In principal, drug discovery approaches can be grouped into target- and function-based, with the ... more In principal, drug discovery approaches can be grouped into target- and function-based, with the respective aims of developing either a target-selective drug or a drug that produces a specific biological effect irrespective of its mode of action. Most analyses of drug discovery approaches focus on productivity, whereas the strategic implications of the choice of drug discovery approach on market position and ability to maintain market exclusivity are rarely considered. However, a comparison of approaches from the perspective of market position indicates that the functional approach is superior for the development of novel, innovative treatments.
Models of human diseases are necessary for experimental research into the biological basis of dis... more Models of human diseases are necessary for experimental research into the biological basis of disease and for the development of treatments. They have an enormous impact upon the success of biomedical research. However, in spite of this, a consistent system for evaluating, expressing and comparing the clinical validity of disease models is not available. The purpose of this paper is, therefore, to provide a theoretical discussion of the concepts behind disease models and to develop a terminology and a framework to analyze and express the clinical validity of disease models.
Phencyclidine (PCP) is a hallucinogenic drug that can mimic several aspects of the schizophrenic ... more Phencyclidine (PCP) is a hallucinogenic drug that can mimic several aspects of the schizophrenic symptomatology in healthy volunteers. In a series of studies PCP was administered to rats to determine whether it was possible to develop an animal model of the positive and negative symptoms of schizophrenia. The rats were tested in the social interaction test and it was found that PCP dose-dependently induces stereotyped behaviour and social withdrawal, which may correspond to certain aspects of the positive and negative symptoms, respectively. The effects of PCP could be reduced selectively by antipsychotic drug treatment, whereas drugs lacking antipsychotic effects did not alleviate the PCP-induced behaviours. Together these findings indicate that PCP effects in the rat social interaction test may be a model of the positive and negative symptoms of schizophrenia with face and predictive validity and that it may be useful for the evaluation of novel antipsychotic compounds.
The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of sev... more The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 micromol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.
Phencyclidine (PCP) can induce a model psychosis in humans that resembles an acute schizophrenic ... more Phencyclidine (PCP) can induce a model psychosis in humans that resembles an acute schizophrenic psychosis. In animal models of schizophrenia, PCP induces locomotor hyperactivity, stereotyped behaviour and social isolation, and the purpose of the present study was to describe the ability of dopamine agonists and antagonists to mimic or interact with these PCP-induced behaviours in rats. The compounds were administered daily for 3 days in combination with vehicle or 2.0 mg/kg PCP and the rats were tested in the social interaction test on the last day of drug administration. The study showed that D1-agonists with relative differences in efficacy at the DA-stimulated adenylate cyclase had limited effects on the PCP-induced behaviours, whereas the D1-antagonist SCH 23391 could alleviate the PCP-induce social isolation following daily treatment for 3 days. However, following long-term treatment for 21 days, the rats develop tolerance to this effect. These data thus suggested that the D1-receptor system only had a modulatory effect on PCP. In contrast, the D2-receptor family may be more directly involved, because the D2/D3/D4-agonist quinpirole could mimic and potentiate the PCP-induced deficits in social behaviour, and the D2/D3-antagonist (-)sulpiride could alleviate the PCP-induced stereotyped behaviour and social isolation. However, a D4-antagonist did not affect the behaviour of vehicle- and PCP-treated rats, suggesting that this system plays a less direct role in the behavioural effects of PCP. In general, however, the effects of SCH 23391, quinpirole and (-)sulpiride on the PCP-induced behaviours were mirrored in the vehicle-treated control groups and it is therefore possible that non-specific effects may have been important.
Studies have reported that d-amphetamine can induce a schizophreniform psychosis in humans and ca... more Studies have reported that d-amphetamine can induce a schizophreniform psychosis in humans and can induce abnormal behaviour patterns in monkeys that resemble the psychotic symptoms observed in man. The purpose of the present study was to identify a drug administration regime that in squirrel monkeys reliably could induce such behaviours in order to use this as a model of schizophrenia. The behavioural effects of acute, subchronic and continuous administration of d-amphetamine were determined in male and female squirrel monkeys during short term separation from the colony and in the home cage. It was found that abnormal behaviours developed in both male and female subjects and that they were most evident in the home cage. The number of subjects responding was highest during continuous infusion followed by subchronic treatment. The study indicated that prolonged administration of high doses of d-amphetamine is necessary for the development of abnormal behaviours. These findings suggest that animal models of schizophrenia based on d-amphetamine should be based on chronic administration or continuous infusion of d-amphetamine instead of acute injections.
Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative ... more Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. In the social interaction test PCP induces stereotyped behaviour and social isolation in rats, and these behaviours can be inhibited by antipsychotic drugs. In order to further evaluate the predictive validity of this model of schizophrenia the anxiolytic diazepam (0.02-17.5 micromol/kg; 0.005-5.0 mg/kg), the antidepressant citalopram (0.62-19.8 micromol/kg; 0.3-4.0 mg/kg), the opioid agonist methadone (0.36-5.8 micromol/kg; 0.13-2.0 mg/kg) and the opioid antagonist naloxone (0.34-22.0 micromol/kg; 0.13-8.0 mg/kg) were tested as examples of drugs without antipsychotic activity. The experiments demonstrated that these compounds did not specifically inhibit the behavioural effects of PCP. So far only antipsychotic drugs have been able to specifically inhibit the PCP-induced behaviours.
The social interaction test is a valuable behavioural model for testing anxiolytic and neurolepti... more The social interaction test is a valuable behavioural model for testing anxiolytic and neuroleptic drugs. The test quantifies the level of social behaviour between pairs of rats and it is usually based on manual analysis of behaviour. Advances in computer technology have made it possible to track the movements of pairs of rats in an arena, and the present paper describes the automation of the social interaction test by the commercial video-tracking programme, the EthoVision system. The ability of the automated system to correctly measure the social behaviour of rats is demonstrated by determining a dose-response relationship in the social interaction test for phencyclidine, a psychotomimetic drug that reduces social behaviour between pairs of rats. These data are subsequently analysed by the manual and automated data-acquisition methods and the results are compared. The study shows that the automated data-acquisition method best describes the behavioural effects of phencyclidine in the social interaction test by the locomotor activity of the rats, how much time the rats spend in different sections of the testing arena, and the level of social behaviour. Correlation analysis of the results from the manual and automated data-acquisition methods shows that the social behaviour measured by the automated system corresponds correctly to the social behaviour measured by the manual analysis. The present study has shown that the automated data-acquisition method can quantify locomotor activity, how rats use a testing arena and the level of social behaviour between rats in the social interaction test. The system cannot distinguish between social and aggressive behaviours, and therefore the rats should be tested in an unfamiliar arena to reduce territorial behaviour. Taking this limitation into consideration, the social interaction test can be automated by this computer-based video-tracking system and can be used as a routine test for quantifying the effects of drugs on the social behaviour of rats.
The changes of gene expression resulting from long-term exposure to monoamine antidepressant drug... more The changes of gene expression resulting from long-term exposure to monoamine antidepressant drugs in experimental animals are key to understanding the mechanisms of action of this class of drugs in man. Many of these genes and their products are either relevant biomarkers or directly involved in structural changes that are perhaps necessary for the antidepressant effect. Tesofensine is a novel triple monoamine reuptake inhibitor that acts to increase noradrenaline, serotonin, and dopamine neurotransmission. This study was undertaken to examine the effect of sub-chronic (5 days) and chronic (14 days) administration of Tesofensine on the expression of brain derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton protein (Arc) in the rat hippocampus. Furthermore, hippocampi from the same animals were used to investigate the effect on cell proliferation by means of Ki-67- and NeuroD-immunoreactivity. We find that chronic, but not sub-chronic treatment with Tesofensine increases BDNF mRNA in the CA3 region of the hippocampus (35%), and Arc mRNA in the CA1 of the hippocampus (65%). Furthermore, the number of Ki-67- and neuroD-positive cells increased after chronic, but not sub-chronic treatment. This study shows that Tesofensine enhances hippocampal gene expression and new cell formation indicative for an antidepressant potential of this novel drug substance.
In principal, drug discovery approaches can be grouped into target- and function-based, with the ... more In principal, drug discovery approaches can be grouped into target- and function-based, with the respective aims of developing either a target-selective drug or a drug that produces a specific biological effect irrespective of its mode of action. Most analyses of drug discovery approaches focus on productivity, whereas the strategic implications of the choice of drug discovery approach on market position and ability to maintain market exclusivity are rarely considered. However, a comparison of approaches from the perspective of market position indicates that the functional approach is superior for the development of novel, innovative treatments.
Models of human diseases are necessary for experimental research into the biological basis of dis... more Models of human diseases are necessary for experimental research into the biological basis of disease and for the development of treatments. They have an enormous impact upon the success of biomedical research. However, in spite of this, a consistent system for evaluating, expressing and comparing the clinical validity of disease models is not available. The purpose of this paper is, therefore, to provide a theoretical discussion of the concepts behind disease models and to develop a terminology and a framework to analyze and express the clinical validity of disease models.
Phencyclidine (PCP) is a hallucinogenic drug that can mimic several aspects of the schizophrenic ... more Phencyclidine (PCP) is a hallucinogenic drug that can mimic several aspects of the schizophrenic symptomatology in healthy volunteers. In a series of studies PCP was administered to rats to determine whether it was possible to develop an animal model of the positive and negative symptoms of schizophrenia. The rats were tested in the social interaction test and it was found that PCP dose-dependently induces stereotyped behaviour and social withdrawal, which may correspond to certain aspects of the positive and negative symptoms, respectively. The effects of PCP could be reduced selectively by antipsychotic drug treatment, whereas drugs lacking antipsychotic effects did not alleviate the PCP-induced behaviours. Together these findings indicate that PCP effects in the rat social interaction test may be a model of the positive and negative symptoms of schizophrenia with face and predictive validity and that it may be useful for the evaluation of novel antipsychotic compounds.
The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of sev... more The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 micromol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.
Phencyclidine (PCP) can induce a model psychosis in humans that resembles an acute schizophrenic ... more Phencyclidine (PCP) can induce a model psychosis in humans that resembles an acute schizophrenic psychosis. In animal models of schizophrenia, PCP induces locomotor hyperactivity, stereotyped behaviour and social isolation, and the purpose of the present study was to describe the ability of dopamine agonists and antagonists to mimic or interact with these PCP-induced behaviours in rats. The compounds were administered daily for 3 days in combination with vehicle or 2.0 mg/kg PCP and the rats were tested in the social interaction test on the last day of drug administration. The study showed that D1-agonists with relative differences in efficacy at the DA-stimulated adenylate cyclase had limited effects on the PCP-induced behaviours, whereas the D1-antagonist SCH 23391 could alleviate the PCP-induce social isolation following daily treatment for 3 days. However, following long-term treatment for 21 days, the rats develop tolerance to this effect. These data thus suggested that the D1-receptor system only had a modulatory effect on PCP. In contrast, the D2-receptor family may be more directly involved, because the D2/D3/D4-agonist quinpirole could mimic and potentiate the PCP-induced deficits in social behaviour, and the D2/D3-antagonist (-)sulpiride could alleviate the PCP-induced stereotyped behaviour and social isolation. However, a D4-antagonist did not affect the behaviour of vehicle- and PCP-treated rats, suggesting that this system plays a less direct role in the behavioural effects of PCP. In general, however, the effects of SCH 23391, quinpirole and (-)sulpiride on the PCP-induced behaviours were mirrored in the vehicle-treated control groups and it is therefore possible that non-specific effects may have been important.
Studies have reported that d-amphetamine can induce a schizophreniform psychosis in humans and ca... more Studies have reported that d-amphetamine can induce a schizophreniform psychosis in humans and can induce abnormal behaviour patterns in monkeys that resemble the psychotic symptoms observed in man. The purpose of the present study was to identify a drug administration regime that in squirrel monkeys reliably could induce such behaviours in order to use this as a model of schizophrenia. The behavioural effects of acute, subchronic and continuous administration of d-amphetamine were determined in male and female squirrel monkeys during short term separation from the colony and in the home cage. It was found that abnormal behaviours developed in both male and female subjects and that they were most evident in the home cage. The number of subjects responding was highest during continuous infusion followed by subchronic treatment. The study indicated that prolonged administration of high doses of d-amphetamine is necessary for the development of abnormal behaviours. These findings suggest that animal models of schizophrenia based on d-amphetamine should be based on chronic administration or continuous infusion of d-amphetamine instead of acute injections.
Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative ... more Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. In the social interaction test PCP induces stereotyped behaviour and social isolation in rats, and these behaviours can be inhibited by antipsychotic drugs. In order to further evaluate the predictive validity of this model of schizophrenia the anxiolytic diazepam (0.02-17.5 micromol/kg; 0.005-5.0 mg/kg), the antidepressant citalopram (0.62-19.8 micromol/kg; 0.3-4.0 mg/kg), the opioid agonist methadone (0.36-5.8 micromol/kg; 0.13-2.0 mg/kg) and the opioid antagonist naloxone (0.34-22.0 micromol/kg; 0.13-8.0 mg/kg) were tested as examples of drugs without antipsychotic activity. The experiments demonstrated that these compounds did not specifically inhibit the behavioural effects of PCP. So far only antipsychotic drugs have been able to specifically inhibit the PCP-induced behaviours.
The social interaction test is a valuable behavioural model for testing anxiolytic and neurolepti... more The social interaction test is a valuable behavioural model for testing anxiolytic and neuroleptic drugs. The test quantifies the level of social behaviour between pairs of rats and it is usually based on manual analysis of behaviour. Advances in computer technology have made it possible to track the movements of pairs of rats in an arena, and the present paper describes the automation of the social interaction test by the commercial video-tracking programme, the EthoVision system. The ability of the automated system to correctly measure the social behaviour of rats is demonstrated by determining a dose-response relationship in the social interaction test for phencyclidine, a psychotomimetic drug that reduces social behaviour between pairs of rats. These data are subsequently analysed by the manual and automated data-acquisition methods and the results are compared. The study shows that the automated data-acquisition method best describes the behavioural effects of phencyclidine in the social interaction test by the locomotor activity of the rats, how much time the rats spend in different sections of the testing arena, and the level of social behaviour. Correlation analysis of the results from the manual and automated data-acquisition methods shows that the social behaviour measured by the automated system corresponds correctly to the social behaviour measured by the manual analysis. The present study has shown that the automated data-acquisition method can quantify locomotor activity, how rats use a testing arena and the level of social behaviour between rats in the social interaction test. The system cannot distinguish between social and aggressive behaviours, and therefore the rats should be tested in an unfamiliar arena to reduce territorial behaviour. Taking this limitation into consideration, the social interaction test can be automated by this computer-based video-tracking system and can be used as a routine test for quantifying the effects of drugs on the social behaviour of rats.
The changes of gene expression resulting from long-term exposure to monoamine antidepressant drug... more The changes of gene expression resulting from long-term exposure to monoamine antidepressant drugs in experimental animals are key to understanding the mechanisms of action of this class of drugs in man. Many of these genes and their products are either relevant biomarkers or directly involved in structural changes that are perhaps necessary for the antidepressant effect. Tesofensine is a novel triple monoamine reuptake inhibitor that acts to increase noradrenaline, serotonin, and dopamine neurotransmission. This study was undertaken to examine the effect of sub-chronic (5 days) and chronic (14 days) administration of Tesofensine on the expression of brain derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton protein (Arc) in the rat hippocampus. Furthermore, hippocampi from the same animals were used to investigate the effect on cell proliferation by means of Ki-67- and NeuroD-immunoreactivity. We find that chronic, but not sub-chronic treatment with Tesofensine increases BDNF mRNA in the CA3 region of the hippocampus (35%), and Arc mRNA in the CA1 of the hippocampus (65%). Furthermore, the number of Ki-67- and neuroD-positive cells increased after chronic, but not sub-chronic treatment. This study shows that Tesofensine enhances hippocampal gene expression and new cell formation indicative for an antidepressant potential of this novel drug substance.
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Papers by Frank Sams-Dodd