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D J Healy

Publications and source records attributed to D J Healy.

17 recordsLinked to original sources
PubMed2000

Ionotropic glutamate receptor modulation preferentially affects NMDA receptor expression in rat hippocampus.

Electrophysiological data suggest that alterations in the function of one glutamate receptor subtype may affect the function of other subtypes. Further, previous studies have demonstrated that NMDA receptor antagonists affect NMDA and kainate receptor expression in rat hippocampus. In order to address the mutual regulation of NMDA, AMPA, and kainate receptor expression in rat hippocampus, we conducted two experiments examining the effects of NMDA and non-NMDA glutamate receptor modulators on NMDA, AMPA, and kainate receptor expression using in situ hybridization and receptor autoradiography. NMDA receptor expression was preferentially affected by systemic treatments, as all drugs significantly altered [(3)H]MK-801 binding, and several drugs increased [(3)H]ifenprodil binding. GYKI52466 and aniracetam treatments resulted in changes in both [(3)H]ifenprodil binding and NR2B mRNA levels, consistent with the association of this subunit and binding site in vitro. There were more modest effects on AMPA and kainate receptor expression, even by direct antagonists. Together, these data suggest that ionotropic glutamate receptors interact at the level of expression. These data also suggest that drug regimens targeting one ionotropic glutamate receptor subtype may indirectly affect other subtypes, potentially producing unwanted side effects.

Animals↗
PubMed2000

Nucleus-specific expression of ionotropic glutamate receptor subunit mRNAs and binding sites in primate thalamus.

Thalamic afferents and efferents utilize glutamate as their primary neurotransmitter. There are four families of glutamate receptors that can transduce this activity, as well as regulate glutamate release from thalamic relay neurons. The three ionotropic subtypes are of particular importance, because subunit composition confers variability in functional properties of each subtype. We have quantified the expression of NMDA, AMPA and kainate receptors in the thalamus of the macaque using receptor autoradiography and in situ hybridization. NMDA receptors are multimeric associations of NR1 and NR2A-NR2D subunits that form ligand-gated ion channels. Particular subunits are associated with modulatory binding sites that affect receptor activity. NR1 was the most abundant subunit mRNA; NR2A, NR2B, and NR2D subunit mRNAs were also present, but were expressed in nucleus-specific patterns. Very high levels of [3H]ifenprodil binding to the polyamine site of the NMDA complex were detected in a fairly homogeneous distribution. Binding of the ion channel ligand [3H]MK-801 was also abundant, and limbic nuclei expressed higher levels than motor nuclei or the reticular nucleus. [3H]CGP39653 binding to the glutamate site of the NMDA receptor was the least abundant of the NMDA receptor binding sites. There was variability in the stoichiometric relationships of binding sites across nuclei, suggesting that there is heterogeneity in the pharmacological properties of NMDA receptors expressed in the thalamus. AMPA and kainate are also multimeric associations of specific subunits that form ligand-gated ion channels. These subunits are encoded by specific genes: gluR1-gluR4 for AMPA receptors, and gluR5-gluR7 and KA1-KA2 for kainate receptors. GluR4 and gluR6 mRNAs were, respectively the most abundant of the AMPA and kainate receptor subunit transcripts. Both AMPA and kainate receptor subunit transcripts were expressed in a nucleus-specific pattern. The binding of [3H]kainate was higher than that of [3H]AMPA throughout the thalamus, but AMPA subunit mRNA levels were three to five orders of magnitude higher than those encoding the kainate receptor subunits. The mismatch between the levels of expression of kainate receptor subunit transcripts and binding sites is suggestive of a presynaptic localization of kainate receptors on thalamic afferents. These results suggest that ionotropic glutamate receptors are heterogeneously expressed in the thalamus of the primate, and that their differential expression is both subunit- and nucleus-specific.

2-Amino-5-phosphonovalerate↗
PubMed2000

Glutamate receptor expression in schizophrenic brain.

Glutamatergic dysfunction has been suggested as a possible substrate of the pathophysiology of schizophrenia. Of the multiple glutamate receptors, those most commonly implicated in schizophrenia are the ionotropic subtypes, the NMDA, AMPA, and kainate receptors. The expression of the glutamate receptors has been determined at multiple levels of gene expression in postmortem brain samples from schizophrenics and controls; while results have not been entirely consistent from study to study, several generalizations have emerged from this literature: (1) The AMPA receptor is abnormally decreased in expression in the schizophrenic hippocampus, involving decreased levels of subunit transcripts and protein levels, as well as binding sites, (2) similar changes are seen for kainate receptor expression in the hippocampus, and (3) the obligate NMDA receptor subunit, NMDAR1, may be abnormally expressed in some cortical regions in schizophrenia. These data support the hypothesis of abnormal glutamatergic neurotransmission involving the ionotropic glutamate receptors in schizophrenia.

Animals↗
PubMed2000

Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia.

OBJECTIVE: Both thalamic and glutamatergic dysfunction have been implicated in the pathophysiology of schizophrenia. The authors examined ionotropic glutamate receptor expression in postmortem samples from patients with schizophrenia and comparison subjects, using the hypothesis that glutamate receptor expression differs in limbic nuclei of the thalamus in schizophrenia. METHOD: N-Methyl-D-aspartate (NMDA), AMPA, and kainate receptor expression was determined in six thalamic nuclei from 12 subjects with DSM-III-R diagnoses of schizophrenia and eight psychiatrically normal individuals. The authors used in situ hybridization to determine NMDAR1, NMDAR2A-NMDAR2D, gluR1-gluR7, KA1, and KA2 subunit mRNA levels and receptor autoradiography to determine binding to glutamate binding sites of the three receptor subtypes and to the glycine, polyamine, and ion channel binding sites of the NMDA receptor. RESULTS: Glutamate receptor expression was lower at both transcriptional (NMDAR1, NMDAR2B, NMDAR2C, gluR1, gluR3, and KA2 subunit mRNAs) and posttranscriptional ([(3)H]ifenprodil and [(3)H]MDL105,519 binding to polyamine and glycine sites of the NMDA receptor) levels in the thalamus in patients with schizophrenia than in comparison subjects, but differences were most prominent in nuclei with reciprocal projections to limbic regions. CONCLUSIONS: Abnormalities in NMDA, AMPA, and kainate receptor expression in limbic thalamus are suggestive of the NMDA receptor hypoactivity hypothesis of schizophrenia and are consistent with diminished glutamatergic activity in the thalamus in schizophrenia. Alternatively, these results could suggest abnormal glutamatergic innervation in afferent and/or efferent regions, which are limbic structures that have been implicated in this illness. These results may provide a neurochemical anatomical substrate for antipsychotic therapies targeting ionotropic glutamate receptors.

Aged↗
PubMed1999

Ionotropic glutamate receptor modulation of 5-HT6 and 5-HT7 mRNA expression in rat brain.

The novel serotonin receptor subtypes, 5-HT6 and 5-HT7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics. These factors have led some to speculate about the involvement of 5-HT6 and 5-HT7 receptors in schizophrenia. However, relatively little is known about these receptor subtypes, including the regulation of their expression in limbic regions. In particular, the regulation of extracellular serotonin levels in the striatum and hippocampal formation by glutamate receptors led us to examine the effects of systemic ionotropic glutamate receptor modulator treatment on 5-HT6 and 5-HT7 receptor expression in these regions. MK-801 treatment induced a dose-dependent decrease in striatal 5-HT6 receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT6 receptor mRNA levels. Hippocampal 5-HT6 and 5-HT7 receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT6 receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and glutamatergic systems. Furthermore, although these two neurotransmitter systems are separately implicated in schizophrenia, the glutamatergic regulation of the expression of a receptor subtype associated with schizophrenia suggests that alterations in serotonin receptor expression in schizophrenia may result, in part, from altered glutamatergic activity.

Animals↗
PubMed1998

AMPA receptor binding and subunit mRNA expression in prefrontal cortex and striatum of elderly schizophrenics.

The dopamine hypothesis of schizophrenia has recently evolved into a model of dysfunctional integration between cortical and subcortical dopaminergic activity. Anatomical data suggest that regional alterations in dopaminergic activity may be linked by means of the rich glutamatergic innervation of the striatum by corticostriatal projections, suggesting a potential role for glutamatergic dysfunction in schizophrenia. Although pharmacological data have implicated the NMDA subtype of glutamate receptor in this illness, disturbance in AMPA receptor expression could potentially lead to the NMDA receptor hypoactivity hypothesized in schizophrenia. To address this possibility, we examined AMPA receptor binding and subunit mRNA levels in prefrontal cortex and striatum of schizophrenics and matched controls. There were no significant differences in AMPA receptor binding or subunit mRNA levels in either prefrontal cortical or striatal regions of schizophrenics. Furthermore, AMPA receptor expression did not seem to be regulated by chronic antipsychotic drug exposure, when neuroleptic treated and drug-free schizophrenics were analyzed separately. These data do not support a role for altered AMPA receptor expression in cortex and striatum in schizophrenia.

Aged↗
PubMed1998

Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings.

OBJECTIVE: The goal of this report is to examine the potential implications of the high prevalence of smoking in schizophrenia for our understanding of this illness. METHOD: A selective review of the relevant clinical and preclinical literature was conducted. The authors present a review of the clinical observations about smoking in schizophrenia, summarize the preclinical data about the complexity of the CNS nicotinic receptor family, and examine the modulatory effects of nicotine on neurotransmitter systems implicated in schizophrenia. RESULTS: Clinical data suggest that smoking in schizophrenia may represent an attempt to self-medicate symptoms of the illness. Preclinical findings support a potential role of nicotine in medicating negative symptoms in particular. Recent preclinical and clinical data suggest that schizophrenic patients have a primary defect in the CNS nicotinergic system that leads to abnormal sensory gating. The complexity of the neuromodulatory effects of CNS nicotinic systems on other neurotransmitter systems underscores both the scope and potential importance of continued advancement of research in this area. CONCLUSIONS: Despite increasing clinical research focused on the extremely high prevalence of smoking in schizophrenia, linkages to the prodigious preclinical data about nicotine and nicotinic receptors are largely unexplored. These linkages are likely to be very important. Integrating nicotine use into our clinical and basic models of schizophrenia leads to a more complex but more realistic representation of brain dysfunction in this illness. Understanding how and why schizophrenic individuals use nicotine may lead to the development of new treatments for both schizophrenia and nicotine dependence.

Adult↗
PubMed1997

Clozapine and haloperidol differentially affect AMPA and kainate receptor subunit mRNA levels in rat cortex and striatum.

Dopamine is the neurotransmitter most often implicated in the pathogenesis of schizophrenia. However, glutamatergic antagonists can cause psychotic symptoms in otherwise normal humans, and exacerbate these symptoms in schizophrenics. These findings have led to a model of dopamine-glutamate interactions in limbic cortex and striatum as a potential substrate for symptom production in schizophrenia. From this model, we might expect that cortical and striatal expression of non-NMDA ionotropic glutamate receptors would be differentially regulated by antipsychotic treatment. To begin to address this question, we examined the regulation of mRNA levels of the AMPA (gluR1-gluR4), low affinity kainate (gluR5-gluR7), and high affinity kainate (KA1-KA2) receptor subunits by clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) treatment for 2 weeks. Both clozapine and haloperidol caused region-specific alterations in the mRNA levels of these subunits, but there was no differential regulation in the cortex vs. the striatum. Haloperidol caused a decrease in gluR2 and gluR4 mRNA levels in both cortex and striatum and an increase in KA2 mRNA levels in the striatum only. However, clozapine treatment caused an increase in gluR7 mRNA expression, and a decrease in gluR3 mRNA expression, in both cortex and striatum while causing an increase in KA2 mRNA levels, and a decrease in gluR4 mRNA levels, in the striatum only. These dissimilarities may represent an interesting mechanism for some of the differential therapeutic or toxic effects of clozapine and haloperidol, and also may be relevant to our understanding of dopamine-glutamate interactions in schizophrenia.

Animals↗
PubMed1996

Dopamine receptor gene expression in hippocampus is differentially regulated by the NMDA receptor antagonist MK-801.

Glutamate agonists have been shown to stimulate the release of dopamine in the striatum, while the NMDA receptor antagonist MK-801 has been shown to cause an increase in extracellular dopamine in the hippocampus. The effects of MK-801 treatment on dopamine receptor gene expression in the hippocampus are largely unknown. To begin to address this question, we treated rats with 0.3, 1.0, and 3.0 mg/kg of MK-801 daily for 1 week, and measured the mRNAs encoding all five of the dopamine receptors in the hippocampus. MK-801 caused changes in dopamine D1, D2, D3, and D4 receptor gene expression in a complex manner that suggests that dopamine receptor gene expression in the hippocampus may be differentially regulated by glutamate, via the NMDA receptor. These findings may have implications both for understanding the pathophysiology and modifying treatment of schizophrenia.

Animals↗
PubMed1996

Differential regulation, by MK-801, of dopamine receptor gene expression in rat nigrostriatal and mesocorticolimbic systems.

Glutamate agonists have been shown to stimulate striatal dopamine release, but less is known about dopamine-glutamate interactions at the receptor level. We treated rats with 0.3, 1.0, or 3.0 mg/kg of MK-801, an NMDA antagonist, daily for 1 week and, using in situ hybridization, measured dopamine receptor mRNA levels in cortical and subcortical structures. MK-801 caused a significant increase of D1 and D2 mRNA in the dorsal and ventral striatum, a significant decrease of D3 mRNA in the nucleus accumbens, and a significant decrease of D1 mRNA in the limbic cortex. Dopamine autoreceptor expression, reflected by D2 mRNA in the midbrain, was increased in the ventral tegmental area, but not in the substantia nigra. Thus, MK-801 appears to differentially regulate the mesocorticolimbic and nigrostriatal dopamine systems.

Animals↗
PubMed1996

Stress controllability influences the ataxic properties of both ethanol and midazolam in the rat.

Rats were administered either 80 escapable shocks or yoked inescapable shocks, were then injected with saline or several ataxic doses of either ethanol or midazolam, and then had their motoric impairment assessed by Rotarod performance. No motoric impairment was observed following saline injection. However, inescapable shock impaired Rotarod performance in response to both ethanol and midazolam at 2 hr, but not immediately poststress. Conversely, escapable shock reduced the ataxic potency of ethanol, although it had no influence on midazolam-induced ataxia. These results indicate functional alterations in behavioral reactivity to low doses of several classes of central nervous system depressants by psychological dynamics of stress exposure. Our findings demonstrate the impact of stress controllability on behavioral reactivity to two classes of drugs of abuse.

Animals↗
PubMed1994

Prodynorphin-derived peptide expression in primate cortex and striatum.

The distributions of four prodynorphin-derived peptides, dynorphin A (1-17), dynorphin A (1-8), dynorphin B, and alpha-neo-endorphin were determined in 10 cortical regions and the striatum of the old world monkey (Macaca nemestrina). alpha-neo-endorphin was the most abundant peptide in both cortex and striatum. The concentrations of all four peptides were significantly greater in the striatum compared to the cortex. In general, concentrations of each peptide tended to be higher in allocortex than in neocortex. Possible inter- and intradomain processing differences, as estimated by ratios of these peptides, did not vary within cortex, but the intradomain peptide ratio, dyn A (1-17)/dyn A (1-8), was significantly greater in cortex than in striatum. These results indicate that prodynorphin is, in some ways, uniquely processed in the primate. Particularly unusual is the relatively low abundance of prodynorphin-derived products in the cortex, in the face of moderately high levels of kappa opiate receptor expression.

Animals↗
PubMed1991

Comparison of the distributions of D1 and D2 dopamine receptor mRNAs in rat brain.

The distributions of messenger RNAs encoding both the D1 and D2 dopamine receptors have been determined in the rat brain by in situ hybridization. High levels of both mRNAs were found in the traditional dopaminoceptive regions of brain, including the caudate-putamen, nucleus accumbens, and olfactory tubercle; lower levels of both were found in a number of other neural structures, such as the lateral septum, olfactory bulb, hypothalamus, and cortex. High levels of D2 but not D1 receptor mRNA were identified in the midbrain dopamine cell groups, suggesting that the autoreceptors found in the substantia nigra and ventral tegmental area are exclusively D2. Other areas demonstrating differential distribution of these two mRNAs included the pituitary, amygdala, and hippocampus. Quantitative densitometric analysis revealed that in most of the brain regions studied in which both messages exist, the amounts of D1 and D2 receptor mRNAs were approximately equal. Finally, using thin (2.5-micron) sections through the caudate-putamen, about half of all cells were found to be positive for D1 receptor mRNA, and approximately 75% of cells contained D2 receptor mRNA. Subsequent analysis in sequential sections revealed that co-localization of D1 and D2 receptor mRNA occurred in 33% +/- 7% of all caudate-putamen cells: about half of all cells containing D1 receptor mRNA also contained D2 receptor mRNA, and approximately half of all D2 receptor mRNA-positive cells also contained D1 receptor mRNA. These results indicate that there is considerable overlap between D1 and D2 dopaminoceptive cells, and provide a basis for future regulatory studies of dopamine systems in brain within a defined anatomic context.

Animals↗
PubMedDate not supplied

Frequency of neuropathology in a brain bank from a long-term, domiciliary population.

Postmortem analysis of brain chemistry and anatomy in the study of psychiatric disorders has enjoyed renewed interest recently. There are myriad difficulties in establishing a brain bank, including proper diagnosis and confounding neuropathology. These difficulties may become more pronounced in a long-term domiciliary facility. In order to begin to address neuropathologic considerations, we performed neuropathological examinations on each patient included in our bank of 20 brains. Forty-five per cent of all patients had significant and unexpected neuropathology. Selection of patients to be included in postmortem studies requires careful screening to enhance accurate neuropathological assessment.

Adult↗