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Predictive validity of FSL rat, an animal model of depression
706
BIOL PSYCHIATRY 1994;35:615-747
only in rats developing learned helplessness. This cortical (5-HT) deficit can be prevented by prior training in escapable stress, by benzodiazepines, or subchronic tficyclic antidepressants 0~CA), via a GABAergic locus in M[~. Helplessness can also be reversed by cortical injection of TCA or of 5-l-IT. The hippocampus (IIPC) is also involved in LII with GABA both preventing and reversing LH and GABA blockade causing LH. Norepinephrine (NE) has a paradoxical effect in HPC, with NE release preventing LH but NE depletion correlating with LH. Septal 5-HT is key to LH reversal with TCA, and hypothalamus receives septohippocampal efferents with 5-HT and NE interactions hypothesized to mediate LI-I. Since LH is itself stressful, a maladaptive cycle is perpetuated, leading to subehronic behavioral deficits. Clinical predictions of the LH model will be discussed.
328. PREDICTIVE VALIDITY OF FSL RAT, AN ANIMAL MODEL OF DEPRESSION D.H. Overstreet, O. Pucilowski, D.S. Janowsky, & A.H. Rezvani Center for Alcohol Studies and Department of Psychiatry, University of North Carolina, Chapel Hill NC 27599-7175 The Hinders Sensitive Line (FSL) rat has been proposed as a genetic animal model of depression because it exhibits increased REM sleep amount, reduced REM sleep latency, increased sensitivity to the behavioral and hormonal effects of cholinergic agonists, and reduced activity in an open field relative to the control, Hinders Resistant Line (FRL) rat. in addition, the FSL rat shows an exaggerated immobility when exposed to mild stres. sots such as an inescapable swim tank and mild foot shock and a greater reduction in saccharin preference (anhedonia) when exposed to chronic mild stress. There is also some limited data that FSL rats "respond" to classical tricyclic antidepressants by increasing their mobility in the swim test. The present series of experiments sought to extend these observations by examining both newer generations antidepressants such as serotonin reuptake inhibitors (false negatives in the standard swim test) and calcium channel blockers and stimulants such as amphetamine and scopolamine (false positives in the standard swim test). The FSL and FRL rats were treated for 14 days twice daily with either desipramine (5 mg/ kg) setlraline (5.7 mg/kg), amphetamine (2 mg/kg), scopolamine (2 rag/ kg), verapamil (5 and 15 nWkg), nicardipine (2.5 and tO mg/kg), or vehicle. The single session, S-rain swim test was conducted 24 hr after the last injection. Under these conditions, only desipramine significantly lowered the very low immobility scores of the FRL rats. In contrast, desipramine, sertraline, verapamil (both doses) and nicardipine (10 mg/kg only) all reduced immobility in the FSL rats, while the stimulants amphetamine and scopolamine had no significant effects. In separate studies it was confirmed that acute or chronically administered scopolamine dramatically increased mobility in the FSL rats when given 30 rain before the swim test. These Findings show that the FSL rats exhibit a p~luction in immobility following chronic treatment with sertraline, a promising new generation antidepressant, desipramine, a classical tricyclic antidepressant, and two calcium channel blockers, which have also been recently reported to have antidepressant potential. Thus, support for the predictive validity of the FSL rat model of depression has been obtained,
329. POSTNATAL _REMODELING OF MONKEY PREFRONTAL CORTICAL CIRCUITRY S.A. Anderson 1, J. Classey2, J.S. Lund2, F. Cond~ I, & D.A. Lewis I University of Pittsburgh, Pittsburgh, PA, 15213; 2University of
SATURDAY, MAY 21
London, London, England Normal cortical development in prin~te.~ appears to involve an initial overproduction of synapses, followed by synapse elimination until adult levels are achieved. It has been suggested ~.batan abnormality in cortical synapse elimination in humans could be involved ;n rite pathophysiology of schizophrenia. Previous electron microscopy studies i~ primate cortex have demonstrated that these changes in synaptic deJ~sity primarily involve asymmetric, presumably excitatory synapses, the majority of which are located on the dendritic spines of pyramidal neurons. The timing of synapse reduction remains unclear, but may occur largely during adolescence. However, the timing and extent of changes of synaptic input to subpopulations of pyramidal neurons have not been determined. In this study, the rapid Golgi technique was used to identify pyramidal neurons in mid-layer !il of areas 9 and 46 of monkey (Macacamulatta) prefrontal cortex. Spine density was found to increase substantially during the first months of life, remain fairly stable between 3 and 18 months of age, and then decline markedly during adolescence. For example, on the apical dendritic tree, spine density decreased 30% between prepubertal and adult animals. Similar reductions in spine density were found on basal dendrites. Immunohistochemical experiments revealed that chandelier neuron axon cartridges, an important source of inhibitory input to these pyramidal neurons, may also undergo a parallel pattern of overproduction and elimination. Since mid-layer !!! pyramidal neurons in prefrontal cortex are critical components of corticocortical information processing, these findings may be relevant to the hypothesis that schizophrenia can result from an abnormality in the process of synapse elimination during adolescence.
330. GENETIC DIFFERENCES IN BEHAVIORAL RESPONSE TO NEONATAL HIPPOCAMPAL DAMAGE IN RATS B.K. Lipska & D.R. Weinberger Clinical Brain Disorders Branch, NIMH, Neuroscience Center at St. Elizabeths, WashingtOn DC 20032 The principal clinical phenomena associated with schizophrenia including postpubertal onset, developmental structural hippocampal abnormality, frontal cortical dysfunction, dysregulation of t,'ze limbic dopaminergic (DA) system and vulnerability to stress have been difficult to explain by a unitary animal model. We recently described a model that may address these features. Excitotoxic ventral hippocampal (VH) lesions induced in neonatal (postnatal day 7, PDT) Sprague-Dawley (SD) male rats do not affect behavioral indices of DA transmission before puberty (PD35), but result in the postpubertal (PD56) emergence of striatal/limbic DA hyperresponsivity. There is important evidence of genetic liability to schizophrenia. Genetic factors that control brain function may be studied in genetically inbred strains of rats. it has been demonstrated that two strains of rats - SD and Fischer F344 (F) differ in responsiveness to stress and in functional states of the mesolimbie DA system. We now report that behavioral effects of neonatal VH lesions differ substantially between these two strains. A similar lesion in terms of size (appr. 50-75% of hippocampal area destroyed) and location (VII) induces more exaggerated locomotor hyperactivity in response to a novel environment and to amphetamine in F rats than in SD rats. Moreover, in contrast to SD rats, in F rats the effects appear early (PD35). On the other hand, a more restricted VH damage confined to appr. 10% of hippocampal area results in postpubertal emergence of hyperactivity in F rats. These data suggest that the developmental lesion may interact with genetic factors involved in dopaminergic function. This could also be the case in schizophrenia where probably several risk factors, such as perinatal hippocampal defect and genetic as well as environmental components, account for the onset of the illness.
BIOL PSYCHIATRY 1994;35:615-747
only in rats developing learned helplessness. This cortical (5-HT) deficit can be prevented by prior training in escapable stress, by benzodiazepines, or subchronic tficyclic antidepressants 0~CA), via a GABAergic locus in M[~. Helplessness can also be reversed by cortical injection of TCA or of 5-l-IT. The hippocampus (IIPC) is also involved in LII with GABA both preventing and reversing LH and GABA blockade causing LH. Norepinephrine (NE) has a paradoxical effect in HPC, with NE release preventing LH but NE depletion correlating with LH. Septal 5-HT is key to LH reversal with TCA, and hypothalamus receives septohippocampal efferents with 5-HT and NE interactions hypothesized to mediate LI-I. Since LH is itself stressful, a maladaptive cycle is perpetuated, leading to subehronic behavioral deficits. Clinical predictions of the LH model will be discussed.
328. PREDICTIVE VALIDITY OF FSL RAT, AN ANIMAL MODEL OF DEPRESSION D.H. Overstreet, O. Pucilowski, D.S. Janowsky, & A.H. Rezvani Center for Alcohol Studies and Department of Psychiatry, University of North Carolina, Chapel Hill NC 27599-7175 The Hinders Sensitive Line (FSL) rat has been proposed as a genetic animal model of depression because it exhibits increased REM sleep amount, reduced REM sleep latency, increased sensitivity to the behavioral and hormonal effects of cholinergic agonists, and reduced activity in an open field relative to the control, Hinders Resistant Line (FRL) rat. in addition, the FSL rat shows an exaggerated immobility when exposed to mild stres. sots such as an inescapable swim tank and mild foot shock and a greater reduction in saccharin preference (anhedonia) when exposed to chronic mild stress. There is also some limited data that FSL rats "respond" to classical tricyclic antidepressants by increasing their mobility in the swim test. The present series of experiments sought to extend these observations by examining both newer generations antidepressants such as serotonin reuptake inhibitors (false negatives in the standard swim test) and calcium channel blockers and stimulants such as amphetamine and scopolamine (false positives in the standard swim test). The FSL and FRL rats were treated for 14 days twice daily with either desipramine (5 mg/ kg) setlraline (5.7 mg/kg), amphetamine (2 mg/kg), scopolamine (2 rag/ kg), verapamil (5 and 15 nWkg), nicardipine (2.5 and tO mg/kg), or vehicle. The single session, S-rain swim test was conducted 24 hr after the last injection. Under these conditions, only desipramine significantly lowered the very low immobility scores of the FRL rats. In contrast, desipramine, sertraline, verapamil (both doses) and nicardipine (10 mg/kg only) all reduced immobility in the FSL rats, while the stimulants amphetamine and scopolamine had no significant effects. In separate studies it was confirmed that acute or chronically administered scopolamine dramatically increased mobility in the FSL rats when given 30 rain before the swim test. These Findings show that the FSL rats exhibit a p~luction in immobility following chronic treatment with sertraline, a promising new generation antidepressant, desipramine, a classical tricyclic antidepressant, and two calcium channel blockers, which have also been recently reported to have antidepressant potential. Thus, support for the predictive validity of the FSL rat model of depression has been obtained,
329. POSTNATAL _REMODELING OF MONKEY PREFRONTAL CORTICAL CIRCUITRY S.A. Anderson 1, J. Classey2, J.S. Lund2, F. Cond~ I, & D.A. Lewis I University of Pittsburgh, Pittsburgh, PA, 15213; 2University of
SATURDAY, MAY 21
London, London, England Normal cortical development in prin~te.~ appears to involve an initial overproduction of synapses, followed by synapse elimination until adult levels are achieved. It has been suggested ~.batan abnormality in cortical synapse elimination in humans could be involved ;n rite pathophysiology of schizophrenia. Previous electron microscopy studies i~ primate cortex have demonstrated that these changes in synaptic deJ~sity primarily involve asymmetric, presumably excitatory synapses, the majority of which are located on the dendritic spines of pyramidal neurons. The timing of synapse reduction remains unclear, but may occur largely during adolescence. However, the timing and extent of changes of synaptic input to subpopulations of pyramidal neurons have not been determined. In this study, the rapid Golgi technique was used to identify pyramidal neurons in mid-layer !il of areas 9 and 46 of monkey (Macacamulatta) prefrontal cortex. Spine density was found to increase substantially during the first months of life, remain fairly stable between 3 and 18 months of age, and then decline markedly during adolescence. For example, on the apical dendritic tree, spine density decreased 30% between prepubertal and adult animals. Similar reductions in spine density were found on basal dendrites. Immunohistochemical experiments revealed that chandelier neuron axon cartridges, an important source of inhibitory input to these pyramidal neurons, may also undergo a parallel pattern of overproduction and elimination. Since mid-layer !!! pyramidal neurons in prefrontal cortex are critical components of corticocortical information processing, these findings may be relevant to the hypothesis that schizophrenia can result from an abnormality in the process of synapse elimination during adolescence.
330. GENETIC DIFFERENCES IN BEHAVIORAL RESPONSE TO NEONATAL HIPPOCAMPAL DAMAGE IN RATS B.K. Lipska & D.R. Weinberger Clinical Brain Disorders Branch, NIMH, Neuroscience Center at St. Elizabeths, WashingtOn DC 20032 The principal clinical phenomena associated with schizophrenia including postpubertal onset, developmental structural hippocampal abnormality, frontal cortical dysfunction, dysregulation of t,'ze limbic dopaminergic (DA) system and vulnerability to stress have been difficult to explain by a unitary animal model. We recently described a model that may address these features. Excitotoxic ventral hippocampal (VH) lesions induced in neonatal (postnatal day 7, PDT) Sprague-Dawley (SD) male rats do not affect behavioral indices of DA transmission before puberty (PD35), but result in the postpubertal (PD56) emergence of striatal/limbic DA hyperresponsivity. There is important evidence of genetic liability to schizophrenia. Genetic factors that control brain function may be studied in genetically inbred strains of rats. it has been demonstrated that two strains of rats - SD and Fischer F344 (F) differ in responsiveness to stress and in functional states of the mesolimbie DA system. We now report that behavioral effects of neonatal VH lesions differ substantially between these two strains. A similar lesion in terms of size (appr. 50-75% of hippocampal area destroyed) and location (VII) induces more exaggerated locomotor hyperactivity in response to a novel environment and to amphetamine in F rats than in SD rats. Moreover, in contrast to SD rats, in F rats the effects appear early (PD35). On the other hand, a more restricted VH damage confined to appr. 10% of hippocampal area results in postpubertal emergence of hyperactivity in F rats. These data suggest that the developmental lesion may interact with genetic factors involved in dopaminergic function. This could also be the case in schizophrenia where probably several risk factors, such as perinatal hippocampal defect and genetic as well as environmental components, account for the onset of the illness.