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J H Meador-Woodruff

Publications and source records attributed to J H Meador-Woodruff.

At least 19 recordsLinked to original sources
PubMed2001

Vesicular glutamate transporter transcript expression in the thalamus in schizophrenia.

Previously, we have reported alterations in thalamic NMDA receptor subunit and excitatory amino acid transporter expression in schizophrenia, consistent with the hypothesis that thalamic glutamatergic dysfunction may contribute to the pathophysiology of this illness. We have generalized this hypothesis to include other molecules of the glutamate synapse. Using riboprobes specific for human brain-specific Na+-dependent inorganic phosphate transporter (BNPi) and differentiation-associated Na+/Pi co-transporter (DNPi), both vesicular glutamate transporters, in situ hybridization was performed in the thalami of persons with schizophrenia and comparison subjects. We detected increased expression of DNPi mRNA in the thalamus in schizophrenia, while BNPi mRNA was not expressed in the thalamus in any subjects. These findings support the hypothesis of glutamatergic dysfunction in the thalamus in schizophrenia.

Aged↗
PubMed2001

Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder.

Abnormalities of the ionotropic glutamate receptors (N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid [AMPA], and kainate) have been reported in the brain in schizophrenia, although in complex, region-specific patterns. While limbic cortex and medial temporal lobe structures have been most often studied in psychiatric illnesses, glutamate receptors are expressed in other brain regions associated with limbic circuitry, especially the striatum. In this study, we have determined striatal ionotropic glutamate receptor expression in brains from persons with schizophrenia, bipolar disorder, major depression, and a comparison group, using samples from the Stanley Foundation Neuropathology Consortium. We have determined the expression of these receptors at multiple levels of gene expression by using both in situ hybridization and receptor autoradiography. The expression of nearly all of these molecules was not different in these psychiatric conditions. The only significant changes noted were NR2D and gluR1 transcripts, and [(3)H]AMPA binding. This is the first comprehensive study of striatal ionotropic glutamate receptor expression in schizophrenia and affective disorders, and suggests that there are minimal changes in these receptors in this region of the brain in these illnesses.

Adult↗
PubMed2001

Ontogeny of ionotropic glutamate receptor expression in human fetal brain.

Glutamate receptors have multiple roles in the central nervous system. Recent evidence suggests that the iontropic glutamate receptors are critical during brain development, particularly for corticogenesis, neuronal migration, and synaptogenesis. In this study, we examined subunit mRNA expression and binding sites of the NMDA, AMPA, and kainate receptors from gestational weeks 8-20 in human fetal brain. Expression of glutamate receptors was high during several periods in these brains. Different levels of expression of each NMDA, AMPA, and kainate receptor subunit transcripts were present during development, with a greater abundance of NR1, NR2B, NR2D, GluR7, and KA1 mRNA at most gestational ages. Binding sites for NMDA, AMPA, and kainate receptors were all detected, but each had a unique pattern of expression. These results demonstrate that glutamate receptors are expressed early in human brain development, and undergo complex changes over time consistent with their role in normal development.

2-Amino-5-phosphonovalerate↗
PubMed2001

Abnormal kainate receptor expression in prefrontal cortex in schizophrenia.

Abnormalities of molecules associated with the glutamate synapse have been implicated in the pathophysiology of schizophrenia. Of the many glutamate receptors, those most commonly suggested to be involved in schizophrenia are the ionotropic subtypes, the NMDA, AMPA, and kainate receptors. Both the NMDA and AMPA subtypes have been extensively studied in postmortem brains of individuals with schizophrenia, but relatively little is known about the expression of the kainate subtype of glutamate receptor. In this study, we have determined cortical and striatal kainate receptor expression in brains from persons with schizophrenia and a comparison group, using both in situ hybridization and receptor autoradiography. At the level of subunit mRNA expression, a shift in subunit stoichiometry was evident in multiple regions of the prefrontal cortex, with increased expression of gluR7 mRNA and decreased expression of KA2 mRNA. Decreased kainate receptor binding was also observed in the subjects with schizophrenia, but was restricted to infragranular laminae of the prefrontal cortex. No differences in kainate receptor binding or subunit mRNA levels were found in striatum or occipital cortex, suggesting that these findings may be restricted to association cortex. These data add to the growing literature implicating ionotropic glutamate receptor disturbances in schizophrenia, and indicate that in addition to AMPA and NMDA receptors, the kainate receptors are also abnormally expressed in this illness.

Aged↗
PubMed2001

Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia.

OBJECTIVE: Recent investigations of schizophrenia have targeted glutamatergic neurotransmission, since phencyclidine, an N-methyl-D-aspartate (NMDA) receptor antagonist, can induce schizophreniform psychosis. The authors previously reported alterations in thalamic NMDA receptor subunit expression in schizophrenia, consistent with the hypothesis that thalamic glutamatergic hypofunction may contribute to the pathophysiology of this illness. In this study they generalized this hypothesis to include other molecules of the glutamate synapse, specifically excitatory amino acid transporters (EAATs), whose normal expression and regulation in the thalamus may also be disrupted in subjects with schizophrenia. METHOD: In situ hybridization with riboprobes specific for the human excitatory amino acid transporter transcripts EAAT1, EAAT2, and EAAT3 was performed in discrete thalamic nuclei in persons with schizophrenia and comparison subjects. RESULTS: Higher expressions of transcripts encoding EAAT1 and EAAT2, but not EAAT3, were detected in the thalamus of subjects with schizophrenia. CONCLUSIONS: These findings support the hypothesis of glutamatergic dysfunction in schizophrenia and suggest that molecules other than glutamate receptors are abnormally expressed in glutamatergic synapses in this illness.

ATP-Binding Cassette Transporters↗
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

Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus.

BACKGROUND: The central role that the thalamus plays in information processing and sensory integration suggests that its dysfunction may be a factor in the pathophysiology of schizophrenia. Glutamate is a key neurotransmitter in thalamic function, and although all aspects of thalamic glutamate neurotransmission have not been elucidated, transcripts encoding members of each family of the glutamate receptors have been identified in the thalamus. Recently, activation of group II metabotropic glutamate receptors (mGluRs) was demonstrated in rats to ameliorate the behavioral effects associated with exposure to phencyclidine, an uncompetitive NMDA receptor antagonist that can induce psychotic symptoms, suggesting the possibility of mGluR abnormalities in schizophrenia. We investigated whether expression of thalamic mGluR mRNA is altered in this illness. METHODS: We examined the expression of the transcripts encoding the mGluR1, 2, 3, 4, 5, 7, and 8 receptors in postmortem thalamic tissue samples from elderly schizophrenic and control subjects, using in situ hybridization. We identified six thalamic nuclei in each section (anterior, dorsomedial, lateral dorsal, central medial, reticular, and nuclei of the ventral tier). RESULTS: There were no differences between elderly schizophrenic and control subjects in the expression of mGluR1, 2, 3, 4, 5, 7, or 8 transcript levels in any of these six thalamic nuclei. CONCLUSIONS: mGluR mRNA expression is not abnormal in the thalamus of patients with schizophrenia. The modulatory roles proposed for mGluRs, and the potentially important relationship between mGluRs and NMDA receptors, suggest that mGluRs may be involved in the pathophysiology of schizophrenia, but this is not detectable at this level of gene expression.

Aged↗
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

Effects of clozapine and haloperidol on 5-HT6 receptor mRNA levels in rat brain.

The high affinity of 5-HT6 receptors for atypical antipsychotic drugs, and their localization in limbic and cortical regions of the brain, suggest that they might play a role in the pathophysiology of schizophrenia. To determine if this receptor is regulated by antipsychotics, rats were injected with clozapine (20 mg/kg/day), haloperidol (2 mg/kg/day), or vehicle daily for 2 weeks, and 5-HT6 receptor mRNA levels were measured by in situ hybridization. Clozapine but not haloperidol significantly decreased 5-HT6 expression in all subfields of the hippocampus. No drug effects were observed in cortical or forebrain structures. These results suggest that downregulation of this receptor in the hippocampus might be a characteristic of atypical antipsychotic drugs, although this hypothesis will require testing with other atypical antipsychotics.

Animals↗
PubMed1999

On the distribution patterns of D1, D2, tyrosine hydroxylase and dopamine transporter immunoreactivities in the ventral striatum of the rat.

The distribution of dopamine D1 and D2 receptor immunoreactivities in the nucleus accumbens and the olfactory tubercle of adult and postnatal male rats were compared with the distribution of tyrosine hydroxylase and dopamine transporter immunoreactivities. An overall co-distribution of D1 and D2 receptor immunoreactivities with tyrosine hydroxylase immunoreactivity was found in the nucleus accumbens and the olfactory tubercle. However, the major finding in this study was, following a more detailed analysis in coronal sections of the shell part of the nucleus accumbens, the existence of nerve cell patches of strong D1 receptor immunoreactivity associated with low D2 receptor, dopamine transporter and tyrosine hydroxylase immunoreactivities. These patches were mainly surrounded by areas of strong D2 receptor, tyrosine hydroxylase and dopamine transporter immunoreactivities and could be found also in the olfactory tubercle. Similar observations were made in postnatal rats. Serial reconstructions of the patches of strong D1 receptor immunoreactivity in the rostrocaudal direction were made. The patches formed a continuous tubular nerve cell system in the shell part of the nucleus accumbens. Since this nerve cell system was found to be surrounded by a high density of dopamine terminals, it may represent a compartment where dopamine transmission mainly acts on D1 receptors via local diffusion (i.e. via volume transmission). However, it must be noted that the D1 receptor rich patches constitute only a small fraction of the nucleus accumbens and the overall density of tyrosine hydroxylase immunoreactive terminals correlates with the density of both D1 and D2 receptors in the nucleus accumbens. In conclusion, the present paper gives new aspects on the chemical microarchitecture of the nucleus accumbens.

Aging↗
PubMed1999

Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia.

The prevalence of smoking is markedly elevated in schizophrenia. Low smoking cessation rates and reports that some smokers with schizophrenia experience an acute increase in symptoms during attempts to quit smoking, suggest a self-medication model. Alternatively, smoking may modulate medication side effects. The effects of treated and untreated smoking abstinence on psychotic symptoms and medication side effects were examined in this study. Nineteen outpatients with schizophrenia or schizoaffective disorder participated in a randomized, double-blind, balanced crossover study: 1 day of ad libitum smoking followed by 3 days of acute smoking abstinence while wearing 22 mg/day active or placebo transdermal nicotine patches, with a return to 3 days of smoking between patch conditions. Daily symptom and side-effect ratings, nicotine and cotinine blood levels were collected. Twelve subjects completed the study. Neither positive symptoms nor mood symptoms changed. An increase in negative symptoms during the first abstinent day occurred in both placebo and active patch conditions, but was not sustained over subsequent abstinent days. Despite physiological signs of withdrawal, completers did not endorse increased nicotine withdrawal symptoms. Dropouts reported higher withdrawal symptoms, but also had no increase in psychiatric symptoms in either phase of the study. Of note, dyskinesias decreased during abstinence and placebo patch treatment, but increased during abstinence and the active patch conditions. Acute exacerbation of psychiatric symptoms is an unlikely explanation for any difficulty smokers with schizophrenia have in early abstinence.

Administration, Cutaneous↗
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↗
PubMed1999

Acute feasibility and safety of a smoking reduction strategy for smokers with schizophrenia.

The authors examined whether smoking while wearing a transdermal nicotine patch over 32 h was well-tolerated and led to smoking suppression in heavy smokers with schizophrenia. In a crossover design, 10 male veteran smokers with schizophrenia were admitted for two brief inpatient stays to smoke while wearing a transdermal nicotine or placebo patch. Carbon monoxide in expired air, self-reported cigarettes per day, nicotine plasma levels, and psychiatric ratings were measured. Nicotine levels increased during active patch treatment, without evidence of nicotine toxicity. Psychiatric symptoms, carbon monoxide and cigarettes per day did not change, although eight subjects had a decrease in expired carbon monoxide on the active patch. Dyskinesias showed a small, but significant, increase during smoking plus active patch. The heaviest smokers (identified by placebo phase nicotine plasma level or CO level above group median; n = 5) had a statistically significant decrease in expired carbon monoxide of at least 20%. Smoking while wearing the nicotine patch over 32 h was well tolerated. Significant decreases in carbon monoxide smoking indices were seen for the heaviest smokers. These findings suggest further investigation of a smoking reduction intervention in this population.

Administration, Cutaneous↗
PubMed1998

Differential prevalence of cigarette smoking in patients with schizophrenic vs mood disorders.

Rates of substance-use disorders among psychiatric patients are consistently higher than in the general population, yet there is no clear specificity to the relationship between types of substance use and psychiatric diagnoses. Cigarette smoking may represent a substance-use behavior which has greater specificity for major psychiatric diagnoses. We examined the self-reported history of cigarette smoking vs marijuana, alcohol and cocaine use among 83 male veteran psychiatric patients with primary mood (major depression or bipolar disorder; n = 20) or schizophrenic (schizophrenia or schizoaffective; n = 63) disorders. Those in the SCZ group compared to those in the AFF group were more likely to be ever-smokers (OR 8.5, 95% CI [2.2, 32.3]), and current smokers (OR 12.0%, 95% CI [3.6, 40]), independent of age differences between the groups. There were no significant differences in marijuana, alcohol or cocaine use between the two groups when age differences were controlled. Generalizability of the findings is limited by small number of subjects, male gender and veteran status; however, the significantly higher prevalence of smoking among individuals with schizophrenic disorders may support the growing evidence of linkages between the effects of nicotine and the neurobiology of schizophrenia.

Adult↗
PubMed1998

Tardive dyskinesia, clozapine, and treatment response.

1. Tardive Dyskinesia (TD) can be a serious consequence of the use of antipsychotic medications to treat psychotic illness. There is evidence to suggest that the atypical antipsychotic, clozapine, is less likely to cause, and may even ameliorate TD. 2. The authors reviewed their experience regarding clozapine and TD among patients in their Clozapine Clinic, and summarize some of the recent clinical literature in this area. 3. Retrospective review of chart records for 13 patients was carried out. Comparisons of TD and symptom rating scales were made: 1) between groups (with and without TD) at baseline; 2) between individuals (self as own control) in the TD group at baseline and at the end of the follow-up period. 4. Subjects with and without TD at baseline had a significant decrease in psychiatric symptoms over the course of treatment. 5. In those with TD at baseline, mean Abnormal Involuntary Movement Scale (AIMS) score decreased by 85% over 10.3 +/- 5.5 (mean +/- S.D.) months at a dose of 358 +/- 196 mg/day of clozapine. 6. The data, and the recently published clinical literature on clozapine and TD, continue to support the striking utility of clozapine for chronically psychotic patients, and particularly those with TD.

Adult↗