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Failure of haloperidol to block the disruption of sensory gating induced by phencyclidine and MK801
Neurobiologyof SchizophreniaII
BIOL PSYCHIATRY 1989;25:169A-184A
169A
interact with the aging process to facilitate late-onset depression. These findings may have implications for the pathophysiology, treatment, and prognosis of late-onset affective disorder.
NEUROBIOLOGY
OF SCHIZOPHRENIA
II
Saturday, May 6, 1:00 to 6:00 Hilton Ballroom B
343 PERIPHERAL INDICES OF FREE RADICAL METABOLISM IN SCHIZOPHRENIA Jayasimha N. Murthy, Sahebarao P. Mahadik, Sukdeb Mukherjee, Ravinder Reddy, David B. Schnur New York, NY
High levels of free radicals, if not removed by specific enzymes, can damage plasma membranes. It has been proposed that free radical induced pathology may be involved in the pathogenesis of tardive dyskinesia and the defect state of schizophrenia. Data will be presented from an ongoing study examining three enzymes (superoxide dismutase, SOD; glutathione peroxidase, GSHPGD; and catalase, CAT) of free radical metabolism in schizophrenic patients. Initial findings in 11 schizophrenic patients and nine normal controls show significant differences between the groups in levels of all three enzymes. Mean SOD levels (Standard SOD Units) were significantly higher in schizophrenic patients (2449.6 + 744.5) than in normals (1025.2 ? 14) (p < .OOl), GSHPOD levels (umoYminute) were also significantly higher in patients (58.4 + 20.7) than in normals (31.2 + 3.7) (p = .OOl), while CAT levels (mmoVminute) were significantly lower in patients (7 1.8 ? 28.6) than in normals (137.9 5 30). All figures represent values per gm of Hb. There was no relation between any of the enzyme levels and either presence of TD or severity of negative symptoms. Data will be presented on a larger series of patients. The findings will be discussed with emphasis on possible clinical significance and consideration of whether the abnormal enzyme levels reflect increased free radical production, or a primary pathology of the enzyme systems independent of rate of free radical production.
344 FAILURE OF HALOPERIDOL TO BLOCK THE DISRUPTION OF SENSORY GATING INDUCED BY PHENCYCLIDINE AND MK801 Mark A. Geyer, David L. Braff, Robert S. Mansbach La Jolla, CA Prepulse inhibition (PPI) of acoustic startle, a form of sensory gating, occurs when a weak pre-stimulus precedes a startling stimulus and inhibits startle. Schizophrenics exhibit less PPI than controls. In rats, PPI is blocked by dopamine agonists such as apomorphine, effects which are antagonized by haloperidol. Here, PPI of acoustic startle was measured in male rats after ip injections of 0.1-10.0 mg/kg phencyclidine (PCP) or 0.01-1.0 mg/kg MK801. PCP has been suggested as a model psychotogen and MK801 is an anticonvulsant that, like PCP, is an NMDA antagonist. Startle was elicited by noise bursts at 108 or 120 dB or by air-puffs and was inhibited by 80 dB
170A
BIOL PSYCHIATRY 1989;25:169A-184A
Neurobiology of Schizophrenia II
prepulses presented 100 milliseconds before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals. PCP and MK801 dose-dependently reduced the amount of PPI independently of the level of startle elicited by the various stimuli. Haloperidol (0.1 mg/kg), which blocks the disruption of PPI induced by apomorphine, did not block that induced by either 5 mg/kg PCP or 0.5 mg/kg MK801. These results demonstrate that putative NMDA antagonists inhibit sensory gating in rats by a mechanism that is insensitive to the effects of haloperidol and different from that of dopamine agonists.
345 QUANTITATIVE AUTORADIOGRAPHIC D1, DZ, AND S2 DIFFERENCES WITH CLOZAPINE AND HALOPERIDOL G. LaHoste, C. Widmark, S. O’Dell, R. Shapiro, J.F. Marshall, S.G. Potkin Irvine, CA and Orange, CA
The atypical antipsychotic clozapine (CLZ) is effective in ameliorating psychosis in treatment-resistant schizophrenics and is relatively free of extrapyramidal side effects. In order to elucidate the neural mechanism by which CLZ can attenuate psychosis without inducing extrapyramidal side effects, we used receptor autoradiography to image and quantify changes in dopamine and serotonin receptors following chronic treatment with CLZ or the typical neuroleptic haloperidol (HAL). Adult male rats were injected daily with CLZ (30 mg/kg ip), HAL (1 .Omg/kg ip), or vehicle (VEH) for 28 days. Doses were chosen to mimic the relative clinical potency of CLZ and HAL. Seventy-two hours after the last drug injection, the rats were sacrificed by decapitation, their brains removed and prepared for receptor autoradiography. Di receptors were labeled with (3H)SCH 23390, D2 receptors with (3H)spiroperidol, and 5-HTz receptors with (3H)ketanserin. Concentrations of receptor binding were determined from autoradiographs that included frontal cortex, caudate-putamen, nucleus accumbens, and substantia nigra. Rats that received CLZ chronically showed CNS receptor changes markedly different from chronic HAL-treated animals. Animals treated chronically with HAL showed enhanced D2 binding (an apparent up-regulation), while those treated with CLZ did not. In contrast, CLZ induced an enhanced D2 receptor binding whereas these sites were unchanged in chronic HAL-treated rats. Finally, CLZ treatment decreased binding of (3H)ketanserin to 5-HTz sites. The opposite effects of CLZ and HAL on D, and D2 receptors may be relevant to their propensity to induce extrapyramidal side effects.
346 EFFECTS OF D, AGONIST IN SCHIZOPHRENIA Philip D. Harvey, Stacey Jaff, Michael Davidson, Kenneth L. Davis New York, NY
Recent studies have suggested a reduced level of activation of the prefrontal cortical regions in chronic schizophrenia. This lack of activation has been measured directly by examination of cortical blood flow while performing tasks that make demands on those regions (i.e., The Wisconsin Card Sort: WCST). Qther recent data have suggested that certain types of dopamine receptors are differentially distributed throughout the brain, with D, receptors being largely cortical and D2 receptors subcortical. In this study we administered a highly selective partial D, agonist, SKF 38393, in order to
BIOL PSYCHIATRY 1989;25:169A-184A
169A
interact with the aging process to facilitate late-onset depression. These findings may have implications for the pathophysiology, treatment, and prognosis of late-onset affective disorder.
NEUROBIOLOGY
OF SCHIZOPHRENIA
II
Saturday, May 6, 1:00 to 6:00 Hilton Ballroom B
343 PERIPHERAL INDICES OF FREE RADICAL METABOLISM IN SCHIZOPHRENIA Jayasimha N. Murthy, Sahebarao P. Mahadik, Sukdeb Mukherjee, Ravinder Reddy, David B. Schnur New York, NY
High levels of free radicals, if not removed by specific enzymes, can damage plasma membranes. It has been proposed that free radical induced pathology may be involved in the pathogenesis of tardive dyskinesia and the defect state of schizophrenia. Data will be presented from an ongoing study examining three enzymes (superoxide dismutase, SOD; glutathione peroxidase, GSHPGD; and catalase, CAT) of free radical metabolism in schizophrenic patients. Initial findings in 11 schizophrenic patients and nine normal controls show significant differences between the groups in levels of all three enzymes. Mean SOD levels (Standard SOD Units) were significantly higher in schizophrenic patients (2449.6 + 744.5) than in normals (1025.2 ? 14) (p < .OOl), GSHPOD levels (umoYminute) were also significantly higher in patients (58.4 + 20.7) than in normals (31.2 + 3.7) (p = .OOl), while CAT levels (mmoVminute) were significantly lower in patients (7 1.8 ? 28.6) than in normals (137.9 5 30). All figures represent values per gm of Hb. There was no relation between any of the enzyme levels and either presence of TD or severity of negative symptoms. Data will be presented on a larger series of patients. The findings will be discussed with emphasis on possible clinical significance and consideration of whether the abnormal enzyme levels reflect increased free radical production, or a primary pathology of the enzyme systems independent of rate of free radical production.
344 FAILURE OF HALOPERIDOL TO BLOCK THE DISRUPTION OF SENSORY GATING INDUCED BY PHENCYCLIDINE AND MK801 Mark A. Geyer, David L. Braff, Robert S. Mansbach La Jolla, CA Prepulse inhibition (PPI) of acoustic startle, a form of sensory gating, occurs when a weak pre-stimulus precedes a startling stimulus and inhibits startle. Schizophrenics exhibit less PPI than controls. In rats, PPI is blocked by dopamine agonists such as apomorphine, effects which are antagonized by haloperidol. Here, PPI of acoustic startle was measured in male rats after ip injections of 0.1-10.0 mg/kg phencyclidine (PCP) or 0.01-1.0 mg/kg MK801. PCP has been suggested as a model psychotogen and MK801 is an anticonvulsant that, like PCP, is an NMDA antagonist. Startle was elicited by noise bursts at 108 or 120 dB or by air-puffs and was inhibited by 80 dB
170A
BIOL PSYCHIATRY 1989;25:169A-184A
Neurobiology of Schizophrenia II
prepulses presented 100 milliseconds before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals. PCP and MK801 dose-dependently reduced the amount of PPI independently of the level of startle elicited by the various stimuli. Haloperidol (0.1 mg/kg), which blocks the disruption of PPI induced by apomorphine, did not block that induced by either 5 mg/kg PCP or 0.5 mg/kg MK801. These results demonstrate that putative NMDA antagonists inhibit sensory gating in rats by a mechanism that is insensitive to the effects of haloperidol and different from that of dopamine agonists.
345 QUANTITATIVE AUTORADIOGRAPHIC D1, DZ, AND S2 DIFFERENCES WITH CLOZAPINE AND HALOPERIDOL G. LaHoste, C. Widmark, S. O’Dell, R. Shapiro, J.F. Marshall, S.G. Potkin Irvine, CA and Orange, CA
The atypical antipsychotic clozapine (CLZ) is effective in ameliorating psychosis in treatment-resistant schizophrenics and is relatively free of extrapyramidal side effects. In order to elucidate the neural mechanism by which CLZ can attenuate psychosis without inducing extrapyramidal side effects, we used receptor autoradiography to image and quantify changes in dopamine and serotonin receptors following chronic treatment with CLZ or the typical neuroleptic haloperidol (HAL). Adult male rats were injected daily with CLZ (30 mg/kg ip), HAL (1 .Omg/kg ip), or vehicle (VEH) for 28 days. Doses were chosen to mimic the relative clinical potency of CLZ and HAL. Seventy-two hours after the last drug injection, the rats were sacrificed by decapitation, their brains removed and prepared for receptor autoradiography. Di receptors were labeled with (3H)SCH 23390, D2 receptors with (3H)spiroperidol, and 5-HTz receptors with (3H)ketanserin. Concentrations of receptor binding were determined from autoradiographs that included frontal cortex, caudate-putamen, nucleus accumbens, and substantia nigra. Rats that received CLZ chronically showed CNS receptor changes markedly different from chronic HAL-treated animals. Animals treated chronically with HAL showed enhanced D2 binding (an apparent up-regulation), while those treated with CLZ did not. In contrast, CLZ induced an enhanced D2 receptor binding whereas these sites were unchanged in chronic HAL-treated rats. Finally, CLZ treatment decreased binding of (3H)ketanserin to 5-HTz sites. The opposite effects of CLZ and HAL on D, and D2 receptors may be relevant to their propensity to induce extrapyramidal side effects.
346 EFFECTS OF D, AGONIST IN SCHIZOPHRENIA Philip D. Harvey, Stacey Jaff, Michael Davidson, Kenneth L. Davis New York, NY
Recent studies have suggested a reduced level of activation of the prefrontal cortical regions in chronic schizophrenia. This lack of activation has been measured directly by examination of cortical blood flow while performing tasks that make demands on those regions (i.e., The Wisconsin Card Sort: WCST). Qther recent data have suggested that certain types of dopamine receptors are differentially distributed throughout the brain, with D, receptors being largely cortical and D2 receptors subcortical. In this study we administered a highly selective partial D, agonist, SKF 38393, in order to