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Biomedical subjects

J J Mann

Publications and source records attributed to J J Mann.

At least 55 records · Page 3Linked to original sources

Suicidal behavior in bipolar mood disorder: clinical characteristics of attempters and nonattempters.

OBJECTIVE: Bipolar Disorder is associated with a higher frequency of attempted suicide than most other psychiatric disorders. The reasons are unknown. This study compared bipolar subjects with a history of a suicide attempt to those without such a history, assessing suicidal behavior qualitatively and quantitatively, and examining possible demographic, psychopathologic and familial risk factors. METHODS: Patients (ages 18 to 75) with a DSM III-R Bipolar Disorder (n = 44) diagnosis determined by a structured interview for Axis I disorders were enrolled. Acute psychopathology, hopelessness, protective factors, and traits of aggression and impulsivity were measured. The number, method and degree of medical damage was assessed for suicide attempts, life-time. RESULTS: Bipolar suicide attempters had more life-time episodes of major depression, and twice as many were in a current depressive or mixed episode, compared to bipolar nonattempters. Attempters reported more suicidal ideation immediately prior to admission, and fewer reasons for living even when the most recent suicide attempt preceded the index hospitalization by more than six months. Attempters had more lifetime aggression and were more likely to be male. However, attempters did not differ from nonattempters on lifetime impulsivity. LIMITATIONS: The generalizability of the results is limited because this is a study of inpatients with a history of suicide attempts. Patients with Bipolar I and NOS Disorders were pooled and a larger sample is needed to look at differences. We could not assess psychopathology immediately prior to the suicide attempt because, only half of the suicide attempters had made attempts in the six months prior to admission. Patients with current comorbid substance abuse were excluded. No suicide completers were studied. CONCLUSIONS: Bipolar subjects with a history of suicide attempt experience more episodes of depression, and react to them by having severe suicidal ideation. Their diathesis for acting on feelings of anger or suicidal ideation is suggested by a higher level of lifetime aggression and a pattern of repeated suicide attempts.

Adult↗

The biology of impulsivity and suicidality.

Abnormalities of 5-HT and noradrenergic functioning have been implicated in aggressive impulsivity, SIB, and suicidal behavior. The role of DA and GABA in human studies of these behaviors requires further investigation. Most studies suggest that impulsive aggression is related to lower levels of CNS 5-HT. Some studies demonstrate that increasing NE correlates to impulsive aggression, whereas other studies demonstrate an opposite relationship. The role of NE in impulsive aggressive behavior is still unclear. Self-injurious behavior is similar to impulsive aggression in that it seems to be mediated by the neurotransmitter systems previously mentioned. For example, the presence of lower levels of 5-HT and abnormalities in the DA system are related to SIB in patients with BPD and depression. SIB severity also seems to be influenced by neglect (e.g., severe isolation during rearing). As animal studies suggest, increasing the amount of isolation and an earlier onset of isolation increase the severity of SIB. Suicidal behaviors and the lethality of suicide attempts may also be linked to the abnormalities in neurotransmitter systems similar to those found in patients with impulsive aggression and SIB, namely, lowered 5-HT transmission and enhanced DA and NE functioning. Understanding the biological triggers of impulsive aggression or SIB may allow for the evaluation of suicidal attempts and completion from a different perspective and, in conjunction with genetic predictors, may eventually help with the early prediction and prevention of suicidal behaviors. Additional studies of live subjects and postmortem brains will assist in clarifying the neurobiology of suicidal behaviors that are common to many disorders and are clinically relevant to BPD.

Aggression↗

Positron emission tomography study of pindolol occupancy of 5-HT(1A) receptors in humans: preliminary analyses.

Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT(1A) receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT(1A) antagonist [carbonyl-(11)C]WAY-100635 or [carbonyl-(11)C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexa necarboxamide abbreviated as [(11)C]WAY-100635. Pindolol dose-dependently decreased [(11)C]WAY-100635 BP. Combining all the regions, occupancy was 20 +/- 8% at scan 2, 14 +/- 8% at scan 3, and 44 +/- 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT(1A) receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT(1A) receptors was higher in the DRN compared to cortical regions, demonstrating a significant in vivo selectivity for DRN 5-HT(1A) autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of concept in the development of 5-HT(1A) agents for this application. Early evaluation of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for clinical trials.

Adult↗

Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility.

To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90+/-0.06 (mean +/- SD of 12 regions) and 0.84+/-0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72+/-0.17 and 0.58+/-0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.

Adult↗

Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tisssue input functions.

Serotonin 5-HT(1A) receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT(1A) receptor parameters in the human brain with positron emission tomography (PET) and [carbonyl-(11)C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT(1A) receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT(1A) receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 +/- 0.14 (mean +/- SD of 15 regions) and 0.84 +/- 0.19, respectively. In contrast, the reliability of k3/k4 was lower, with ICC of 0.53 +/- 0.28, 0.47 +/- 0.28, and 0.55 +/- 0.29 for kinetic, graphical, and reference tissue methods, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test-retest reproducibility, lower vulnerability to experimental noise, and absence of bias.

Adult↗

Anxiety in major depression: relationship to suicide attempts.

OBJECTIVE: This study was an examination of the relationship of lifetime panic disorder and anxiety symptoms at index hospitalization to a history of a suicide attempt in patients with a major depressive episode. METHOD: A total of 272 inpatients with at least one major depressive episode, with or without a history of a suicide attempt, were entered into the study. They were given structured diagnostic interviews for axis I and axis II disorders. Suicide attempt history, current psychopathology, and traits of aggression and impulsivity were also assessed. RESULTS: The rates of panic disorder did not differ in the suicide attempters and nonattempters. Agitation, psychic anxiety, and hypochondriasis were more severe in the nonattempter group. A multivariate analysis confirmed that this effect was independent of aggression and impulsivity. CONCLUSIONS: Comorbid panic disorder in patients with major depression does not seem to increase the risk for lifetime suicide attempt. The presence of greater anxiety in the nonattempters warrants further investigation.

Adolescent↗

Characteristics of suicide attempts of patients with major depressive episode and borderline personality disorder: a comparative study.

OBJECTIVE: Suicidal behavior is highly prevalent in borderline personality disorder and major depressive episode, although the characteristics of suicide attempts in the two disorders are believed to differ. Comorbidity of borderline personality disorder and major depressive episode may obscure characteristics of suicide attempts that are uniquely related to the psychopathology of each disorder. We compared suicidal behavior in patients with borderline personality disorder, major depressive episode, and borderline personality disorder plus major depressive episode to determine whether characteristics of suicide attempts differed between groups and if aspects of core psychopathology predicted specific attempt characteristics. METHOD: Eighty-one inpatients with borderline personality disorder, including 49 patients with borderline personality disorder plus major depressive episode, were compared to 77 inpatients with major depressive episode alone on measures of depressed mood, hopelessness, impulsive aggression, and suicidal behavior, including lifetime number of attempts, degree of lethal intent, objective planning, medical damage, and degree of violence of suicide methods. RESULTS: No significant differences were found in the characteristics of suicide attempts between patients with borderline personality disorder and those with major depressive episode. However, patients with both disorders had the greatest number of suicide attempts and the highest level of objective planning. An increase in either impulsive aggression or hopelessness or a diagnosis of borderline personality disorder predicted a greater number of attempts. Hopelessness predicted lethal intent in all three groups and predicted objective planning in the group with both disorders. Medical damage resulting from the most serious lifetime suicide attempt was predicted by number of attempts. CONCLUSIONS: Comorbidity of borderline personality disorder with major depressive episode increases the number and seriousness of suicide attempts. Hopelessness and impulsive aggression independently increase the risk of suicidal behavior in patients with borderline personality disorder and in patients with major depressive episode.

Adolescent↗

Association of aggressive behavior with altered serotonergic function in patients who are not suicidal.

OBJECTIVE: The purpose of this study was to determine whether aggression and serotonergic dysfunction are related in the absence of a history of suicidal behavior. Although serotonergic dysfunction has been implicated in aggressive and impulsive behavior, most studies of such behavior have included individuals with a history of suicide attempts. Low concentrations of CSF 5-hydroxyindoleacetic acid (5-HIAA) have been consistently associated with suicidal behavior, presenting a potential confound in the link between aggression and serotonergic dysfunction. METHOD: The authors examined the association between aggression and CSF 5-HIAA concentrations in a group of 64 patients who had different DSM-III-R axis I diagnoses and no past suicidal behavior. Aggressive (N=35) and nonaggressive (N=29) groups were defined by a median split on a six-item history of adulthood aggressive behavior. RESULTS: The aggressive group had significantly lower CSF 5-HIAA concentrations than the nonaggressive group. Aggressive individuals also scored significantly higher on self-report measures of hostility, impulsiveness, and sensation seeking. CSF 5-HIAA concentrations, however, did not correlate with self-reported hostility and impulsivity. CONCLUSIONS: There is an association between aggressive behavior and serotonergic dysfunction independent of suicidal behavior in patients with axis I disorders who exhibit relatively milder forms of aggressive behavior. Analogous to findings with suicidal behavior, a low concentration of CSF 5-HIAA is related to aggressive behavior but does not show the same relationship to the continuum of aggressive feelings and thoughts.

Adult↗

Protective factors against suicidal acts in major depression: reasons for living.

OBJECTIVE: Over 30,000 people a year commit suicide in the United States. Prior attempted suicide and hopelessness are the most powerful clinical predictors of future completed suicide. The authors hypothesized that "reasons for living" might protect or restrain patients with major depression from making a suicide attempt. METHOD: Inpatients with DSM-III-R major depression were assessed for depression, general psychopathology, suicide history, reasons for living, and hopelessness. Of the 84 patients, 45 had attempted suicide and 39 had not. RESULTS: The depressed patients who had not attempted suicide expressed more feelings of responsibility toward family, more fear of social disapproval, more moral objections to suicide, greater survival and coping skills, and a greater fear of suicide than the depressed patients who had attempted suicide. Scores for hopelessness, subjective depression, and suicidal ideation were significantly higher for the suicide attempters. Reasons for living correlated inversely with the combined score on these measures, considered an indicator of "clinical suicidality." Neither objective severity of depression nor quantity of recent life events differed between the two groups. CONCLUSIONS: During a depressive episode, the subjective perception of stressful life events may be more germane to suicidal expression than the objective quantity of such events. A more optimistic perceptual set, despite equivalent objective severity of depression, may modify hopelessness and may protect against suicidal behavior during periods of risk, such as major depression. Assessment of reasons for living should be included in the evaluation of suicidal patients.

Adaptation, Psychological↗

Recent life events, social adjustment, and suicide attempts in patients with major depression and borderline personality disorder.

This study investigated the impact of recent life events and social adjustment on suicide attempter status in 34 patients with major depression, 24 patients with borderline personality disorder, and 22 patients with co-morbid major depression and borderline personality disorder. Suicide attempters reported more recent life events and scored lower on a measure of social adjustment in their families and overall social adjustment, compared with non-attempters. Borderline disordered and borderline or depressed patients were more likely to have attempted suicide than patients with major depression only. Recent life events did not predict attempter status. Lower social adjustment in the immediate family and lower overall social adjustment were predictive of suicide attempter classification, regardless of diagnosis. Borderline disordered patients low on overall social adjustment were over 16 times more likely to have attempted suicide than patients diagnosed with major depression only. Recent life events may elevate suicide risk in groups already at high risk for suicide completion, whereas high levels of social adjustment may be protective against stress-related suicidal behavior.

Adult↗

In vivo quantification of brain serotonin transporters in humans using [11C]McN 5652.

UNLABELLED: Abnormal brain regional densities of serotonin (5-hydroxytryptamine [5-HT]) transporters have been reported in postmortem studies in several neuropsychiatric conditions, such as major depression and schizophrenia. trans-1,2,3,5,6,10-beta-Hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([11C]McN 5652) is the first PET radioligand successfully developed to label 5-HT transporters in the living human brain. The purpose of this study was to develop an imaging protocol and analytic method to measure regional 5-HT transporter binding potential (BP) with [11C]McN 5652 in humans. METHODS: The arterial input function and brain uptake of (+)-[11C]McN 5652 and (-)-[11C]McN 5652, the active and inactive enantiomers, respectively, were measured in 6 healthy volunteers. RESULTS: (+)-[11C]McN 5652 concentrated in brain regions rich in 5-HT transporters (midbrain, thalamus, basal ganglia, and medial temporal lobe structures), whereas the uptake of (-)-[11C]McN 5652 was more uniformly distributed. Total distribution volumes (V(T)) were derived using kinetic 2-compartment analysis and graphic analysis. V(T) derived by both methods were highly correlated. (+)-[11C]McN 5652 regional V(T) ranged from 18 +/- 2 mL/g in the cerebellum to 46 +/- 13 mL/g in the midbrain. (-)-[11C]McN 5652 regional VT ranged from 10 +/- 2 mL/g in the cerebellum to 14 +/- 3 mL/g in the thalamus. (+)-[11C]McN 5652 V(T) were higher than (-)-[11C]McN 5652 V(T) in all regions, including the cerebellum, a region devoid of 5-HT transporters. Blocking experiments were also performed in baboons with saturating doses of citalopram and in humans with nonsaturating doses of paroxetine. Cerebellar and neocortical (+)-[11C]McN 5652 V(T) were unaffected by pretreatment with 5-HT transporter blockers. In areas of high receptor concentration (midbrain, caudate, and thalamus) 5-HT transporter blockers decreased (+)-[11C]McN 5652 V(T) to the level of cerebellum (+)-[11C]McN 5652 V(T). CONCLUSION: These experiments indicate that the use of the difference between (+)- and (-)-[11C]McN 5652 V(T) to define specific binding to 5-HT transporters leads to an overestimation of specific binding. 5-HT transporter BP was derived as the difference between the regional and cerebellar (+)-[11C]McN 5652 V(T). BP values were in good agreement with the distribution of 5-HT transporters in the human brain, except for regions of relatively low 5-HT transporter concentration, such as the prefrontal cortex, where no specific binding was detected using (+)-[11C]McN 5652. (+)-[11C]McN 5652 is an appropriate radiotracer to quantify 5-HT transporters in regions with relatively high concentration of 5-HT transporters, such as the midbrain, thalamus, and basal ganglia, and should prove useful in elucidating abnormalities of 5-HT transmission in neuropsychiatric conditions.

Adult↗

Pursuit tracking impairments in schizophrenia and mood disorders: step-ramp studies with unmedicated patients.

BACKGROUND: Eye tracking abnormalities are highly prevalent in schizophrenia, and are among the most promising phenotypic familial markers for the disorder. The neurophysiologic mechanisms underlying these disturbances and their diagnostic specificity for schizophrenia are not yet well characterized. METHODS: This study assessed eye tracking deficits using foveopetal and foveofugal step-ramp tasks (ramps moving toward and away from central fixation after an initial step respectively) across a range of target velocities in anti-psychotic-naive schizophrenia patients, previously treated but currently unmedicated chronic schizophrenia patients, unmedicated patients with either bipolar or unipolar mood disorders, and healthy volunteers. RESULTS: All patient groups demonstrated reduced pursuit gain in open loop and closed loop visual tracking conditions. There were no significant group differences in the latency or accuracy of catch-up saccades on foveofugal ramp tasks. CONCLUSIONS: These findings indicate that open and closed loop pursuit eye movements are impaired during acute episodes of schizophrenia and mood disorders. The intact accuracy of saccades to moving targets in all patient groups indicates that an adequate representation of motion information is available to the saccade system. Therefore, pursuit disturbances in mood disorders and schizophrenia seem to result, at least in part, from a disturbance in sensorimotor integration in the pursuit system after the initial extraction of sensory motion information. No eye movement abnormalities observed during performance of step ramp tasks were specific to schizophrenia.

Adult↗

Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims.

BACKGROUND: The serotonin deficiency hypothesis of suicide has been important heuristically. Few studies have directly examined the brainstem dorsal raphe nucleus (DRN) serotonin neurons. We determined the number and morphometry of DRN serotonergic neurons in suicide victims (n = 7) compared to controls (n = 6). METHODS: Brainstems were collected at autopsy, fixed and cryoprotected. Tissue was sectioned, stained for Nissl and processed with an antiserum that cross-reacts with tryptophan hydroxylase. All DRN neurons were identified, counted and analyzed every 1000 microns. Neuron morphometry was characterized by soma area (micron 2), sphericity, perimeter, length and density (neurons per mm3). RESULTS: Neuron number and density was higher in suicide victims (1,780 +/- 127 neurons/mm3) than controls (1,349 +/- 68). The DRN volume did not differ between groups (66 +/- 9 mm3 for controls vs. 67 +/- 5 mm3 for suicides). Mean neuronal area and sphericity did not differ between suicides and controls. The total number and the density of DRN neurons did not correlate with age. CONCLUSIONS: The finding of an increased number of neurons indicates that impaired serotonergic transmission found in association with serious suicide attempts is not due to fewer neurons.

Adolescent↗

Dorsal raphe nucleus serotonergic neurons innervate the rostral ventrolateral medulla in rat.

Stimulation of the dorsal raphe nucleus (DRN) alters arterial pressure, heart rate and cerebral blood flow, yet projections from the DRN to medullary autonomic nuclei have not been described. We examined whether serotonergic (5-HT) projections from the DRN terminate in the rostral ventrolateral medulla (RVL) and if so, whether the projection mediates cardiovascular responses to DRN stimulation. Studies were performed in adult male Sprague-Dawley rats. Horseradish peroxidase or choleratoxin B was injected unilaterally or bilaterally into the RVL. Levels of 5-HT, its precursors L-tryptophan and 5-hydroxytryptophan and the metabolite 5-hydroxyindole acetic acid were measured in the ventral medulla by HPLC three weeks following placement of electrolytic lesions in DRN. Serotonin transporter (3H-cyanoimipramine binding) was quantified by autoradiography in DRN-lesioned animals. Horseradish peroxidase or choleratoxin B injections into the medulla at the level of the RVL resulted in retrogradely labeled neurons bilaterally, with ipsilateral predominance, in the DRN. Labeled cells were preponderant in rostral ventrolateral portions of the DRN, but were also observed in the dorsal, lateral and interfascicular DRN subnuclei; fewer neurons were observed in caudal portions of the DRN. Three weeks following placement of electrolytic lesions in the DRN, the concentrations of 5-HT and 5-hydroxyindole acetic acid, but not L-tryptophan or 5-hydroxytryptophan, were reduced in the medulla by 45 and 48%, respectively, compared to sham-operated or unoperated controls. DRN lesions reduced binding to the 5-HT transporter in the RVL by approximately 30% compared to unlesioned controls. Unilateral lesions of the RVL reduced the evoked blood pressure response by 53+/-15%; bilateral RVL lesions reduced the response by 86+/-9%. The increase in cortical blood flow elicited by DRN stimulation was unchanged after unilateral or bilateral RVL lesions. These studies demonstrate that there is a descending serotonergic projection from the DRN to the RVL. This projection may mediate autonomic changes elicited by DRN stimulation.

Animals↗

Stability of [123I]IBZM SPECT measurement of amphetamine-induced striatal dopamine release in humans.

Binding competition between endogenous dopamine (DA) and the D2 receptor radiotracer [123I]IBZM allows measurement of the change in synaptic DA following amphetamine challenge with SPECT in the living human brain. Previous investigations using this technique in healthy subjects have shown that the magnitude of amphetamine effect on [123I]IBZM binding potential (BP) is small (range between 5 to 15% decrease), and that a large between-subject variability in this effect is observed. Therefore, it was unclear how much of the apparent between-subject variability was due to a low signal-to-noise ratio in the measurement, vs. true between-subject differences in the magnitude of the response. The goals of this investigation were to test the within-subject reproducibility and reliability of amphetamine-induced decrease in [123I]IBZM BP with a test/retest paradigm, and to establish the presence or absence of tolerance or sensitization to single administration ofi.v. amphetamine. Six healthy male subjects, never previously exposed to psychostimulants, twice underwent measurement of striatal amphetamine-induced DA release (between-measurement interval 16 +/- 10 days) using SPECT and the [123I]IBZM constant infusion technique. Results demonstrated an excellent within-subject reproducibility of amphetamine-induced DA release: amphetamine-induced decreases in [123I]IBZM BP were significant on each day, and had an intraclass correlation coefficient (ICC) of 0.89. Moreover, values from the second experiment were not significantly different from first experiment, suggesting the absence of either sensitization or tolerance to the effect of amphetamine on DA release in these experimental conditions. The subjective activation, as rated by the subjects on analog scales, was also highly reproducible. In conclusion, this scanning technique provides a reliable measurement of amphetamine-induced reduction of [123I]IBZM BP and enables detection of between-subject differences that appear stable over time.

Adult↗

Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene.

BACKGROUND: Central nervous system (CNS) serotonergic activity correlates inversely with human aggressive behavior, and individual differences in aggressive disposition are at least partially heritable. This study was conducted to evaluate the possible association between measures of antagonistic behavior and an intronic polymorphism of the gene coding for tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. METHODS: Locally recruited men and women (n = 251) were genotyped for the A218C polymorphism located in intron 7 of the TPH gene. All subjects were administered standard interview and questionnaire indices of aggression and anger-related traits of personality; in a portion of subjects, CNS serotonergic activity was assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). RESULTS: Persons having any TPH U allele scored significantly higher on measures of aggression and tendency to experience unprovoked anger and were more likely to report expressing their anger outwardly than individuals homozygous for the alternate L allele. In men, but not women, peak prolactin response to fenfluramine was also attenuated among subjects having any U allele, relative to LL homozygotes. CONCLUSIONS: Individual differences in aggressive disposition are associated with an intronic polymorphism of the TPH gene in a nonpatient sample of community-derived volunteers.

Aggression↗

PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756.

NNC 756 ((+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine) is a new high affinity dopamine (DA) D1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotracer to visualize D1 receptors both in striatal and extrastriatal areas, such as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D1 receptor binding potential (BP) with [11C]NNC 756 in baboons, and to use these methods to assess the vulnerability of [11C]NNC 756 binding to competition by endogenous DA. A three-compartment model provided a good fit to PET data acquired following a single bolus injection. BP values obtained with this analysis were in good agreement with values derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n=2) were similar to values measured under control conditions. Kinetic parameters derived from single bolus experiments were used to design a bolus plus continuous infusion administration protocol aimed at achieving a state of sustained binding equilibrium. Injection of amphetamine during sustained equilibrium did not affect [11C]NNC 756 binding. Similar results were observed with another D1 radiotracer, [11C]SCH 23390. Doses of amphetamine used in this study are known to reduce by 20-40% the binding potential of several D2 receptors radiotracers. Therefore, the absence of displacement of [11C]NNC 756 by an endogenous DA surge may indicate important differences between D1 and D2 receptors in vivo, such as differences in proportion of high affinity states not occupied by DA at baseline. These findings may also imply that a simple binding competition model is inadequate to account for the effects of manipulation of endogenous DA levels on the in vivo binding of radiolabeled antagonists.

Amphetamine↗

Methodological considerations for the human platelet 5-HT2A receptor binding kinetic assay.

Analysis of an extensive database of human platelet 5-HT2A receptor binding assays has been conducted in order to identify factors that may affect the assay results. Despite anecdotal reports that storage of frozen platelet pellets may affect 5-HT2A binding affinity and capacity, no quantitative study has been reported in the literature. Analysis of binding data for 373 frozen samples with a storage time up to three years is presented in this paper. It is shown that prolonged storage significantly decreases binding. The loss of binding capacity begins in the first six month of storage. Bmax declines by half after 17 month. The impact of storage time on the binding affinity is much smaller. There is only about 20% increase in the value of affinity K(D) during the half-life of Bmax. Differences in sample storage time may partly explain discrepancies in results between different research groups. Nonspecific binding due to binding to filter material diminishes accuracy and reliability of the binding assays as a result of a decrease in the ratio of specific to nonspecific ratio. A data analysis based on our suggested mathematical model shows that this effect depends on tissue concentration in test tube and becomes pronounced when the concentration is below 0.1 mg protein/ml (at 0.2 nM of ligand). Above 0.1 mg protein/ml, percentage of specific to total binding exceeds 65%, which is an acceptable level for the ratio. The majority of the binding studies reported in the literature employed a tissue concentration more than 0.5 mg/ml, well above the minimal limit sufficient for a reliable assay. However, development of microassays to conserve precious tissue must take the limit into consideration.

Blood Platelets↗