesson, A. Carlsson, J. Tedroff, N. Waters Carlsson Research, G#teborg, Sweden DA stabilisers constitutes a pharmacological class of compounds, whose primary site of action is the dopaminergic systems of the brain. Dopaminergic stabilisers can either enhance or counteract dopaminergic effects, depending on the initial level of dopaminergic activity. This property does not depend on high binding affinity at dopamine, or other monoaminergic, amino acid, or peptidergic, neuroreceptors as studied in conventional in vitro assays. In contrast, the stabilising feature of these compounds is investigated in vivo by interaction experiments with dopaminergic systems. Dopaminergic stabilisers suppress the hyperactive behaviour induced by high doses of direct and indirect dopamine agonists. On the other hand, dopaminergic stabilisers have at most weakly inhibitory, but rather subtle stimulant effects on the behaviour of normal, non-pretreated rats. Another essential feature of dopaminergic stabilisers is their ability not only to reduce hyperactivity but also to normalise the behavioural pattern induced by psychostimulants such as d-amphetamine or cocaine. Further, their ability to normalise perturbed behaviour includes states of hypoglutamatergia, such as that induced by eg dizocilpine or phencyclidine. Accompanying these effects on behavioural patterns, regional patterns of monoaminergic neurochemistry tend to be restored. Thus, the normalizing power of dopaminergic stabilizers on perturbed states is of a general nature, thus not limited to perturbations residing in any specific transmitter system. The DA stabilizer concept is demonstrated by ACR16, a compound which has recently entered the phase of clinical exploration. Furthermore, extensions of the DA stabiliser concept will be discussed.
SOCIAL RECOGNITION IN MICE: BEHAVIORAL DISRUPTION WITH KETAMINE AND BLOCKADE WITH ANTIPSYCHOTIC DRUG A. N. White,* X. M. Gao, C. A. Tamminga Maryland Psychiatric"Research Centeg University of Maryland School of Medicine, Baltimore, MD, USA Phencyclidine and its congeners have been used to produce animal preparations which mimic aspects of psychotic illnesses. Because schizophrenia involves dysfunctional hippocampal activity (Medoff et al, Hippocampus, 11: 543-50, 2001), a hippocampallydependent behavior like "social recognition" in mice could be particularly vulnerable to the action of a psychotomimetic drug. Social recognition is an animal behavior involving learning and memory and is dependent on an intact hippocampus. We have previously reported that PCP complexly alters zif268 expression in rat hippocampus, a measure of regional response to drug administration (Gao et al, Synapse, 29: 14-28, 1998). Ketamine, a PCP congener, affects regional cerebral blood flow (rCBF) in the human hippocampus in schizophrenia but not in normals. Thus, in the present study, we investigated the effects of ketamine on social recognition across a dose range (5-30mg/kg) and a time-course (60 min7 days) in mice and the ability of antipsychotic drugs to block this action. Our results demonstrate that ketamine disrupts long-term social memory. Furthermore, in the mice treated with antipsychotic drugs (haloperidol 2mg/kg/day or olanzapine 4mg/kg/day) for 4
MOLECULAR ANALYSIS OF N-METHYL-DASPARTATE RECEPTOR NR 1 SUBUNIT KNOCKDOWN MICE: A MODEL OF SCHIZOPHRENIA E B. Wingrove,* G. O'Meara, R. Newman, R. Heavens, D. Reynolds, C. Hayes, T. Rosahl, E J. Whiting, S. Patel Biochemistry & Molecular Biology, Merck Sharp & Dohme, Harlow, Essex, United Kingdom Ionotropic glutamate receptors are the major excitatory receptor in the mammalian CNS. NMDA-type glutamate receptors are composed of at least two subunit types from NR1, NR2 and NR3 classes. Loss of the obligatory NR1 subunit by genetic disruption of the corresponding gene is lethal in mice. However, a viable transgenic strain of mice has been created in which expression levels of the NR1 subunit is reduced by insertion of a neomycin resistance gene into intron 20 (Mohn et al., 1999, Cell, 98,427-36). The homozygous progeny display abnormal behaviours believed to be correlates of human schizophrenia. We have investigated the underlying basis of the phenotype using molecular and radioligand binding techniques. Radioligand binding assays using the glycine site ligand [3H]L-689,560 or channel site ligand [3H]MK801 reveal a significant reduction in binding. Behavioural studies confirm the increase in locomotor activity and deficits in pre-pulse inhibition (PP1). Quantification of the NR 1 transcript by RT-PCR and Taqman sequence detection indicates a large down regulation of the C-terminal part (after the point of neomycin insertion) but negligible change in expression of the N-terminus of the transcript. These data suggest that the disruption of the gene may have resulted in truncation of the peptide rather than a reduction in receptor number. Recombinant expression of a C-terminally truncated NR1 subunit with NR2A produces no detectable functional receptors (Meddows et al., 2001, J Biol Chem, 276, 18795-803). These data are consistent with disruption of NMDA receptor activity.
A N IN VIVO A S S E S S M E N T OF ARIPIPRAZOLE,
ZIPRASIDONE, RISPERIDONE AND OLANZAPINE IN RAT ASSAYS INDICATIVE OF 5-HT1A AND D2 RECEPTOR ACTIVITY M. C. Wolff,* D. B. Wainscott, D. L. Nelson, N. A. Moore, C. D. Overshiner, J. D. Leander, E R Bymaster, K. Knitowski, D. L. McKinzie Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA Although atypical antipsychoties (AAP) share some properties, (e.g. a higher affinity for the 5-HT2A receptor than the dopamine D2 receptor), there are other characteristics, such as affinity for the 5-HTIA receptor, which they do not have in common and which may be important in understanding the mechanism(s) of their therapeutic activity. The objective of the present study was
International Congress on Schizophrenia Research 2003
119 weeks, the ketamine-associated disruption in social memory was blocked and memory was normalized. This study supports the use of a hippocampally-dependent animal learning model in development of new antipsychotic drugs.
DA STABILISERS - FOURTH GENERATION ANTIPSYCHOTIC DRUGS S. Waters,* J. Kullingsj6, C. Sonesson, A. Carlsson, J. Tedroff, N. Waters Carlsson Research, G#teborg, Sweden DA stabilisers constitutes a pharmacological class of compounds, whose primary site of action is the dopaminergic systems of the brain. Dopaminergic stabilisers can either enhance or counteract dopaminergic effects, depending on the initial level of dopaminergic activity. This property does not depend on high binding affinity at dopamine, or other monoaminergic, amino acid, or peptidergic, neuroreceptors as studied in conventional in vitro assays. In contrast, the stabilising feature of these compounds is investigated in vivo by interaction experiments with dopaminergic systems. Dopaminergic stabilisers suppress the hyperactive behaviour induced by high doses of direct and indirect dopamine agonists. On the other hand, dopaminergic stabilisers have at most weakly inhibitory, but rather subtle stimulant effects on the behaviour of normal, non-pretreated rats. Another essential feature of dopaminergic stabilisers is their ability not only to reduce hyperactivity but also to normalise the behavioural pattern induced by psychostimulants such as d-amphetamine or cocaine. Further, their ability to normalise perturbed behaviour includes states of hypoglutamatergia, such as that induced by eg dizocilpine or phencyclidine. Accompanying these effects on behavioural patterns, regional patterns of monoaminergic neurochemistry tend to be restored. Thus, the normalizing power of dopaminergic stabilizers on perturbed states is of a general nature, thus not limited to perturbations residing in any specific transmitter system. The DA stabilizer concept is demonstrated by ACR16, a compound which has recently entered the phase of clinical exploration. Furthermore, extensions of the DA stabiliser concept will be discussed.
SOCIAL RECOGNITION IN MICE: BEHAVIORAL DISRUPTION WITH KETAMINE AND BLOCKADE WITH ANTIPSYCHOTIC DRUG A. N. White,* X. M. Gao, C. A. Tamminga Maryland Psychiatric"Research Centeg University of Maryland School of Medicine, Baltimore, MD, USA Phencyclidine and its congeners have been used to produce animal preparations which mimic aspects of psychotic illnesses. Because schizophrenia involves dysfunctional hippocampal activity (Medoff et al, Hippocampus, 11: 543-50, 2001), a hippocampallydependent behavior like "social recognition" in mice could be particularly vulnerable to the action of a psychotomimetic drug. Social recognition is an animal behavior involving learning and memory and is dependent on an intact hippocampus. We have previously reported that PCP complexly alters zif268 expression in rat hippocampus, a measure of regional response to drug administration (Gao et al, Synapse, 29: 14-28, 1998). Ketamine, a PCP congener, affects regional cerebral blood flow (rCBF) in the human hippocampus in schizophrenia but not in normals. Thus, in the present study, we investigated the effects of ketamine on social recognition across a dose range (5-30mg/kg) and a time-course (60 min7 days) in mice and the ability of antipsychotic drugs to block this action. Our results demonstrate that ketamine disrupts long-term social memory. Furthermore, in the mice treated with antipsychotic drugs (haloperidol 2mg/kg/day or olanzapine 4mg/kg/day) for 4
MOLECULAR ANALYSIS OF N-METHYL-DASPARTATE RECEPTOR NR 1 SUBUNIT KNOCKDOWN MICE: A MODEL OF SCHIZOPHRENIA E B. Wingrove,* G. O'Meara, R. Newman, R. Heavens, D. Reynolds, C. Hayes, T. Rosahl, E J. Whiting, S. Patel Biochemistry & Molecular Biology, Merck Sharp & Dohme, Harlow, Essex, United Kingdom Ionotropic glutamate receptors are the major excitatory receptor in the mammalian CNS. NMDA-type glutamate receptors are composed of at least two subunit types from NR1, NR2 and NR3 classes. Loss of the obligatory NR1 subunit by genetic disruption of the corresponding gene is lethal in mice. However, a viable transgenic strain of mice has been created in which expression levels of the NR1 subunit is reduced by insertion of a neomycin resistance gene into intron 20 (Mohn et al., 1999, Cell, 98,427-36). The homozygous progeny display abnormal behaviours believed to be correlates of human schizophrenia. We have investigated the underlying basis of the phenotype using molecular and radioligand binding techniques. Radioligand binding assays using the glycine site ligand [3H]L-689,560 or channel site ligand [3H]MK801 reveal a significant reduction in binding. Behavioural studies confirm the increase in locomotor activity and deficits in pre-pulse inhibition (PP1). Quantification of the NR 1 transcript by RT-PCR and Taqman sequence detection indicates a large down regulation of the C-terminal part (after the point of neomycin insertion) but negligible change in expression of the N-terminus of the transcript. These data suggest that the disruption of the gene may have resulted in truncation of the peptide rather than a reduction in receptor number. Recombinant expression of a C-terminally truncated NR1 subunit with NR2A produces no detectable functional receptors (Meddows et al., 2001, J Biol Chem, 276, 18795-803). These data are consistent with disruption of NMDA receptor activity.
A N IN VIVO A S S E S S M E N T OF ARIPIPRAZOLE,
ZIPRASIDONE, RISPERIDONE AND OLANZAPINE IN RAT ASSAYS INDICATIVE OF 5-HT1A AND D2 RECEPTOR ACTIVITY M. C. Wolff,* D. B. Wainscott, D. L. Nelson, N. A. Moore, C. D. Overshiner, J. D. Leander, E R Bymaster, K. Knitowski, D. L. McKinzie Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA Although atypical antipsychoties (AAP) share some properties, (e.g. a higher affinity for the 5-HT2A receptor than the dopamine D2 receptor), there are other characteristics, such as affinity for the 5-HTIA receptor, which they do not have in common and which may be important in understanding the mechanism(s) of their therapeutic activity. The objective of the present study was
International Congress on Schizophrenia Research 2003