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M B Knable

Publications and source records attributed to M B Knable.

36 records · Page 2Linked to original sources
PubMed1997

Analysis of the metabolites of [I-123] beta-CIT in plasma of human and nonhuman primates.

[I-123] beta-CIT is a single photon emission computed tomography (SPECT) radioligand that has been used for in vivo studies of the dopamine and serotonin transporters. Two metabolite peaks of beta-CIT have been observed by high performance liquid chromatography (HPLC), but neither has been chemically identified. One major metabolite is clearly hydrophilic. Previous reports have not agreed on the amount of the second metabolite and the extent to which it may cross the blood-brain barrier. To clarify this controversy, we have studied beta-CIT metabolites using a protein precipitation method and an organic extraction method followed by HPLC separation. Plasma from both human and nonhuman (rhesus) primates was analyzed. Concentrations of the second metabolite were substantially lower in rhesus than in human for nearly equal parent concentrations. Furthermore, in rhesus the second metabolite is partially soluble in the organic solvent ethyl acetate, whereas in human it is essentially insoluble. These observations account for the contradictions in the literature. The hydrophilic nature of the human metabolite renders it unlikely that it crosses the blood-brain barrier in sufficient quantities to interfere with the quantitative assessment of dopamine transporter densities.

Animals↗
PubMed1997

Dopamine, the prefrontal cortex and schizophrenia.

Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been suspected based on observations from clinical, neuropsychological and neuroimaging studies. Since the PFC receives a dense dopaminergic innervation, abnormalities of the mesocortical dopamine system have been proposed to contribute to the pathophysiology of schizophrenia. In this review, aspects of the anatomy, physiology and pharmacology of the mesencephalic-frontal cortical dopamine system as they may relate to schizophrenia are described, and evidence for altered dopaminergic neurotransmission in the frontal cortex of schizophrenic patients is presented.

Antipsychotic Agents↗
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

A postmortem study of frontal cortical dopamine D1 receptors in schizophrenics, psychiatric controls, and normal controls.

We tested the hypothesis that aberrant dopaminergic innervation in frontal and cingulate cortices of schizophrenic patients might be revealed by examining dopamine D1 receptor density in these brain regions. A quantitative autoradiographic assay with [3H]-SCH 23390 was performed with samples from schizophrenic patients, normal controls, neuroleptic-treated controls, and suicides. There was a significant elevation in specific binding of [3H]-SCH 23390 in the intermediate layer of the prefrontal cortex from neuroleptic-treated controls (p = .05). Elevated [3H]-SCH 23390 binding in several layers from prefrontal and cingulate cortex was observed in schizophrenic subjects, although these results did not reach statistical significance. When data from subjects who had received neuroleptics (schizophrenics and neuroleptic controls) were compared to subjects who had not received neuroleptics (normal controls and suicides), there was a significant elevation in receptor density in both the prefrontal (p = .05) and cingulate cortices (p = .03). These data suggest that elevated [3H]-SCH 23390 binding in human prefrontal and cingulate cortices may occur with chronic neuroleptic treatment, although increased receptor density that may exist as a feature of psychotic illnesses cannot be excluded.

Autoradiography↗
PubMed1996

Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding.

Tourette syndrome, a chronic tic disorder with autosomal dominant inheritance, exhibits considerable phenotypic variability even within monozygotic twin pairs. The origins of this variability remain unclear. Recent findings have implicated the caudate nucleus as a locus of pathology, and pharmacological evidence supports dopaminergic involvement. Within monozygotic twins discordant for Tourette syndrome severity, differences in D2 dopamine receptor binding in the head of the caudate nucleus predicted differences in phenotypic severity (r = 0.99); this relation was not observed in putamen. These data may link Tourette syndrome with a spectrum of neuropsychiatric disorders that involve associative striatal circuitry.

Adult↗
PubMed1996

Distribution of dopamine D1-D4 receptor subtypes in human dorsal vagal complex.

The distribution of D1/D5, D2/D3, D2/D3/D4, and individually, putative D2-D4 receptors across the dorsal vagal complex of the human medulla was assessed with quantitative receptor autoradiography. D1/D5 receptors were found in very low levels. D2 receptors were concentrated in the intermediate and medial subnuclei of the nucleus of the solitary tract (NTS), and in the dorsal motor nucleus of the vagus (DMN), while D3 receptors were more homogeneous across the entire NTS, area postrema (AP), and DMN. In contrast, D4 receptors were found almost exclusively in the intermediate and medial subnuclei of the NTS, and in the DMN. These findings suggest that the "D2 family" of receptors is an important component of brain stem mechanisms regulating visceral function, including gastrointestinal systems, such as emesis, along with cardiovascular and pulmonary systems. Compounds with individual selectivity for D2, D3, or D4 receptors may be useful in the manipulation of neural networks regulating these visceral systems.

Adolescent↗
PubMed1996

Individual variation in D2 dopamine receptor occupancy in clozapine-treated patients.

OBJECTIVE: The objectives of this study were 1) to pursue the question of clozapine's striatal D2 occupancy in relation to its clinical effectiveness; 2) to investigate the relation between schizophrenic symptoms, clozapine blood levels, and estimated D2 occupancy during clinically stable and unstable conditions; and 3) to examine long-term stability in D2 occupancy. METHOD: Specific binding of the D2 radioligand [123I]benzamide ([123I]IBZM) was studied with single photon emission computed tomography in 13 patients with schizophrenia when they were clinically stable during chronic clozapine treatment, after clozapine dose reduction of > or = 50%, and in a subgroup (N = 7) after restabilization on clozapine regimens. Clozapine's estimated D2 occupancy was based on comparison with values from drug-free normal subjects. RESULTS: A wide range of estimated D2 occupancies (18% to > or = 80%) were associated with sustained, favorable response to clozapine without correlation with residual symptoms. Clozapine blood levels were negatively related to [123I]IBZM specific binding. Acute dose reduction was associated with predicted worsening in positive and negative symptoms and increases in [123I]IBZM specific binding. Independent of clozapine blood level, patients with more symptoms showed lower [123I]IBZM specific binding, consistent with competition of endogenous dopamine for D2 binding sites in patients with greater symptoms. Restabilization on clozapine regimens produced D2 occupancies closely correlated with baseline values. CONCLUSIONS: There was no evidence for a critical degree of D2 occupancy required to sustain clozapine's therapeutic effects across subjects. Simple linear regression was the best-fit model for clozapine's D2 occupancy. Longitudinal follow-up suggests stability over time of D2 occupancy in relation to dose and clinical response within individual patients.

Adult↗
PubMed1996

Dopamine D2 receptor imaging and neuroleptic drug response.

Studies with positron emission tomography and single photon emission computed tomography have yielded important findings concerning the relationship between dopamine D2 receptor occupancy and neuroleptic dose, plasma neuroleptic levels, and clinical response. For "typical" neuroleptics, therapeutic response is associated with occupancy levels as low as 60%-70%, which can be achieved at lower doses than are routinely used. For these drugs, extrapyramidal side effects increase, and therapeutic response remains unchanged with higher occupancy levels. Although the mechanisms responsible for the improved clinical efficacy and tolerability of atypical neuroleptics are still poorly understood, antipsychotic efficacy has been observed at lower D2 receptor occupancy rates than with typical neuroleptics. It is unclear whether the lower incidence of extrapyramidal side effects observed with the atypical neuroleptic clozapine can be attributed to its lower D2 occupancy, its relatively specific effects on the ventral striatum, or its nondopaminergic effects. There are a number of additional unresolved issues, including the high interindividual variation in scan outcome measurements, possible effects of concomitant medication, possible effects of endogenous dopamine, and assumptions in various strategies used to model receptor densities and occupancy rates.

Antipsychotic Agents↗
PubMed1996

An improved method for rapid and efficient radioiodination of iodine-123-IQNB.

UNLABELLED: The SPECT radioligand, 3-quinuclidinyl-4-[123I]iodobenzilate ([123I]IQNB), binds to muscarinic receptors and has generated interest as a potential agent for clinical SPECT. Unfortunately, cumbersome and inefficient radioiodination procedures have limited the practicality of [123I]IQNB SPECT imaging. METHODS: We report a rapid (5 min) and simple radioiodination procedure for preparing [123I]IQNB from a tri-n-butylstannyl precursor in a no-carrier-added reaction that yields high specific activity with radiochemical yield exceeding 60%. The radiochemical purity of the final product exceeds 95%. RESULTS: We have used this procedure to radioiodinate the four stereoisomers of [123I]IQNB. The procedure is highly reliable and reproducible. SPECT studies on a healthy human volunteer at 1, 2, 6 and 24 hr after injection of each of the four stereoisomers reveal expected differences in the kinetic and binding characteristics of the four stereoisomers. (R,S)-[123I]IQNB appears to be the SPECT agent of choice. CONCLUSION: Radioiodination of [123I]IQNB from our tri-n-butylstannyl precursor is simpler, more efficient and less expensive than previous techniques. The potential exists for a "kit" which would be practical in a typical clinical setting.

Adult↗
PubMed1995

Are mental diseases brain diseases? The contribution of neuropathology to understanding of schizophrenic psychoses.

Nearly a century after the seminal contributions of Emil Kraepelin, the search for neuropathologic correlates of schizophrenic psychoses continues. A multitude of neuroanatomic and neurochemical findings has emerged in recent years, but many of these findings are not replicated or are difficult to interpret in light of methodologic problems. In this review replicated neuropathologic and neuroimaging studies are discussed. The hypothesis that emerges from these studies is that schizophrenia is a developmental abnormality affecting the connectivity of the prefrontal and medial temporal cortices.

Brain↗
PubMed1995

Lateralized differences in iodine-123-IBZM uptake in the basal ganglia in asymmetric Parkinson's disease.

UNLABELLED: We used equilibrium analysis of SPECT data from patients with asymmetric Parkinson's disease to determine if lateralized differences in the striatal uptake of [123I]IBZM correlate with asymmetry in clinical findings and, by inference, with lateralized differences in the concentration of extracellular dopamine. METHODS: Twelve patients with asymmetric clinical signs of idiopathic Parkinson's disease were injected with a bolus of [123I]IBZM, and multiple SPECT scans recorded the time course of radioligand uptake. The time integral method was used to estimate peak specific binding, so that a ratio of specific-to-nonspecific binding in the left and right striatum of each subject at equilibrium could be determined. Nine patients also had 99mTc-HMPAO SPECT scans which were examined for evidence of blood flow asymmetries. RESULTS: Paired t-tests comparing [123I]IBZM uptake revealed significantly greater (mean = 7.3%) availability of dopamine-D2 receptors in the basal ganglia contralateral to maximal clinical signs. Differences in receptor availability correlated significantly with differences in every measure of the clinical assessment. No significant differences in regional cerebral blood flow between the two sides were observed with 99mTc-HMPAO. CONCLUSION: These results demonstrate the ability of [123I]IBZM SPECT to reveal clinically meaningful variations in striatal dopamine receptor availability in patients with asymmetric Parkinson's disease. The equilibrium analysis technique used to determine these findings is a simple and robust method of measuring relative receptor availability and may be useful in studying other illnesses where dysfunction of dopaminergic neurotransmission is suspected.

Adult↗
PubMed1995

Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia.

The identification of five dopamine receptor subtypes has given the dopamine hypothesis of schizophrenia new life. The D4 receptor is particularly intriguing because it binds clozapine with high affinity. Putative D4 receptors were labeled in postmortem human brain by subtracting the binding of a saturating concentration of 3H-raclopride (6 nM, which labels D2 and D3 receptors) from that labeled by a saturating concentration of [3H]YM 09151-2 (1-1.3 nM, which labels D2, D3, and D4 receptors). In the control brain, putative D4 receptors show a homogenous distribution in striatum and nucleus accumbens. This is also true in schizophrenic brains, although the levels are significantly higher (twofold). These data are inconsistent with mRNA studies that have shown negligible amounts in striatum and accumbens, with modest amounts reported in most of cerebral cortex. These findings suggest that the putative D4 receptors are not synthesized in this region, but are presynaptically localized on striatal afferent terminals. Our findings confirm and extend the report of Seeman et al. (1993). Extension of these findings into the nucleus accumbens is important because of its extensive connections to the limbic system while the putamen is exclusively "motor" striatum.

Adult↗
PubMed1994

Quantitative autoradiography of dopamine-D1 receptors, D2 receptors, and dopamine uptake sites in postmortem striatal specimens from schizophrenic patients.

A number of previously published homogenate receptor binding studies have postulated that dopaminergic dysfunction in schizophrenia may be related to abnormalities in dopamine receptors. In this study, postmortem striatal specimens from patients with schizophrenia, normal controls, and psychiatric controls that had received neuroleptics were studied with quantitative autoradiography for dopamine receptors. Autoradiography with single concentrations of [3H]-SCH 23390 for D1 receptors, [3H]-raclopride for D2 receptors, and [3H]-CFT for dopamine uptake sites failed to define significant differences between the study groups. [3H]-CFT bound in a patchy distribution in the striatum that is believed to correspond to striosomal and matrix striatal compartments. There were no differences between groups when [3H]-CFT binding density was examined in the striosomal and matrix compartments. There were also no differences between groups in the percentage of striatal area occupied by striosomal or matrix compartments as defined by [3H]-CFT binding. We conclude that abnormalities of these dopamine receptor subtypes are probably not primary features of the schizophrenic syndrome in the brain collection examined. Previous reports of elevated D2 receptor binding in schizophrenia may have been related to drug treatment effects. Alternatively, the relatively high affinity of ligands used in previous studies for D4 receptors may explain the discrepancy in our findings. Unchanged [3H]-CFT binding in the schizophrenic group also suggests that the density of mesostriatal neuronal terminals is not altered in schizophrenia.

Autoradiography↗
PubMed1994

Quantitative autoradiography of striatal dopamine D1, D2 and re-uptake sites in rats with vacuous chewing movements.

Rats treated with haloperidol that developed vacuous chewing movements (VCM), a possible animal model of tardive dyskinesia, were studied with quantitative autoradiography for dopamine type-1 (D1) and type-2 (D2) receptors as well as dopamine re-uptake sites. Haloperidol increased striatal D2 receptors, but did not affect D1 receptors or the dopamine re-uptake site. D2 receptor increases occurred in rats with and without VCMs. In so far as VCM is a model for tardive dyskinesia, haloperidol induced increases in striatal D2 receptors do not appear to be etiologic for these abnormal movements.

Animals↗
PubMed1994

The subnuclear distribution of 5-HT3 receptors in the human nucleus of the solitary tract and other structures of the caudal medulla.

The distribution of 5-HT3 receptors was examined in the human medulla using [3H]LY278584, a highly selective 5-HT3 receptor antagonist. The highest density of 5-HT3 receptors was found in the substantia gelatinosus subnucleus of nucleus of the solitary tract (NTS) throughout its rostrocaudal extent, followed by the dorsal subnucleus, the area postrema (AP), the commissural subnucleus, the medial subnucleus, and in an arc corresponding to the pars gelatinosus of the spinal trigeminal nucleus (nSp5). The distribution of 5-HT3 receptors in the brain may help explain some of the reported CNS activities of 5-HT3-selective drugs. The anti-emetic and antinociceptive activities of 5-HT3 antagonists may be mediated by receptors in sensory areas of the brainstem.

Adolescent↗
PubMed1994

Limbic-prefrontal connectivity and clozapine.

The mechanisms of the antipsychotic efficacy and side effect profile of clozapine are incompletely understood. In vivo pharmacologic studies suggest that while clozapine does produce D2 receptor blockade, its unusual clinical profile may relate to activity at other receptor sites and to anatomical areas outside the striatum. Rodent studies indicate that acute administration of clinical doses of antipsychotic drugs, including clozapine, induces Fos (the protein product of the immediate early gene, c-fos) in the nucleus accumbens. However, unlike typical antipsychotic drugs, clozapine does not induce Fos in the dorsal striatum and does induce Fos in medial portions of the prefrontal cortex. Clozapine seems to produce a unique signature effect on long-term neuronal metabolism in its induction of Fos in the shell of the nucleus accumbens and in the medial prefrontal cortex. Future in vivo studies of cerebral blood flow and glucose metabolism in human patients may help to elucidate the specificity and reproducibility of the effects of clozapine in the ventral striatum and prefrontal cortex.

Animals↗