Biomedical subjects

M F Egan

Publications and source records attributed to M F Egan.

At least 37 records · Page 2Linked to original sources

PubMed2000

Selective relationship between prefrontal N-acetylaspartate measures and negative symptoms in schizophrenia.

OBJECTIVE: Certain cognitive, behavioral, and emotional deficits (so-called negative symptoms) in patients with schizophrenia have often been attributed to prefrontal cortical pathology, but direct evidence for a relationship between prefrontal neuronal pathology and negative symptoms has been lacking. The authors hypothesized that an in vivo measure of prefrontal neuronal pathology (N:-acetylaspartate [NAA] levels) in patients with schizophrenia would predict negative symptoms. METHOD: Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and rating scales for negative and positive symptoms were used to study 36 patients with schizophrenia. Magnetic resonance spectra were analyzed as metabolite ratios, and parametric correlations were performed. RESULTS: A regionally selective negative correlation was found between prefrontal NAA-creatine ratio and negative symptom ratings in this group of patients with schizophrenia. CONCLUSIONS: Lower prefrontal NAA-and by inference greater neuronal pathology-predicted more severe negative symptoms in patients with schizophrenia. These data demonstrate a relationship between an intraneuronal measure of dorsolateral prefrontal cortex integrity and negative symptoms in vivo and represent further evidence for the involvement of the dorsolateral prefrontal cortex in negative symptoms associated with schizophrenia.

Adult↗

PubMed2000

Relative risk of attention deficits in siblings of patients with schizophrenia.

OBJECTIVE: Impaired attention has frequently been observed in studies of unaffected siblings of patients with schizophrenia. To assess the suitability of impaired attention for use as an intermediate phenotype in genetic studies, the authors estimated the relative risk of impaired attention in a large group of siblings. METHOD: The authors used the Continuous Performance Test, 1-9 version, with and without a distraction condition, to study 147 patients with schizophrenia, 193 of their siblings, and 47 normal comparison subjects. Relative risk (l) was estimated by using cutoff scores that were one, two, and three standard deviations below the mean sensitivity index value (d cent) of the normal comparison group in both Continuous Performance Test conditions. RESULTS: Patients but not their siblings performed worse than the normal comparison subjects in both conditions. Fifty percent of the patients, 24% of their siblings, and 18% of the normal comparison subjects scored one standard deviation below the mean score of the comparison group for the more difficult distraction version of the Continuous Performance Test. The patients with Continuous Performance Test scores one standard deviation below the mean score of the comparison group had a total of 97 siblings. Compared with the comparison group, this subgroup of siblings had significantly lower Continuous Performance Test scores. Relative risk was also significantly higher for the siblings of patients whose scores were one standard deviation (l=2. 1) and two standard deviations (l=3.3) below the mean of comparison subjects. Attempts to assess ascertainment bias suggest that this may be an underestimate. CONCLUSIONS: Poor performance on the Continuous Performance Test appears to be familial and, possibly, genetic. Relative risk estimates were in the moderate range. Given the ease of administering the Continuous Performance Test, the use of impaired attention as an intermediate phenotype could increase the power of genetic studies of schizophrenia.

Adult↗

PubMed1999

In vivo determination of striatal dopamine D2 receptor occupancy in patients treated with olanzapine.

In vivo studies of dopamine D2 receptor occupancy with atypical antipsychotics have suggested good clinical efficacy at occupancy rates less than those observed with typical neuroleptics, and few extrapyramidal side effects (EPS), possibly even at high levels of D2 occupancy. We used [123I]IBZM-SPECT to investigate striatal D2 receptor occupancy in 10 schizophrenic patients who were treated with both a low (5 mg) and a high dose (20 mg) of the novel antipsychotic olanzapine without concomitant medications. The mean D2 occupancy at 5 mg was 59.8% (range 33-81%); the mean D2 occupancy at 20 mg was 82.8% (range 56-97%). Although the D2 occupancy rates on 5 and 20 mg olanzapine were significantly different (P < 0.001), there were no significant differences in clinical ratings for psychiatric symptoms or extrapyramidal side effects between the two doses of olanzapine. These data suggest that: (1) olanzapine doses below those used routinely occupy D2 receptors at levels approaching those associated with therapeutic response; (2) higher doses produce relatively high levels of D2 occupancy rates; and (3) EPS are mild even at relatively high levels of D2 occupancy.

Adult↗

PubMed1998

Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype.

BACKGROUND: Shared neurobiological characteristics of patients with schizophrenia and their siblings may represent "intermediate phenotypes" that may more closely reflect the genetic susceptibility underlying this illness. We sought evidence of such phenotypes using magnetic resonance spectroscopy based on previously described regional abnormalities in levels of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophrenia. METHODS: We studied 47 schizophrenics, 60 unaffected siblings, and 66 healthy control subjects with long echo time multislice proton magnetic resonance spectroscopic imaging, primarily measuring NAA, creatine plus phosphocreatine (CRE), and choline-containing compounds. RESULTS: Both patients and their unaffected siblings had significant reductions in hippocampal area NAA/CRE as compared with control subjects. As exploratory analyses, estimates of heritability were performed. Although quantitative correlation of hippocampal NAA between patients and sibs was low (likely reflecting measurement noise), qualitatively defined "low hippocampal NAA/CRE phenotypes" yielded relative risk estimates (lambda s) of between 3.8 and 8.8, suggesting this characteristic is heritable. CONCLUSIONS: Our finding adds to the evidence that hippocampal abnormalities are associated with schizophrenia and may represent a novel biological phenotype for genetic studies of schizophrenia.

Adult↗

PubMed1998

Effects of prefrontal cortical lesions on neuropeptide and dopamine receptor gene expression in the striatum-accumbens complex.

In the rat, neurochemical, behavioral, and anatomical investigations suggest that medial prefrontal cortical input modulates the activity of the basal ganglia. To understand how prefrontal dysfunction might alter striatal-accumbens function, in situ hybridization histochemistry with S35-labeled oligonucleotide probes was used to assess changes in striatal-accumbens gene expression following bilateral excitotoxic ibotenic acid (IA) lesions of the rat medial prefrontal cortex. Quantitative densitometry was used to measure changes in mRNA levels for preproenkephalin A (ENK), D1 dopamine receptor, protachykinin (SubP), glutamic acid decarboxylase (GAD65), and D2 dopamine receptor. No differences were found between sham and lesion groups for ENK, D1, SubP, or GAD65 mRNA levels in the striatum or nucleus accumbens (NAC). D2 receptor mRNA levels were, however, significantly higher in the dorsomedial striatum and in the core area of the NAC of the lesioned rats. Although the functional significance of increased D2 mRNA is unclear, these findings demonstrate that glutamate mPFC projections modulate gene expression in relatively regionally-localized subcortical neuronal populations.

Animals↗

PubMed1998

Failure to down regulate NMDA receptors in the striatum and nucleus accumbens associated with neuroleptic-induced dyskinesia.

The syndrome of vacuous chewing movements (VCMs) in rats is similar in many respects to tardive dyskinesia (TD) in humans. Both syndromes are characterized by delayed onset of persistent orofacial dyskinesias in a sub-group of subjects chronically treated with neuroleptics. Using the rat model, we examined the role of NMDA receptor-mediated corticostriatal neurotransmission in the expression of VCMs. Rats were treated for 36 weeks with haloperidol decanoate or vehicle and then withdrawn for an additional 28 weeks. Chronic persistent VCMs were induced in one subgroup of treated animals (+VCM), but not in another group (-VCM). Rats from +VCM, -VCM groups and vehicle-treated controls were selected for post mortem studies (n = 12 to 14 per group). NMDA receptor levels were assessed using [3H]-MK-801 binding in sections from the mid-striatum and nucleus accumbens. Chronic haloperidol treatment produced a marked reduction of NMDA receptor binding levels throughout the striatum and nucleus accumbens. Post hoc comparisons demonstrated that -VCM rats had lower NMDA receptor binding levels than +VCM and vehicle-treated controls. Ventromedial striatum and nucleus accumbens core were the most affected areas. These findings suggest that down-regulation of striatal NMDA receptor binding levels may protect against the expression of neuroleptic-induced dyskinesia.

Animals↗

PubMed1997

Neurobiology of schizophrenia.

Schizophrenia appears to be a neurodevelopmental disorder involving dysfunctional prefrontal and temporal cortical neural systems. Recent data implicate presynaptic changes in subcortical dopamine neurotransmission, as well as alterations in cortical glutamatergic and GABAergic systems. Functional neuroimaging studies, combined with tests of neuropsychological function, suggest that cortical abnormalities underlie the cognitive deficits associated with schizophrenia. These deficits appear to account for much of the psychosocial dysfunction of schizophrenia and are particularly treatment refractory. Genetic studies have implicated several minor susceptibility loci; however, the clinical impact of these loci on the neurobiology of schizophrenia is still unclear. The use of neurobiological traits as phenotypes, such as cognitive deficits and cortical abnormalities, in genetic linkage studies may facilitate the identification of loci that underlie the most debilitating features of schizophrenia.

Animals↗

PubMed1997

Treatment of tardive dyskinesia.

Although the new generation of atypical antipsychotic agents could some day eliminate concerns about tardive dyskinesia (TD), this disorder remains a significant clinical problem for both patients and physicians. Fortunately, many, if not most, cases of TD are mild. For patients with mild to moderate TD, therapeutic efforts are primarily directed at minimizing neuroleptic exposure or, when possible, changing to atypical agents. Most cases of TD do not seem to progress, suggesting that the risk of remaining on typical neuroleptics is probably small. Patients with moderate to severe forms of TD present greater challenges. These patients frequently require medication to suppress their dyskinesias. A variety of suppressive agents have been tried with limited success. No treatment strategy has emerged that is clearly superior or even successful in most patients. Increasing doses of typical neuroleptics may be useful for short-term suppression; however, the long-term efficacy and risk of this strategy have not been studied carefully. Data on atypical neuroleptics are scant. Clozapine's short-term suppressive effects seem, at best, weak, but patients may improve with long-term treatment. Medications with relatively few side effects that may have suppressive efficacy for some patients include calcium channel blockers, adrenergic antagonists, and vitamin E. Gamma-amino-butyric acid agonists agents and dopamine depleters are frequently useful, but have troubling side effects of their own. A variety of other medications have been employed, but are not well studied. For patients with tardive dystonia, anticholinergic agents or botulinum toxin has been particularly effective. Efforts to understand the neurobiology of TD may shed light on this persistent clinical conundrum.

Antioxidants↗

PubMed1997

Altered dopaminergic function and negative symptoms in drug-free patients with schizophrenia. [123I]-iodobenzamide SPECT study.

BACKGROUND: Previous in vivo studies of schizophrenia with dopamine D2 receptor radioligands have yielded contradictory results. No prior study has used multiple scans to examine within-subject clinical change. METHOD: Twenty-one patients were studied with [123I]-iodobenzamide single photon emission computed tomography about two weeks after neuroleptic withdrawal. Thirteen of the 21 completed a second scan about four weeks after neuroleptic withdrawal. Sixteen controls were scanned for comparison. RESULTS: There was no significant difference between groups in [123I]-iodobenzamide uptake at either scanning session. No significant correlations with demographic variables (age, illness duration, drug-free period), or clinical ratings (positive and negative symptoms, movement disorder) were observed at either scanning session. There was a significant correlation between change in [123I]-iodobenzamide uptake and change in negative symptom ratings for the subjects who underwent two scans (r = 0.72, P < 0.05). CONCLUSIONS: Worsening of negative symptoms may be associated with increased availability of striatal D2 receptors, perhaps because of decreased concentrations of endogenous dopamine.

Adult↗

PubMed1996

Effects of chronic neuroleptic treatment on dopamine release: insights from studies using 3-methoxytyramine.

Antipsychotic medications appear to exert their therapeutic effects by blocking D2 receptors. While D2 blockade occurs rapidly, reduction in psychotic symptoms is often delayed. This time discrepancy has been attributed to the relatively slow development of depolarization inactivation (DI) of dopaminergic neurons. The reduced firing rates associated with DI has been hypothesized to reduce dopamine release and thus psychotic symptoms. Studies assessing changes in dopamine release during chronic neuroleptic treatment, using microdialysis and voltammetry, have been inconsistent. This may be due to methodological differences between studies, the invasive nature of these procedures, or other confounds. To investigate the effects of DI on dopamine release, 3-MT accumulation, an index of dopamine release that does not involve disruption of brain tissue, was measured during acute and chronic neuroleptic treatment. These results are compared with those using other techniques. 3-MT levels remained elevated after chronic treatment, suggesting that DI does not markedly reduce release. Regulation of dopamine release during DI was examined using two techniques known to block dopamine neuronal impulse flow. 3-MT levels were markedly reduced by both, implying that DI does not alter the portion of dopamine release mediated by neuronal impulse flow. Overall, studies to date suggest that the delayed therapeutic effects of neuroleptics are not due to reductions in impulse dependent dopamine release. Recent studies using a neurodevelopmental animal model of schizophrenia have pointed to altered pre- and post-synaptic indices of dopamine neurotransmission. The results suggest that neuroleptics may exert their therapeutic effects, in part, by limiting the fluctuations in dopamine release, and raise new issues for future research.

Animals↗

PubMed1996

Pharmacological and neurochemical differences between acute and tardive vacuous chewing movements induced by haloperidol.

Late onset vacuous chewing movements (VCMs) from chronic neuroleptic treatment have been used as a rat model of tardive dyskinesia (TD). Early onset VCMs have also been observed, raising questions about the validity of this model. To assess the relationship between these two types of VCMs, pharmacological and neurochemical properties of early and late onset VCMs were compared. "Acute" VCMs were induced by daily intraperitoneal injections for 1-21 days. "Tardive" VCMs were induced by intramuscular injections of haloperidol decanoate every 3 weeks for 30 weeks followed by a 24-week withdrawal period. Suppression was attempted for both types of VCMs using several doses of intraperitoneal haloperidol. Striatonigral activation was assessed by measuring mRNA expression levels of the neuropeptides dynorphin and substance P using in situ hybridization histochemistry. Enkephalin mRNA was also measured as an index of striatopallidal activation. The results indicate that acute VCMs cannot be suppressed with increased doses of haloperidol and are associated with reduced dynorphin and substance P. This profile is similar to that seen with an animal model of parkinsonism. Tardive VCMs, in contrast, were markedly suppressed by haloperidol. They have previously been shown to be associated with increased striatonigral activation as indicated by increased dynorphin mRNA. Enkephalin mRNA was elevated following both short and long term treatment. Although superficially similar, acute and tardive VCMs appear to have different pharmacological and neurochemical profiles, suggesting they are related to acute extrapyramidal side effects and tardive dyskinesia, respectively.

Animals↗

PubMed1996

Effects of rating parameters on assessment of neuroleptic-induced vacuous chewing movements.

Long-term administration of neuroleptics to rats produces a syndrome of vacuous chewing movements (VCMs). The validity of the VCM syndrome as a model for tardive dyskinesia (TD) in humans is unclear. This is due, in part, to inconsistencies between studies. Methods for rating VCMs have varied markedly and could account for the inconsistencies. The purpose of this study was to evaluate the importance of the different methods on VCM scores. The effects of habituation and length of rating sessions were examined in rats habituated for 2 min, 1 h, or several hours over 4 days, compared to unhabituated rats. Ratings with and without habituation were highly correlated, as were ratings from 2- and 5-min observation periods. Ratings from neuroleptic-treated rats in restraining tubes, however, were significantly correlated with unrestrained ratings only following several hours of habituation. Locomotor activity was not correlated with VCM scores. These results suggest that habituation to open cages is not an important factor in assessing VCMs. Use of restraining tubes, however, may alter scores. The lack of an habituation effect or of a relationship between activity and VCMs suggests that locomotor and oral behaviors are not necessarily in competition. Restraining rats to rate VCMs does not appear to be necessary and could alter the neurobiology of VCMs.

Animals↗

PubMed1996

The effects of acute and chronic haloperidol treatment on dopamine release mediated by the medial forebrain bundle in the striatum and nucleus accumbens.

The delayed therapeutic effects of neuroleptics have been attributed to D2-mediated depolarization inactivation (DI) of mesolimbic dopaminergic neurons and concomitant reduction in dopamine release. Several studies have suggested, however, that DI may not reduce dopamine release and have hypothesized that this is due to increased impulse independent release. To examine the mechanisms that modulate dopamine release during DI, tetrodotoxin (TTX) was infused into the left medial forebrain bundle (MFB) of Sprague Dawley rats. Three-methoxytyramine (3-MT) levels 10 minutes after pargyline (75 mg/kg) were used as a measure of dopamine release. A dose response study showed that infusions of 10(-5) mol/L and 10(-4) mol/L TTX reduced 3-MT levels on the infused side by 70% in the striatum and 50% to 60% in the nucleus accumbens. In a time course study, 10(-5) mol/L TTX reduced striatal 3-MT at 30, 90, and 120 minutes. After intraperitoneal injections of haloperidol (0.4 mg/kg) for 1 or 21 days, TTX infusions again reduced 3-MT levels by approximately 70% in the striatum and 53% to 59% in the nucleus accumbens on the infused side. Acute and chronic haloperidol treatment did not alter the percent of TTX-induced reductions. These data suggest that dopaminergic neuronal impulse flow modulates similar amounts of total transmitter release after both acute and chronic haloperidol treatment. The results do not support the notion that DI mediates the antipsychotic effects of neuroleptics by markedly reducing total basal dopamine release or increasing impulse independent release. Alternatively, DI could reduce psychotic symptoms by changing the responsiveness of the dopamine system to external stimuli or by reducing synaptic dopamine levels that have been hypothesized to be elevated in psychotic patients.

Animals↗

PubMed1995

Diurnal variation in tardive dyskinesia.

Tardive dyskinesia (TD) is a common movement disorder that is associated with chronic neuroleptic exposure. To better characterize the clinical aspects of TD, we investigated the diurnal pattern of involuntary movements by blindly rating videotaped examinations of patients from the morning shortly after awakening and later in the same afternoon. In 10 patients, average TD ratings were worse in the afternoon than in the morning, especially in the case of limb-trunk dyskinesias. These findings suggest that it is important to rate patients at the same time of day in TD studies. Moreover, patients should be evaluated at least several hours after awakening.

Adult↗

PubMed1995

Neonatal excitotoxic ventral hippocampal damage alters dopamine response to mild repeated stress and to chronic haloperidol.

The effects of neonatal excitotoxic ventral hippocampus (VH) lesions on dopamine release in response to repeated stress (saline injections) and to chronic haloperidol treatment were investigated in Sprague-Dawley rats infused with ibotenic acid or vehicle into the VH on day 7 of postnatal life (PD7). Beginning on PD35, lesioned and sham-operated rats were injected i.p. with saline (INJ) once daily for 3 weeks or were not treated (NO INJ). Another cohort of rats was given haloperidol (HAL, 0.4 mg/kg, i.p.) or vehicle beginning on PD35 and thereafter once daily for 3 weeks. 3-Methoxytyramine (3-MT) was measured by combined gas chromatography/mass spectrometry in the frontal cortex (FC), nucleus accumbens (NAcc), and striatum (STR) at PD56 following MAO inhibition with pargyline. At baseline (NO INJ), 3-MT was reduced in STR of lesioned rats. Repeated saline injections resulted in a further 3-MT reduction in STR, FC, and NAcc of lesioned animals, but had no effect in sham rats. Chronic HAL, compared with vehicle, suppressed locomotor activity, and increased 3-MT accumulation in the FC, NAcc, and STR in sham and lesioned rats. This increase was enhanced in the FC of lesioned rats. These data show that mild repeated stress attenuates dopamine release in FC, NAcc, and STR of lesioned rats, while chronic HAL augments it in FC of lesioned animals versus controls. We conclude that the neonatal excitotoxic lesion of VH alters the functioning of midbrain dopamine systems during environmental and pharmacological challenge.

Animals↗

PubMed1995

Neuroleptic-induced vacuous chewing movements in rodents: incidence and effects of long-term increases in haloperidol dose.

Rats treated chronically with neuroleptics develop vacuous chewing movements (VCMs), similar in some respects to tardive dyskinesia (TD) in man. The VCM syndrome was used as a model of TD to examine the ability of increased neuroleptic doses to produce long-term suppression of dyskinetic movements. The incidence and persistence of the VCM syndrome in individual rats were also assessed to look for affected and unaffected subgroups. Rats were initially treated for 15 weeks and haloperidol decanoate. For the next 21 weeks, half the group received a 50-150% increase in dose while the other half continued to receive the same dose. Animals were also followed during a 28-week withdrawal period. Total VCM ratings showed a skewed distribution, with some rats exhibiting few movements while others developed marked and persistent movements. Increasing doses did not suppress VCMs, nor did they exacerbate movements during the withdrawal period. To the extent that the VCM syndrome models TD, the absence of long-term suppression of the VCM syndrome suggests that, at this dosage range, increasing depot neuroleptic doses may not be a useful long-term strategy for TD suppression.

Animals↗

PubMed1995

Persistent catalepsy associated with severe dyskinesias in rats treated with chronic injections of haloperidol decanoate.

Patients who develop persistent parkinsonism while on chronic neuroleptic therapy may be predisposed towards the development of tardive dyskinesia (TD). We investigated this issue in an animal model of TD by examining the association between catalepsy and the syndrome of neuroleptic-induced vacuous chewing movements (VCMs). VCMs were measured every 3 weeks for 33 weeks while rats received injections of haloperidol decanoate. Catalepsy was measured after the second through the seventh injections of the depot neuroleptic. There were no correlations between the severity of catalepsy scores after the second or third injections of haloperidol and the severity of the overall VCM syndrome. However, the severity of the catalepsy score following the third through seventh injections of haloperidol strongly correlated with the concurrent number of VCMs. Persistent high catalepsy scores across the six catalepsy rating sessions were strongly associated with the development of persistent severe VCMs. These findings suggest that, to the extent that persistent parkinsonian signs in humans are associated with a propensity towards the development of TD, the VCM syndrome in rats is at least a partially faithful animal model of this relationship.

Animals↗

PubMed1995

Effects of chronic naloxone administration on vacuous chewing movements and catalepsy in rats treated with long-term haloperidol decanoate.

Most antipsychotic medications produce motoric side effects, including parkinsonism and tardive dyskinesia (TD). Correlates of these behaviors in rats (catalepsy and vacuous chewing movements, respectively) were used as a model to assess the usefulness of chronic naloxone administration in symptom reduction. Previous studies have suggested that increased neurotransmission in the endogenous opioid system modulates neuroleptic-induced motoric side effects. Rats were treated with haloperidol decanoate or vehicle for 27 weeks, and withdrawn for 30 weeks. Subsequently, naloxone (0.5 to 2.0 mg/kg SC twice daily) was given for 5 weeks. Long-term haloperidol treatment produced a syndrome of vacuous chewing movements (VCMs) that persisted during the drug withdrawal period. Catalepsy developed rapidly and also persisted. Naloxone treatment had little effect on VCMs but increased catalepsy scores in both haloperidol and vehicle treated groups. Naloxone reduced rearing and grooming in haloperidol rats while increasing these measures in vehicle treated rats. The results indicate that neuroleptic-induced motoric side effects are not reversed by naloxone in rats. Furthermore, they suggest that increased opioid neurotransmission may not underlie the expression of VCMs. This does not rule out the possibility that endogenous opioid system may be involved in the development of VCMs. To the extent that this animal model is valid, naloxone may not be effective in treating TD and neuroleptic-induced parkinsonism in humans.

Animals↗