Objective: This study's goal was to replicate the finding that family members of schizo- phre... more Objective: This study's goal was to replicate the finding that family members of schizo- phrenia patients show poor P50 suppression during a paired-click auditory evoked re- sponse paradigm. Method: The paired-click paradigm was used to test 44 schizophrenia patients, 60 of their clinically unaffected first-degree relatives, and 45 normal subjects. Two clicks (83 dB(A) over a 60-dB(A) white noise background)
Psychiatric researchers need specific animal models to better understand the neurobiology of schi... more Psychiatric researchers need specific animal models to better understand the neurobiology of schizophrenia. Prepulse inhibition (PPI), the reduction in startle produced by a prepulse stimulus, is diminished in schizophrenic patients. Theoretically, deficient PPI in schizophrenic patients reflects a loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In rats, PPI is disrupted by systemic administration of dopamine agonists or by manipulations of neural circuitry linking the limbic cortex, striatum, pallidum, and pontine reticular formation. This loss of PPI in rats may be a useful model for studying the neurobiology of impaired sensorimotor gating in schizophrenic patients. We assessed the face, predictive, and construct validity of this animal model. Face validity was supported: stimulus manipulations produced parallel changes in PPI in humans and rats, and the dopamine agonist apomorphine disrupted PPI in rats, mimicking PPI deficits in schizophrenics. Predictive validity was supported: the ability of antipsychotics to restore PPI in apomorphine-treated rats correlated with clinical antipsychotic potency (rs = .991) and D2-receptor affinity (rs = .893). Antipsychotics that restore PPI in apomorphine-treated rats include "typical" antipsychotics and the "atypical" antipsychotic clozapine. Construct validity was supported: PPI was disrupted in rats when dopamine was infused into the nucleus accumbens; this effect was blocked by haloperidol. The loss of PPI in dopamine-activated rats may be a valid animal model of sensorimotor gating deficits in schizophrenic patients. This model may help us understand the neurobiology of cognitive deficits in schizophrenic patients.
Schizophrenic patients are known to suffer from a number of information processing disturbances, ... more Schizophrenic patients are known to suffer from a number of information processing disturbances, including deficits in both prep&e inhibition of startle and latent inhibition. Since these behavioral phenomena can also be observed in animals, they represent an ideal starting point for de- veloping animal models having construct validity for spe- cific deficits observed in schizophrenia. The principal question is how
Although the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses ... more Although the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses on the pathogenesis of this disease, it is still highly topical. The concept of how the serotonin system is involved in the origin and progress of schizophrenia has considerably changed over the past decades. Therefore, the present work will give an overview about the development and the
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 24, 2015
Serious mental illness occurs in 25% of the general population, with many disorders being neurode... more Serious mental illness occurs in 25% of the general population, with many disorders being neurodevelopmental, life-long, and debilitating. The wide variation and overlap in symptoms across disorders increases the difficulty of research and treatment development. The NIMH Research Domain of Criteria initiative aims to improve our understanding of the molecular and behavioral consequences of specific neurodevelopmental mechanisms across disorders, enabling targeted treatment development. The transcription factor Specificity Protein 4 (SP4) is important for neurodevelopment and is genetically associated with both schizophrenia and bipolar disorder. Reduced Sp4 expression in mice (hypomorphic) reproduces several characteristics of psychiatric disorders. We further tested the utility of Sp4 hypomorphic mice as a model organism relevant to psychiatric disorders by assessing cognitive control plus effort and decision-making aspects of approach motivation using cross-species-relevant tests....
There is increasing concern that a prolonged period of untreated psychosis may be associated with... more There is increasing concern that a prolonged period of untreated psychosis may be associated with increased severity of symptoms and decreased overall quality of life in persons with schizophrenia. Taken together with the extremely debilitating nature of schizophrenia, there is a renewed interest in the early identification and treatment of psychotic disorders, including prodromal symptoms. Because the efficacy, safety, and ethics of early intervention are being examined in the clinical arena, preclinical studies on the therapeutic potential and long-term consequences of prophylactic treatments in animals are warranted in order to inform this debate. Because some forms of schizophrenia appear to be attributable to early developmental perturbations along with genetic risk factors, many animal studies have examined the influences of specific developmental or genetic manipulations on behaviors and neural circuitry relevant to schizophrenia. Based on the timing of insult and manifestation of deficits, these animal models will be particularly useful in assessing the efficacy and safety of potential prophylactic antipsychotic treatments. The following review will: (1) highlight the clinical literature on the need for and the ongoing studies of prophylactic antipsychotic treatment for schizophrenia; (2) illustrate several examples of neurodevelopmental and genetic animal models of schizophrenia; and (3) demonstrate the potential for these preclinical models to be used in the evaluation of prophylactic treatment during ontogeny. q
We propose a translational approach to the study of anorexia nervosa (AN) based on our human subj... more We propose a translational approach to the study of anorexia nervosa (AN) based on our human subject studies where there are characteristic elevations in 5-HT(1A) receptor binding, associated harm avoidance behaviors, reduced impulsivity, and comorbid anxiety disorders. Towards this goal, the hyponeophagia assay was implemented whereby food-deprived mice show increased latency to begin feeding in a novel, anxiogenic environment. The non-selective serotonin agonist, 5-MeODMT, potentiates feeding inhibition compared to the inhibition generated by the anxiogenic environment in a drug-by-environment interaction. Thus, using hyponeophagia in mice, it was possible to study the following key components of AN: anxiety; feeding inhibition; and a modulatory role of the serotonergic system. A major prediction of the proposed AN model is that 5-HT(1A) receptor activation is necessary for feeding inhibition. In support of this model, the 5-HT(1A) receptor antagonist, WAY100635, reverses the 5-Me...
Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recen... more Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms. The "Marine Resiliency Study II" (MRS-II; October 2011-October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the associat...
Sensorimortor gating and locomotion are behaviors that reflect pre-attentive sensory filtering an... more Sensorimortor gating and locomotion are behaviors that reflect pre-attentive sensory filtering and higher order, top-down, sensory processing, respectively. These processes are thought to affect either the perception of novelty in an environment (filtering) or cognition (higher order processing), salient features of models of altered states of consciousness (ASC). Drugs with highly selective receptor affinities that produce ASC can help to establish neural correlates, pathways, and mechanisms underlying ASC. Furthermore, screening for substances that selectively reverse drug-induced sensory processing departures is valuable for development of experimental antipsychotics. This study investigated the anomalous opioid sub-type, the kappa opioid (KA) system, within the two ASC models. Significant interaction and reversal effects between KA and the serotonin/2A (5-HT2A) system - the serotonin sub-type associated with classical psychedelics - were observed in three BPM measures. These mea...
Posttraumatic stress disorder (PTSD) is a major public health concern, which has been seeing incr... more Posttraumatic stress disorder (PTSD) is a major public health concern, which has been seeing increased recent attention partly due to the wars in Iraq and Afghanistan. Historically, research attempting to understand the etiology and treatment of PTSD has made frequent use of psychophysiological measures of arousal as they provide a number of advantages in providing objective, non-self-report outcomes that are closely related to proposed neurobiological mechanisms and provide opportunity for cross-species translation. Further, the ongoing shift in classification of psychiatric illness based on symptom clusters to specific biological, physiological, and behavioral constructs, as outlined in the US National Institute of Mental Health (NIMH) Research Domain Criteria project (RDoC), promises that psychophysiological research will continue to play a prominent role in research on trauma-related illnesses. This review focuses on the current state of the knowledge regarding psychophysiologic...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2013
One of the oldest models of schizophrenia is based on the effects of serotonergic hallucinogens s... more One of the oldest models of schizophrenia is based on the effects of serotonergic hallucinogens such as mescaline, psilocybin, and (+)-lysergic acid diethylamide (LSD), which act through the serotonin 5-HT(2A) receptor. These compounds produce a 'model psychosis' in normal individuals that resembles at least some of the positive symptoms of schizophrenia. Based on these similarities, and because evidence has emerged that the serotonergic system plays a role in the pathogenesis of schizophrenia in some patients, animal models relevant to schizophrenia have been developed based on hallucinogen effects. Here we review the behavioural effects of hallucinogens in four of those models, the receptor and neurochemical mechanisms for the effects and their translational relevance. Despite the difficulty of modelling hallucinogen effects in nonverbal species, animal models of schizophrenia based on hallucinogens have yielded important insights into the linkage between 5-HT and schizoph...
The startle response evoked by repeated presentation of a loud acoustic stimulus is regulated by ... more The startle response evoked by repeated presentation of a loud acoustic stimulus is regulated by the independent processes of sensitization and habituation. While schizophrenia is associated with information processing impairments, there is conflicting evidence regarding the existence of habituation deficits in schizophrenic patients. Recent clinical evidence, however, indicates that patients with schizophrenia display exaggerated startle sensitization and diminished habituation. Given the linkage between dopaminergic abnormalities and schizophrenia, the goal of the present investigation was to examine the effect of deleting D1 and D2-like dopamine receptors on sensitization and habituation of the acoustic startle reflex in mice. For these experiments, the acoustic startle reflex was assessed in dopamine D1, D2, and D3 receptor wild-type (WT) and knockout (KO) mice on a C57BL/6J background, using a methodology that can measure both sensitization and habituation. Mice lacking the D1 ...
208 words) Manuscript (2729 words) The number of references (40) Abstract Background: Ketamine pr... more 208 words) Manuscript (2729 words) The number of references (40) Abstract Background: Ketamine produces schizophrenia-like behavioral phenotypes in healthy people.
Developing reliable, predictive animal models for complex psychiatric disorders, such as schizoph... more Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble 'positive-like' symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed.
The Journal of pharmacology and experimental therapeutics, 2001
Several reports describe substantive behavioral differences between strains of mice both at basel... more Several reports describe substantive behavioral differences between strains of mice both at baseline and in response to pharmacological manipulations. For example, mouse strain differences have been reported in prepulse inhibition (PPI) and patterns of locomotor activity, two behavioral processes that are altered by dopamine (DA) agonists such as amphetamine. Here, we characterized acoustic and tactile startle reactivity, acoustic PPI, and both the amounts and spatial patterns of locomotor activity in C57BL/6J, 129SvEv (129S6), and 129SvJ (129X1) mice at baseline and in amphetamine dose-response studies. Because hearing loss is common in numerous strains of mice, we also assessed cross-modal PPI using a light prepulse with an airpuff startle stimulus. The results establish that these three inbred strains of mice display both intra- and cross-modal PPI, and that amphetamine decreases PPI and startle reactivity in a dose-, sensory modality-, and strain-specific manner. Furthermore, th...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in s... more Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We reported strain differences in the sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in adult rats, with greater sensitivity in Harlan Sprague Dawley (SDH) versus Wistar (WH) rats. However, Kinney et al. (1999) recently reported opposite findings, using Bantin-Kingman Sprague Dawley (SDBK) and Wistar (WBK) rats; in fact, SDBK rats did not exhibit clear apomorphine-induced reductions in sensorimotor gating. These new findings of Kinney et al. (1999) directly conflict with over 15 years of results from our laboratories and challenge interpretations from a large body of literature. The present studies carefully a...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
The involvement of dopamine neurotransmission in behavioral responses to novelty is suggested by ... more The involvement of dopamine neurotransmission in behavioral responses to novelty is suggested by reports that reward is related to increased dopamine activity, that dopamine modulates exploratory behavior in animals, and that Parkinson's disease patients report diminished responses to novelty. Some studies have reported that polymorphisms of the human dopamine D4 receptor (D4R) gene are associated with personality inventory measures of the trait called "novelty-seeking". To explore a potential role for the D4R in behavioral responses to novelty, we evaluated D4R-knock-out (D4R-/-) and wild-type (D4R+/+) mice in three approach-avoidance paradigms: the open field, emergence, and novel object tests. These three paradigms differ in the degree to which they elicit approach, or exploratory behavior, and avoidance, or anxiety-related behavior. Thus, we used these three tests to determine whether the D4R primarily influences the exploratory or the anxious component of response...
The corticotropin-releasing factor (CRF) family of peptides and receptors coordinates the mammali... more The corticotropin-releasing factor (CRF) family of peptides and receptors coordinates the mammalian endocrine, autonomic, and behavioral responses to stress. Excessive CRF production has been implicated in the etiology of stress-sensitive psychiatric disorders such as posttraumatic stress disorder (PTSD), which is associated with alterations in startle plasticity. The CRF family of peptides and receptors mediate acute startle response changes during stress, and chronic CRF activation can induce startle abnormalities. To determine what neural circuits modulate startle in response to chronic CRF activation, transgenic mice overexpressing CRF throughout the central nervous system (CNS; CRF-COE(CNS)) or restricted to inhibitory GABAergic neurons (CRF-COE(GABA)) were compared across multiple domains of startle plasticity. CRF overexpression throughout the CNS increased startle magnitude and reduced ability to inhibit startle (decreased habituation and decreased prepulse inhibition (PPI)), similar to previous reports of exogenous effects of CRF. Conversely, CRF overexpression confined to inhibitory neurons decreased startle magnitude but had no effect on inhibitory measures. Acute CRF receptor 1 (CRF1) antagonist treatment attenuated only the effects on startle induced by CNS-specific CRF overexpression. Specific deletion of CRF1 receptors from forebrain principal neurons failed to alter the effects of exogenous CRF or stress on startle, suggesting that these CRF1 expressing neurons are not required for CRF-induced changes in startle behaviors. These data indicate that the effects of CRF activation on startle behavior utilize an extensive neural circuit that includes both forebrain and non-forebrain regions. Furthermore, these findings suggest that the neural source of increased CRF release determines the startle phenotype elicited. It is conceivable that this may explain why disorders characterized by increased CRF in cerebrospinal fluid (e.g. PTSD and major depressive disorder) have distinct symptom profiles in terms of startle reactivity.
Objective: This study's goal was to replicate the finding that family members of schizo- phre... more Objective: This study's goal was to replicate the finding that family members of schizo- phrenia patients show poor P50 suppression during a paired-click auditory evoked re- sponse paradigm. Method: The paired-click paradigm was used to test 44 schizophrenia patients, 60 of their clinically unaffected first-degree relatives, and 45 normal subjects. Two clicks (83 dB(A) over a 60-dB(A) white noise background)
Psychiatric researchers need specific animal models to better understand the neurobiology of schi... more Psychiatric researchers need specific animal models to better understand the neurobiology of schizophrenia. Prepulse inhibition (PPI), the reduction in startle produced by a prepulse stimulus, is diminished in schizophrenic patients. Theoretically, deficient PPI in schizophrenic patients reflects a loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In rats, PPI is disrupted by systemic administration of dopamine agonists or by manipulations of neural circuitry linking the limbic cortex, striatum, pallidum, and pontine reticular formation. This loss of PPI in rats may be a useful model for studying the neurobiology of impaired sensorimotor gating in schizophrenic patients. We assessed the face, predictive, and construct validity of this animal model. Face validity was supported: stimulus manipulations produced parallel changes in PPI in humans and rats, and the dopamine agonist apomorphine disrupted PPI in rats, mimicking PPI deficits in schizophrenics. Predictive validity was supported: the ability of antipsychotics to restore PPI in apomorphine-treated rats correlated with clinical antipsychotic potency (rs = .991) and D2-receptor affinity (rs = .893). Antipsychotics that restore PPI in apomorphine-treated rats include "typical" antipsychotics and the "atypical" antipsychotic clozapine. Construct validity was supported: PPI was disrupted in rats when dopamine was infused into the nucleus accumbens; this effect was blocked by haloperidol. The loss of PPI in dopamine-activated rats may be a valid animal model of sensorimotor gating deficits in schizophrenic patients. This model may help us understand the neurobiology of cognitive deficits in schizophrenic patients.
Schizophrenic patients are known to suffer from a number of information processing disturbances, ... more Schizophrenic patients are known to suffer from a number of information processing disturbances, including deficits in both prep&e inhibition of startle and latent inhibition. Since these behavioral phenomena can also be observed in animals, they represent an ideal starting point for de- veloping animal models having construct validity for spe- cific deficits observed in schizophrenia. The principal question is how
Although the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses ... more Although the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses on the pathogenesis of this disease, it is still highly topical. The concept of how the serotonin system is involved in the origin and progress of schizophrenia has considerably changed over the past decades. Therefore, the present work will give an overview about the development and the
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 24, 2015
Serious mental illness occurs in 25% of the general population, with many disorders being neurode... more Serious mental illness occurs in 25% of the general population, with many disorders being neurodevelopmental, life-long, and debilitating. The wide variation and overlap in symptoms across disorders increases the difficulty of research and treatment development. The NIMH Research Domain of Criteria initiative aims to improve our understanding of the molecular and behavioral consequences of specific neurodevelopmental mechanisms across disorders, enabling targeted treatment development. The transcription factor Specificity Protein 4 (SP4) is important for neurodevelopment and is genetically associated with both schizophrenia and bipolar disorder. Reduced Sp4 expression in mice (hypomorphic) reproduces several characteristics of psychiatric disorders. We further tested the utility of Sp4 hypomorphic mice as a model organism relevant to psychiatric disorders by assessing cognitive control plus effort and decision-making aspects of approach motivation using cross-species-relevant tests....
There is increasing concern that a prolonged period of untreated psychosis may be associated with... more There is increasing concern that a prolonged period of untreated psychosis may be associated with increased severity of symptoms and decreased overall quality of life in persons with schizophrenia. Taken together with the extremely debilitating nature of schizophrenia, there is a renewed interest in the early identification and treatment of psychotic disorders, including prodromal symptoms. Because the efficacy, safety, and ethics of early intervention are being examined in the clinical arena, preclinical studies on the therapeutic potential and long-term consequences of prophylactic treatments in animals are warranted in order to inform this debate. Because some forms of schizophrenia appear to be attributable to early developmental perturbations along with genetic risk factors, many animal studies have examined the influences of specific developmental or genetic manipulations on behaviors and neural circuitry relevant to schizophrenia. Based on the timing of insult and manifestation of deficits, these animal models will be particularly useful in assessing the efficacy and safety of potential prophylactic antipsychotic treatments. The following review will: (1) highlight the clinical literature on the need for and the ongoing studies of prophylactic antipsychotic treatment for schizophrenia; (2) illustrate several examples of neurodevelopmental and genetic animal models of schizophrenia; and (3) demonstrate the potential for these preclinical models to be used in the evaluation of prophylactic treatment during ontogeny. q
We propose a translational approach to the study of anorexia nervosa (AN) based on our human subj... more We propose a translational approach to the study of anorexia nervosa (AN) based on our human subject studies where there are characteristic elevations in 5-HT(1A) receptor binding, associated harm avoidance behaviors, reduced impulsivity, and comorbid anxiety disorders. Towards this goal, the hyponeophagia assay was implemented whereby food-deprived mice show increased latency to begin feeding in a novel, anxiogenic environment. The non-selective serotonin agonist, 5-MeODMT, potentiates feeding inhibition compared to the inhibition generated by the anxiogenic environment in a drug-by-environment interaction. Thus, using hyponeophagia in mice, it was possible to study the following key components of AN: anxiety; feeding inhibition; and a modulatory role of the serotonergic system. A major prediction of the proposed AN model is that 5-HT(1A) receptor activation is necessary for feeding inhibition. In support of this model, the 5-HT(1A) receptor antagonist, WAY100635, reverses the 5-Me...
Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recen... more Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms. The "Marine Resiliency Study II" (MRS-II; October 2011-October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the associat...
Sensorimortor gating and locomotion are behaviors that reflect pre-attentive sensory filtering an... more Sensorimortor gating and locomotion are behaviors that reflect pre-attentive sensory filtering and higher order, top-down, sensory processing, respectively. These processes are thought to affect either the perception of novelty in an environment (filtering) or cognition (higher order processing), salient features of models of altered states of consciousness (ASC). Drugs with highly selective receptor affinities that produce ASC can help to establish neural correlates, pathways, and mechanisms underlying ASC. Furthermore, screening for substances that selectively reverse drug-induced sensory processing departures is valuable for development of experimental antipsychotics. This study investigated the anomalous opioid sub-type, the kappa opioid (KA) system, within the two ASC models. Significant interaction and reversal effects between KA and the serotonin/2A (5-HT2A) system - the serotonin sub-type associated with classical psychedelics - were observed in three BPM measures. These mea...
Posttraumatic stress disorder (PTSD) is a major public health concern, which has been seeing incr... more Posttraumatic stress disorder (PTSD) is a major public health concern, which has been seeing increased recent attention partly due to the wars in Iraq and Afghanistan. Historically, research attempting to understand the etiology and treatment of PTSD has made frequent use of psychophysiological measures of arousal as they provide a number of advantages in providing objective, non-self-report outcomes that are closely related to proposed neurobiological mechanisms and provide opportunity for cross-species translation. Further, the ongoing shift in classification of psychiatric illness based on symptom clusters to specific biological, physiological, and behavioral constructs, as outlined in the US National Institute of Mental Health (NIMH) Research Domain Criteria project (RDoC), promises that psychophysiological research will continue to play a prominent role in research on trauma-related illnesses. This review focuses on the current state of the knowledge regarding psychophysiologic...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2013
One of the oldest models of schizophrenia is based on the effects of serotonergic hallucinogens s... more One of the oldest models of schizophrenia is based on the effects of serotonergic hallucinogens such as mescaline, psilocybin, and (+)-lysergic acid diethylamide (LSD), which act through the serotonin 5-HT(2A) receptor. These compounds produce a 'model psychosis' in normal individuals that resembles at least some of the positive symptoms of schizophrenia. Based on these similarities, and because evidence has emerged that the serotonergic system plays a role in the pathogenesis of schizophrenia in some patients, animal models relevant to schizophrenia have been developed based on hallucinogen effects. Here we review the behavioural effects of hallucinogens in four of those models, the receptor and neurochemical mechanisms for the effects and their translational relevance. Despite the difficulty of modelling hallucinogen effects in nonverbal species, animal models of schizophrenia based on hallucinogens have yielded important insights into the linkage between 5-HT and schizoph...
The startle response evoked by repeated presentation of a loud acoustic stimulus is regulated by ... more The startle response evoked by repeated presentation of a loud acoustic stimulus is regulated by the independent processes of sensitization and habituation. While schizophrenia is associated with information processing impairments, there is conflicting evidence regarding the existence of habituation deficits in schizophrenic patients. Recent clinical evidence, however, indicates that patients with schizophrenia display exaggerated startle sensitization and diminished habituation. Given the linkage between dopaminergic abnormalities and schizophrenia, the goal of the present investigation was to examine the effect of deleting D1 and D2-like dopamine receptors on sensitization and habituation of the acoustic startle reflex in mice. For these experiments, the acoustic startle reflex was assessed in dopamine D1, D2, and D3 receptor wild-type (WT) and knockout (KO) mice on a C57BL/6J background, using a methodology that can measure both sensitization and habituation. Mice lacking the D1 ...
208 words) Manuscript (2729 words) The number of references (40) Abstract Background: Ketamine pr... more 208 words) Manuscript (2729 words) The number of references (40) Abstract Background: Ketamine produces schizophrenia-like behavioral phenotypes in healthy people.
Developing reliable, predictive animal models for complex psychiatric disorders, such as schizoph... more Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble 'positive-like' symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed.
The Journal of pharmacology and experimental therapeutics, 2001
Several reports describe substantive behavioral differences between strains of mice both at basel... more Several reports describe substantive behavioral differences between strains of mice both at baseline and in response to pharmacological manipulations. For example, mouse strain differences have been reported in prepulse inhibition (PPI) and patterns of locomotor activity, two behavioral processes that are altered by dopamine (DA) agonists such as amphetamine. Here, we characterized acoustic and tactile startle reactivity, acoustic PPI, and both the amounts and spatial patterns of locomotor activity in C57BL/6J, 129SvEv (129S6), and 129SvJ (129X1) mice at baseline and in amphetamine dose-response studies. Because hearing loss is common in numerous strains of mice, we also assessed cross-modal PPI using a light prepulse with an airpuff startle stimulus. The results establish that these three inbred strains of mice display both intra- and cross-modal PPI, and that amphetamine decreases PPI and startle reactivity in a dose-, sensory modality-, and strain-specific manner. Furthermore, th...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in s... more Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We reported strain differences in the sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in adult rats, with greater sensitivity in Harlan Sprague Dawley (SDH) versus Wistar (WH) rats. However, Kinney et al. (1999) recently reported opposite findings, using Bantin-Kingman Sprague Dawley (SDBK) and Wistar (WBK) rats; in fact, SDBK rats did not exhibit clear apomorphine-induced reductions in sensorimotor gating. These new findings of Kinney et al. (1999) directly conflict with over 15 years of results from our laboratories and challenge interpretations from a large body of literature. The present studies carefully a...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
The involvement of dopamine neurotransmission in behavioral responses to novelty is suggested by ... more The involvement of dopamine neurotransmission in behavioral responses to novelty is suggested by reports that reward is related to increased dopamine activity, that dopamine modulates exploratory behavior in animals, and that Parkinson's disease patients report diminished responses to novelty. Some studies have reported that polymorphisms of the human dopamine D4 receptor (D4R) gene are associated with personality inventory measures of the trait called "novelty-seeking". To explore a potential role for the D4R in behavioral responses to novelty, we evaluated D4R-knock-out (D4R-/-) and wild-type (D4R+/+) mice in three approach-avoidance paradigms: the open field, emergence, and novel object tests. These three paradigms differ in the degree to which they elicit approach, or exploratory behavior, and avoidance, or anxiety-related behavior. Thus, we used these three tests to determine whether the D4R primarily influences the exploratory or the anxious component of response...
The corticotropin-releasing factor (CRF) family of peptides and receptors coordinates the mammali... more The corticotropin-releasing factor (CRF) family of peptides and receptors coordinates the mammalian endocrine, autonomic, and behavioral responses to stress. Excessive CRF production has been implicated in the etiology of stress-sensitive psychiatric disorders such as posttraumatic stress disorder (PTSD), which is associated with alterations in startle plasticity. The CRF family of peptides and receptors mediate acute startle response changes during stress, and chronic CRF activation can induce startle abnormalities. To determine what neural circuits modulate startle in response to chronic CRF activation, transgenic mice overexpressing CRF throughout the central nervous system (CNS; CRF-COE(CNS)) or restricted to inhibitory GABAergic neurons (CRF-COE(GABA)) were compared across multiple domains of startle plasticity. CRF overexpression throughout the CNS increased startle magnitude and reduced ability to inhibit startle (decreased habituation and decreased prepulse inhibition (PPI)), similar to previous reports of exogenous effects of CRF. Conversely, CRF overexpression confined to inhibitory neurons decreased startle magnitude but had no effect on inhibitory measures. Acute CRF receptor 1 (CRF1) antagonist treatment attenuated only the effects on startle induced by CNS-specific CRF overexpression. Specific deletion of CRF1 receptors from forebrain principal neurons failed to alter the effects of exogenous CRF or stress on startle, suggesting that these CRF1 expressing neurons are not required for CRF-induced changes in startle behaviors. These data indicate that the effects of CRF activation on startle behavior utilize an extensive neural circuit that includes both forebrain and non-forebrain regions. Furthermore, these findings suggest that the neural source of increased CRF release determines the startle phenotype elicited. It is conceivable that this may explain why disorders characterized by increased CRF in cerebrospinal fluid (e.g. PTSD and major depressive disorder) have distinct symptom profiles in terms of startle reactivity.
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Papers by Mark Geyer