The Experts below are selected from a list of 336 Experts worldwide ranked by ideXlab platform
Robert P. Yezierski - One of the best experts on this subject based on the ideXlab platform.
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effects of agmatine interleukin 10 and cyclosporin on spontaneous pain behavior after excitotoxic spinal cord injury in rats
The Journal of Pain, 2003Co-Authors: Carolyn A Fairbanks, George L Wilcox, Robert P. YezierskiAbstract:Abstract Intraspinal injection of the AMPA/Metabotropic Receptor Agonist quisqualic acid (QUIS) results in a pathophysiology that leads to excessive grooming behavior, which has been proposed as a model of spontaneous at-level pain after spinal cord injury (SCI). To further characterize the onset and progression of this behavior we evaluated the effects of 3 drugs, agmatine (Agm), interleukin-10 (IL-10), and cyclosporin A (CsA), on different characteristics of this behavior. In these experiments rats were given saline, Agm, CsA10, or CsA20 once daily for 14 days (or a single injection of IL-10) starting either 30 minutes post-QUIS (group 1) or 10 to 18 days post-QUIS when excessive grooming behavior had been established (group 2). In the first group of animals agmatine, IL-10, CsA10, or CsA20 reduced the longitudinal extent of neuronal loss in the spinal cord compared to QUIS-injected animals treated with saline. The behavioral consequences of this effect included the delayed onset of excessive grooming behavior, reduction in the area of skin targeted for excessive grooming, and reduced grooming severity. Animals treated at the time of excessive grooming onset showed significantly reduced grooming area, grooming severity, and neuronal loss in the spinal cord compared to QUIS animals treated with saline. In conclusion, systemic administration of Agm, IL-10, or CsA significantly delayed the onset and reduced the severity of a spontaneous pain-like behavior. These effects are believed to be due, in part, to the neuroprotective properties of these drugs against QUIS-induced excitotoxicity. The effective treatment of excessive grooming behavior suggests that Agm, IL-10, and CsA modulate ongoing cellular events responsible for the progression of this behavior. [copy ] 2003 by the American Pain Society
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Chronic, selective forebrain responses to excitotoxic dorsal horn injury
Experimental neurology, 2000Co-Authors: Thomas J. Morrow, Robert P. Yezierski, Pamela E. Paulson, Kori L. Brewer, Kenneth L. CaseyAbstract:Abstract Intraspinal injection of the AMPA/Metabotropic Receptor Agonist quisqualic acid (QUIS) results in excitotoxic injury which develops pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI) (R. P. Yezierski et al., 1998, Pain 75: 141–155; R. P. Yezierski et al., 1993, J. Neurotrauma 10: 445–456). Since spinal injury can lead to partial or complete deafferentation of ascending supraspinal structures, it is likely that secondary to the disruption of spinal pathways these regions could undergo significant reorganization. Recently, T. J. Morrow et al. ( Pain 75: 355–365) showed that autoradiographic estimates of regional cerebral blood flow (rCBF) can be used to simultaneously identify alterations in the activation of multiple forebrain structures responsive to noxious formalin stimulation. Accordingly, we examined whether excitotoxic SCI produced alterations in the activation of supraspinal structures using rCBF as a marker of neuronal activity. Twenty-four to 41 days after unilateral injection of QUIS into the T12 to L3 spinal segments, we found significant increases in the activation of 7 of 22 supraspinal structures examined. As compared to controls, unstimulated SCI rats exhibited a significant bilateral increase in rCBF within the arcuate nucleus (ARC), the hindlimb region of S1 cortex (HL), parietal cortex (PAR), and the thalamic posterior (PO), ventral lateral (VL), ventral posterior lateral (VPL), and ventral posterior medial (VPM) nuclei. All structures showing significantly altered rCBF are associated with the processing of somatosensory information. These changes constitute remote responses to injury and suggest that widespread functional changes occur within cortical and subcortical regions following injury to the spinal cord.
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Diffusion-weighted MR imaging in a rat model of syringomyelia after excitotoxic spinal cord injury.
AJNR. American journal of neuroradiology, 1999Co-Authors: Eric D. Schwartz, Robert P. Yezierski, Pradip M. Pattany, Robert M. Quencer, Raymond G. WeaverAbstract:BACKGROUND AND PURPOSE: Recent experimental data have shown that an increase of excitatory amino acids and the initiation of inflammatory responses within the injured spinal cord may play a role in post-traumatic syringomyelia. The purpose of this study was to determine whether diffusion-weighted MR imaging with apparent diffusion coefficient (ADC) maps could provide earlier evidence of spinal cord cavitation in a rat model of syringomyelia than available with conventional MR imaging. METHODS: The spinal cord gray matter of four rats was injected with the α-amino-3 hydroxy-5 methyl-4 isoxazole propionic acid/Metabotropic Receptor Agonist quisqualic acid. Animals were sacrificed at 1, 4, or 8 weeks after injection, and the spinal cords were fixed in formalin for 1 week and imaged with T1-, T2-, and diffusion-weighted sequences. One control specimen was also imaged. ADC maps were constructed from the diffusion-weighted data. Histopathologic analyses of sections stained with cresyl violet were compared with the MR images. RESULTS: By 1 week after injection, ADC maps at the level of injection showed areas within the gray matter of increased intensity and increased ADC values as compared with the control specimen. These bright areas corresponded to cysts or cavities within the cord parenchyma on the histopathologic sections. The ADC values within affected gray matter areas progressively increased at 4 and 8 weeks, also corresponding to cyst formation. Conventional T1- and T2-weighted images showed corresponding lesions with cystic characteristics at 4 and 8 weeks, but not at 1 week. CONCLUSION: In an animal model of syringomyelia, diffusion-weighted imaging with ADC maps detected cystic lesions within spinal cord gray matter before they were seen on conventional T1- and T2-weighted images.
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Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model
Pain, 1998Co-Authors: Robert P. Yezierski, Shanliang Liu, G.l Ruenes, K.j Kajander, K.l BrewerAbstract:Intraspinal injections of the AMPA-Metabotropic Receptor Agonist quisqualic acid (QUIS) were made in an effort to simulate injury induced elevations of excitatory amino acids (EAAs), a well documented neurochemical change following spinal cord injury (SCI). The progressive pathological sequela associated with QUIS injections closely resembles the cascade of events described following ischemic and traumatic SCI and the pathogenesis of cavities in the clinical condition of post-traumatic syringomyelia. Using different injection parameters, i.e. depth and volume, to deliver QUIS into the cord the results have shown that the technique of intraspinal injection can be used to produce graded patterns of neuronal loss in specific regions of the spinal gray matter. Furthermore, neuronal loss in the dorsal horn, sparing the superficial laminae, results in the onset of spontaneous (excessive grooming behavior) and evoked (mechanical allodynia and thermal hyperalgesia) behaviors commonly associated with experimental models of chronic neuropathic pain. Thus, the present results provide a morphological correlate of spontaneous and evoked pain related behaviors following excitotoxic SCI. The behavioral characteristics combined with the similarities between QUIS induced injury and the clinical pathology of SCI support the use of the excitotoxic model in studies related to the central mechanism(s) of altered sensation, including pain, following spinal injury.
Richard S. Jope - One of the best experts on this subject based on the ideXlab platform.
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Agonist‐Induced, GTP‐Dependent Phosphoinositide Hydrolysis in Postmortem Human Brain Membranes
Journal of neurochemistry, 2008Co-Authors: Richard S. Jope, Ling Song, Richard E. PowersAbstract:Membranes prepared from postmortem human brain were used to measure the activities of three components of the phosphoinositide second messenger system. [3H]Phosphatidylinositol ([3H]PI) hydrolysis was stimulated by directly activating phospholipase C with calcium, by activating guanine nucleotide-binding proteins (G proteins) with guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S) or with AIF4, and by Receptors activated with several Agonists (in the presence of GTP gamma S), including (in order of increasing magnitudes of responses) carbachol, pilocarpine, histamine, trans-1-aminocyclopentyl-1,3-dicarboxylic acid (a selective excitatory amino acid Metabotropic Receptor Agonist), serotonin, and ATP. Gq/11 was identified as the G protein most likely to mediate [3H]PI hydrolysis in human brain membranes based on the findings that this process was not impaired by pretreatment with pertussis toxin and it was inhibited by antibodies specific for the alpha-subunit of Gq/11 but not by antibodies for G0 or Gi1. The effects of postmortem delay on [3H]PI hydrolysis were examined by studying tissues obtained 6-21 h postmortem. A slight increase in basal [3H]PI hydrolysis was associated with increased postmortem time, suggesting a slow loss of the normal inhibitory control of phospholipase C. GTP gamma S-stimulated [3H]PI hydrolysis was unaffected by postmortem times within this range, but carbachol-induced [3H]PI hydrolysis tended to decrease with increasing postmortem times. These results demonstrate that the entire phosphoinositide complex remains functional and experimentally detectable in postmortem human brain membranes. This method provides a means to study the function, regulation, effects of diseases, and responses to drugs of the phosphoinositide system in human brain.
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Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain.
Brain Research, 1996Co-Authors: Mary A. Pacheco, Craig A. Stockmeier, Herbert Y. Meltzer, James C. Overholser, Ginny E. Dilley, Richard S. JopeAbstract:Abstract The function of the phosphoinositide signal transduction system and the levels of heterotrimeric G-protein α-subunits were examined in postmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without psychiatric illness. The hydrolysis of [3H]phosphatidylinositol (PI) stimulated by phospholipase C, GTP-γ-S, NaF, and neurotransmitter Receptor Agonists was measured in membrane preparations from both groups. Phospholipase C-β activity was similar in depressed suicide and control subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-γ-S concentration-dependent stimulation of [3H]PI hydrolysis was significantly lower (30%) in the depressed suicide group compared to the control group. Receptor-coupled, G-protein-mediated [3H]PI hydrolysis induced with carbachol, histamine, trans- 1-aminocyclopentyl-1,3-dicarboxylic acid (ACPD, a glutamatergic Metabotropic Receptor Agonist), serotonin, or 2-methylthio-adenosine triphosphate (2mATP, a purinergic Receptor Agonist) in the presence of GTP-γ-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of Gαs and in prefrontal cortex (8/9) there was a significant decrease (21%) in the level of Gαi2 in the depressed suicide group compared to the control group. Levels of other heterotrimeric G-protein α-subunits (Gαq/11, Gαil, and Gαo) were not different in depressed suicide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-β or protein kinase C-α in the two groups of subjects in either brain region examined. These results demonstrate that in the prefrontal cortex of suicide victims with major depression compared to normal control subjects there is a region-specific alteration of G-protein-induced activation of the phosphoinositide signal transduction system and in the levels of G-protein α-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signal transduction systems are altered in suicide subjects with major depression.
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[3H]PtdIns hydrolysis in postmortem human brain membranes is mediated by the G-proteins Gq/11 and phospholipase C-beta.
Biochemical Journal, 1994Co-Authors: Richard S. Jope, Ling Song, R PowersAbstract:Abstract A method utilizing exogenously added [3H]PtdIns incubated with membranes prepared from postmoretem human brain has been shown to provide a means of measuring Agonist-induced, guanosine 5'-O-(thiotriphosphate) (GTP[S])-dependent hydrolysis of [3H]PtdIns, thus allowing investigations of the activity of the phosphoinositide second-messenger system in accessible human brain tissue. Agonists inducing [3H]PtdIns hydrolysis include carbachol, trans-1-aminocyclopentyl-1,3-dicarboxylate (ACPD; a glutamatergic Metabotropic Receptor Agonist), serotonin and ATP, with the latter two Agonists producing the largest responses. In addition to ATP, [3H]PtdIns hydrolysis was induced by ADP and by 2-methylthio-ATP, indicating that P2-purinergic Receptors mediate this process. Subtype-selective antibodies we used to identify Gq/11 and phospholipase C-beta as the G-protein and phospholipase C subtypes that mediated GTP[S]-induced and Agonist-induced [3H]PtdIns hydrolysis. These results demonstrate that this method reveals that Agonist-induced, GTP[S]-dependent [3H]PtdIns hydrolysis is retained in postmortem human brain membranes with properties similar to rat brain. This method should allow studies of the modulation of phosphoinositide hydrolysis in human brain and investigations of potential alterations in postmortem brain from subjects with neurological and psychiatric diseases.
Mary A. Pacheco - One of the best experts on this subject based on the ideXlab platform.
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Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain.
Brain Research, 1996Co-Authors: Mary A. Pacheco, Craig A. Stockmeier, Herbert Y. Meltzer, James C. Overholser, Ginny E. Dilley, Richard S. JopeAbstract:Abstract The function of the phosphoinositide signal transduction system and the levels of heterotrimeric G-protein α-subunits were examined in postmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without psychiatric illness. The hydrolysis of [3H]phosphatidylinositol (PI) stimulated by phospholipase C, GTP-γ-S, NaF, and neurotransmitter Receptor Agonists was measured in membrane preparations from both groups. Phospholipase C-β activity was similar in depressed suicide and control subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-γ-S concentration-dependent stimulation of [3H]PI hydrolysis was significantly lower (30%) in the depressed suicide group compared to the control group. Receptor-coupled, G-protein-mediated [3H]PI hydrolysis induced with carbachol, histamine, trans- 1-aminocyclopentyl-1,3-dicarboxylic acid (ACPD, a glutamatergic Metabotropic Receptor Agonist), serotonin, or 2-methylthio-adenosine triphosphate (2mATP, a purinergic Receptor Agonist) in the presence of GTP-γ-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of Gαs and in prefrontal cortex (8/9) there was a significant decrease (21%) in the level of Gαi2 in the depressed suicide group compared to the control group. Levels of other heterotrimeric G-protein α-subunits (Gαq/11, Gαil, and Gαo) were not different in depressed suicide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-β or protein kinase C-α in the two groups of subjects in either brain region examined. These results demonstrate that in the prefrontal cortex of suicide victims with major depression compared to normal control subjects there is a region-specific alteration of G-protein-induced activation of the phosphoinositide signal transduction system and in the levels of G-protein α-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signal transduction systems are altered in suicide subjects with major depression.
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Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain.
Brain research, 1996Co-Authors: Mary A. Pacheco, Craig A. Stockmeier, Herbert Y. Meltzer, James C. Overholser, Ginny E. Dilley, R S JopeAbstract:The function of the phosphoinositide signal transduction system and the levels of heterotrimeric G-protein alpha-subunits were examined in postmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without psychiatric illness. The hydrolysis of [3H]phosphatidylinositol (PI) stimulated by phospholipase C, GTP-gamma-S, NaF, and neurotransmitter Receptor Agonists was measured in membrane preparations from both groups. Phospholipase C-beta activity was similar in depressed suicide and control subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-gamma-S concentration-dependent stimulation of [3H]PI hydrolysis was significantly lower (30%) in the depressed suicide group compared to the control group. Receptor-coupled, G-protein-mediated [3H]PI hydrolysis induced with carbachol, histamine, trans-1-aminocyclopentyl-1, 3-dicarboxylic acid (ACPD, a glutamatergic Metabotropic Receptor Agonist), serotonin, or 2-methylthio-adenosine triphosphate (2mATP, a purinergic Receptor Agonist) in the presence of GTP-gamma-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of G alpha s and in prefrontal cortex (8/9) there was a significant decrease (21%) in the level of G alpha i2 in the depressed suicide group compared to the control group. Levels of other heterotrimeric G-protein alpha-subunits (G alpha q/11, G alpha i1, and G alpha o) were not different in depressed suicide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-beta or protein kinase C-alpha in the two groups of subjects in either brain region examined. These results demonstrate that in the prefrontal cortex of suicide victims with major depression compared to normal control subjects there is a region-specific alteration of G-protein-induced activation of the phosphoinositide signal transduction system and in the levels of G-protein alpha-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signal transduction systems are altered in suicide subjects with major depression.
R S Jope - One of the best experts on this subject based on the ideXlab platform.
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Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain.
Brain research, 1996Co-Authors: Mary A. Pacheco, Craig A. Stockmeier, Herbert Y. Meltzer, James C. Overholser, Ginny E. Dilley, R S JopeAbstract:The function of the phosphoinositide signal transduction system and the levels of heterotrimeric G-protein alpha-subunits were examined in postmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without psychiatric illness. The hydrolysis of [3H]phosphatidylinositol (PI) stimulated by phospholipase C, GTP-gamma-S, NaF, and neurotransmitter Receptor Agonists was measured in membrane preparations from both groups. Phospholipase C-beta activity was similar in depressed suicide and control subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-gamma-S concentration-dependent stimulation of [3H]PI hydrolysis was significantly lower (30%) in the depressed suicide group compared to the control group. Receptor-coupled, G-protein-mediated [3H]PI hydrolysis induced with carbachol, histamine, trans-1-aminocyclopentyl-1, 3-dicarboxylic acid (ACPD, a glutamatergic Metabotropic Receptor Agonist), serotonin, or 2-methylthio-adenosine triphosphate (2mATP, a purinergic Receptor Agonist) in the presence of GTP-gamma-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of G alpha s and in prefrontal cortex (8/9) there was a significant decrease (21%) in the level of G alpha i2 in the depressed suicide group compared to the control group. Levels of other heterotrimeric G-protein alpha-subunits (G alpha q/11, G alpha i1, and G alpha o) were not different in depressed suicide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-beta or protein kinase C-alpha in the two groups of subjects in either brain region examined. These results demonstrate that in the prefrontal cortex of suicide victims with major depression compared to normal control subjects there is a region-specific alteration of G-protein-induced activation of the phosphoinositide signal transduction system and in the levels of G-protein alpha-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signal transduction systems are altered in suicide subjects with major depression.
T N Chase - One of the best experts on this subject based on the ideXlab platform.
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Glutamate Metabotropic Receptor Agonist 1S,3R-ACPD induces internucleosomal DNA fragmentation and cell death in rat striatum.
Brain research, 1997Co-Authors: Y Wang, Z H Qin, M Nakai, T N ChaseAbstract:Glutamate Metabotropic Receptor mediated mechanisms have been implicated in both neuroprotection and neurotoxicity. To characterize these mechanisms further in vivo, the effects of an intrastriatally injected Metabotropic Receptor Agonist, trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD), were studied alone and together with N-methyl-D-aspartate (NMDA) or kainic acid (KA) Receptor Agonists on DNA fragmentation and nerve cell death. 1S,3R-ACPD induced internucleosomal DNA fragmentation of striatal cells in a dose-dependent manner. TUNEL and propidium iodide staining showed DNA fragmentation and profound nuclear condensation around the injection site. Fragmented nuclei were occasionally seen under light microscopy. Internucleosomal DNA fragmentation induced by 1S,3R-ACPD was attenuated by the protein synthesis inhibitor cycloheximide as well as by the non-selective and selective Metabotropic Receptor antAgonists L-(+)-2-amino-3-phosphonopionic acid (L-AP3), (RS)-aminoindan-1,5-dicarboxylic acid and (RS)-alpha-methylserine-o-phosphate monophenyl ester, respectively. The 1S,3R-ACPD (100-900 nmol) induced death of striatal neurons was suggested by the reduction in NMDA and D1 dopamine Receptors by up to 13% (P < 0.05) and 20% (P < 0.05) as well as by the decline in GAD67 mRNA (25%, P < 0.01) and proenkephalin mRNA levels (35%, P < 0.01). Interestingly, 1S,3R-ACPD attenuated internucleosomal DNA fragmentation induced by NMDA, but potentiated that induced by KA. These results suggest that Metabotropic Receptor stimulation leads to the death of striatal neurons by a mechanism having the biochemical stigmata of apoptosis. Moreover, Metabotropic Receptor stimulation evidently exerts opposite effects on pre- or postsynaptic mechanisms contributing to the NMDA and KA-induced apoptotic-like death of these neurons.
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Glutamate Metabotropic Receptor Agonist 1S,3R-ACPD induces internucleosomal DNA fragmentation and cell death in rat striatum.
Brain Research, 1997Co-Authors: Y Wang, Z H Qin, M Nakai, T N ChaseAbstract:Abstract Glutamate Metabotropic Receptor mediated mechanisms have been implicated in both neuroprotection and neurotoxicity. To characterize these mechanisms further in vivo, the effects of an intrastriatally injected Metabotropic Receptor Agonist, trans -(1 S ,3 R )-1-amino-1,3-cyclopentanedicarboxylic acid (1 S ,3 R -ACPD), were studied alone and together with N -methyl- d -aspartate (NMDA) or kainic acid (KA) Receptor Agonists on DNA fragmentation and nerve cell death. 1 S ,3 R -ACPD induced internucleosomal DNA fragmentation of striatal cells in a dose-dependent manner. TUNEL and propidium iodide staining showed DNA fragmentation and profound nuclear condensation around the injection site. Fragmented nuclei were occasionally seen under light microscopy. Internucleosomal DNA fragmentation induced by 1 S ,3 R -ACPD was attenuated by the protein synthesis inhibitor cycloheximide as well as by the non-selective and selective Metabotropic Receptor antAgonists l -(+)-2-amino-3-phosphonopionic acid ( l -AP3), ( R S )-aminoindan-1,5-dicarboxylic acid and ( R S )-α-methylserine- o -phosphate monophenyl ester, respectively. The 1 S ,3 R -ACPD (100–900 nmol) induced death of striatal neurons was suggested by the reduction in NMDA and D 1 dopamine Receptors by up to 13% ( P P 67 mRNA (25%, P P S ,3 R -ACPD attenuated internucleosomal DNA fragmentation induced by NMDA, but potentiated that induced by KA. These results suggest that Metabotropic Receptor stimulation leads to the death of striatal neurons by a mechanism having the biochemical stigmata of apoptosis. Moreover, Metabotropic Receptor stimulation evidently exerts opposite effects on pre- or postsynaptic mechanisms contributing to the NMDA and KA-induced apoptotic-like death of these neurons.