Cognitive factors and stress-induced changes in catecholamine biochemistry.

The purpose of the present research was to determine whether dysfunctional attitudes, a cognitive attribute, predicted changes in catecholamine biochemistry. A cognitive task was used to induce stress in female subjects (n=21), and levels of plasma norepinephrine (NE) and homovanillic acid (HVA) were measured at three time points: at baseline (T1); immediately after stress exposure (T2); and 40 min later (T3). Dysfunctional attitudes were significantly and positively related to levels of plasma NE at T3, controlling for baseline levels. Dysfunctional attitudes were not significantly related to plasma HVA levels at any time point. Our findings provide initial support for the idea that dysfunctional attitudes, an attribute shown to play an important role in some forms of unipolar depression, predict stress-induced alterations in noradrenergic output.

Effects of repeated amphetamine treatment on regional GABAA receptor binding.

The present study examined the effects of repeated exposure to amphetamine on GABAA receptor binding in cortical and subcortical areas. The goal of the study was to determine whether changes in specific binding were related to behavioral sensitization. Animals were exposed to either saline (0.3 ml, s.c.; n=12) or d-amphetamine (2.5 mg/kg, s.c.; n=12) for 6 consecutive days and sacrificed after a 14-day withdrawal period. Differences in GABAA receptor binding in these two groups of animals were assessed using the GABAA receptor antagonist [3H]SR 95531. To verify that the preceding treatment regimen led to the development of behavioral sensitization, a separate set of animals (n=8/group) was exposed to the same regimen and challenged with d-amphetamine (2.5 mg/kg, s.c.) after the 14-day withdrawal period. As expected, preexposure to amphetamine led to the development of amphetamine sensitization. There were no differences in GABAA receptor binding in animals preexposed to saline and amphetamine in the prefrontal cortex, caudate-putamen, hypothalamus, or cerebellum. These findings do not provide support for the idea that changes in GABAA receptor binding in the medial prefrontal cortex or various subcortical areas are related to the development of behavioral sensitization.

Vulnerability to stress: self-criticism and stress-induced changes in biochemistry.

It has been hypothesized that individuals who are high on the attribute of self-criticism are particularly vulnerable to failure stress. To test this hypothesis, we examined the relationship between self-criticism and changes in plasma homovanillic acid (HVA; the metabolite of dopamine) and emotion during exposure to an induced-failure task. Participants consisted of 21 women. Plasma HVA and emotion were assessed at three time points: baseline (T1), during stress exposure (T2), and 40 minutes after cessation of the stressor (T3). We found that self-criticism was significantly and positively related to changes in plasma HVA during stress exposure. In addition, the personality attribute was significantly and positively related to subjective ratings of stress and changes in scores on the Confusion-Bewilderment scale of the Profile of Mood States during the task. To our knowledge, this is the first study to report that self-criticism is related to stress-induced changes in biochemistry.

Novelty-associated locomotion: correlation with cortical and sub-cortical GABAA receptor binding.

The present study was designed to determine whether variability in GABA (eta-aminobutyric acid)A receptor binding in cortical and subcortical brain regions was correlated with locomotor activity in a novel environment. Twenty four animals were rated for locomotor activity in a novel circular runway. Eight days later, locomotor activity was assessed following 1.5 mg/kg amphetamine sulfate (i.p.). After four to six days, animals were killed and samples were pooled in groups of four animals ranked according to novely locomotor score, and specific binding of the GABAA receptor antagonist [2-(3'-carboxy-2'-propyl)-3-amino-6-p-methoxy phenylpyridazinium bromide] ([3H]SR95531) was determined. Significant negative correlations were seen between specific ([3H]SR95531) binding and novelty induced locomotion in the cingulate and prefrontal cortices, and in the ventral pallidum. A near-significant negative correlation was seen in the striatum. Correlation coefficients between locomotion scores in the novel environment and specific [3H]SR95531 binding were: cingulate cortex, R = -0.91, P = 0.012; prefrontal cortex, R = -0.85, P = 0.032; ventral pallidum, R = -0.85, P = 0.030; striatum, R = -0.73, P = 0.097; and nucleus accumbens, R = -0.09, P = 0.85. The positive correlation between novelty- and amphetamine-induced locomotion was also quite high (R = 0.95, P = 0.004). These results are discussed in terms of their relevance to potential biochemical correlates of drug abuse vulnerability.

Functional outcome of patients with unstable pelvic ring fractures stabilized with open reduction and internal fixation.

An unstable pelvic ring fracture represents a severe injury and is associated with high morbidity and mortality. Little data are available assessing the long-term functional limitations, including disability, in a patient with an unstable pelvic ring fracture. The purpose of this study was to describe the impairment and functional outcome (disability) for patients with unstable pelvic ring fractures managed with open reduction and internal fixation (ORIF). Disability was measured at a minimum of 1 year postinjury using the Sickness Impact Profile (SIP), a measure of the health-related quality of life as perceived by the patient. Of the 230 consecutive patients with a pelvic ring fracture, 54 had unstable fractures requiring ORIF; 48 patients were available at a 1 year follow-up. The follow-up roentgenograms confirmed an osseous union and an anatomic alignment of the pelvis. Thirty-seven (77%) of the patients had mild disability (total SIP < 10); 11 (23%) of the patients had moderate disability (SIP > 10) at 1 year. Of the patients who were employed preinjury, 76% were employed 1 year postinjury; 62% had returned to full time work and 14% had returned with job modification. Of the 7 patients who had been in school, 6 had returned full time and 1 student returned part time. Mean SIP scores for subcategories were: physical health = 6.8 +/- 9.4, psychosocial health = 7.4 +/- 12.7, work = 17.6 +/- 25.5, home management = 8.3 +/- 13.0, ambulation = 10.7 +/- 13.7, and mobility = 5.3 +/- 13.0. Despite the magnitude of the bony injuries, the majority of patients with unstable pelvic ring fractures managed with ORIF had mild disability 1 year postinjury; the majority of the patients had returned to work.

Alterations in GABAA receptor binding in the prefrontal cortex following exposure to chronic stress.

The present study was designed to examine the effects of chronic stress on GABAA receptor binding. Animals were randomly assigned to either a control, acute, or chronic stress condition and changes in specific binding were assessed using the GABAA receptor antagonist [3H]SR 95531. Exposure to chronic restraint stress led to a significant reduction in GABAA receptor binding in the prefrontal cortex. Alterations in specific binding were not observed in the cerebellum, caudate-putamen, hippocampus, or cingulate cortex however, suggesting that the effects of chronic stress may be regionally specific. Exposure to acute restraint did not lead to a significant alteration in [3H]SR 95531 binding in any brain region examined.

The diagnosis of deep vein thrombosis in the multiply injured patient with pelvic ring or acetabular fractures.

Thirty-one patients with unstable displaced pelvic or acetabular fractures were admitted and underwent an open reduction and internal fixation of their fracture. All patients were studied prospectively for the incidence of proximal deep vein thrombosis (DVT) utilizing venous duplex ultrasound. Duplex scans were repeated at 1 week postoperatively in all patients. Additional scans were performed when clinically indicated. A total of 61 scans were completed. DVT developed in three patients (approximately 10%). Two of the three positive scans were noted only on postoperative examination. The third scan was positive on the preoperative phase. Duplex ultrasound was easily applied and well tolerated by the multiply injured patient.

The acute management of hemodynamically unstable multiple trauma patients with pelvic ring fractures.

The management of hemodynamically unstable patients with displaced pelvic ring fractures and associated abdominal, thoracic, or head injuries is controversial. We studied 312 consecutive trauma patients with pelvic fractures admitted from July 1, 1989 through June 30, 1993: thirty-six of these patients were in shock (SBP < or = 90 mm Hg) and were treated by a protocol including volume resuscitation, and treatment of the associated injuries, without use of acute external fixation. Evaluation of the pelvic fractures revealed 39% to be rotationally unstable; 61% were both rotationally and vertically unstable. The mean injury Severity Score was 27 +/- 12, the average Glasgow Coma Scale score was 12 +/- 5, and the Abbreviated Injury Scale (AIS) scores stratified for the abdomen and the thorax were 1.9 +/- 1.7 and 1.6 +/- 1.8, respectively. Eighteen patients required thoracotomy, laparotomy, or both. The total blood requirement in the initial 24 hours postinjury was 4.0 +/- 4 Units. Deaths of four patients (11%) were a function of associated injuries and comorbid factors, not the result of uncontrolled pelvic hemorrhage. The data suggest that aggressive resuscitation of these patients and treatment of extrapelvic injuries in conjunction with early or delayed ORIF, without application of acute external fixation, resulted in a low overall mortality rate.

Tonic inhibition of striatal dopamine transmission: effects of benzodiazepine and GABAA receptor antagonists on extracellular dopamine levels.

At present, it is unclear whether ligands which bind at the benzodiazepine/GABA receptor complex play a tonic modulatory role with regard to striatal dopamine (DA) transmission. The present study was designed to examine the effects of Ro15-1788, a benzodiazepine (BZ) receptor antagonist, and SR 95531, a GABAA receptor antagonist, on striatal extracellular DA (DA[e]) concentrations in anesthetized and awake rats using the technique of in vivo microdialysis. Local administration of Ro15-1788 resulted in a dose-dependent increase in DA[e] in both anesthetized and awake animals. The Ro15-1788-induced increase in DA[e] was blocked by coadministration of the BZ agonist diazepam, as well as GABA. Local administration of SR 95531 also resulted in a dose-dependent alteration in striatal DA levels in both anesthetized and awake animals. The SR 95531-induced increase in DA was blocked by coadministration of GABA. The results suggest that GABA may play a tonic inhibitory role with regard to striatal DA transmission.

Individual differences in behavioral measures: correlations with nucleus accumbens dopamine measured by microdialysis.

Rats were placed in one of two novel test environments for behavioral observation. In one, exploratory behavior (assessed by hole pokes) and locomotion were assessed during a 10-min test session. In the other, the chewing of varied objects on the cage floor was rated over a 20-min session. Within 2-18 days, animals were anesthetized and microdialysis probes were implanted into the nucleus accumbens for measurement of basal and d-amphetamine-stimulated levels of dopamine (DA). These measures were then correlated with the individual behavioral rating collected earlier from the drug-free animals. We found a significant correlation between duration of exploratory behavior and amphetamine-induced DA release. Locomotor activity did not correlated with either basal or amphetamine-stimulated DA release. Duration of chewing episodes correlated with basal levels of DA, as well as with amphetamine-induced DA release. Our studies indicate that differences in the dopaminergic responsivity of the nucleus accumbens (or other circuitry influencing nucleus accumbens DA function) may contribute to individual differences in certain behaviors displayed by the animals when placed in a novel environment.

Do endogenous excitatory amino acids influence striatal dopamine release?

In vivo microdialysis techniques were used to examine whether endogenous excitatory amino acids exert a tonic facilitatory influence on striatal dopamine release. Local application of NMDA and non-NMDA antagonists at 10 microM was without an effect on basal dopamine release while 100 microM and 1 mM of these drugs significantly enhanced the release. Our findings do not support the idea that excitatory amino acids have a tonic excitatory effect on striatal dopamine release.

Effect of L-glutamate on the release of striatal dopamine: in vivo dialysis and electrochemical studies.

Microdialysis and in vivo voltammetry combined with K(+)-selective microelectrodes were utilized to study the effect of L-glutamate (GLU) on the in vivo release of dopamine (DA) from the rat striatum. Perfusion of 500 nM-5 mM GLU through the microdialysis probe was without an effect on DA outflow whereas 10 mM GLU resulted in a significant (295%) increase in the basal level of DA. This increase was blocked in the presence of 2-amino-5-phosphonopentanoic acid, an N-Methyl-D-aspartate (NMDA) receptor antagonist. Repetitive local applications of 10 mM GLU were also required to observe an increase in extracellular DA measured by in vivo voltammetry. These signals were accompanied with a massive increase in extracellular K+ and a large negative shift in the field potential resembling the ionic changes seen after the phenomenon spreading depression. These studies suggest that high concentrations of GLU are required to enhance the extracellular concentration of DA in vivo. Further, pathophysiological conditions such as spreading depression may be responsible for the observed increase in extracellular DA concentration.

Perinatal diazepam exposure: alterations in exploratory behavior and mesolimbic dopamine turnover.

Perinatal exposure to diazepam has been shown to lead to alterations in motor activity and exploratory behavior in neonatal animals. Exploratory and locomotor behavior have been associated with changes in mesotelencephalic dopamine function. We have therefore examined the effects of perinatal diazepam administration on both exploratory behavior and mesotelencephalic dopamine turnover in the adult rat. Animals exposed to the benzodiazepine during the perinatal period engaged in significantly less exploratory behavior than did control subjects. The diazepam-induced alterations in behavior were developmentally specific: decreased exploratory behavior was observed at 90, but not 60, days of age. At 90 days of age, specific changes in dopamine turnover in diazepam-treated animals were restricted to mesolimbic (nucleus accumbens and ventral tegmental area) sites; alterations in dopamine turnover were not seen in other mesotelencephalic sites examined. The findings indicate that perinatal exposure to benzodiazepines leads to behavioral changes that are present in adulthood. These changes in exploratory behavior may be associated with alterations in mesolimbic dopamine function.

Regionally specific alterations in the low-affinity GABAA receptor following perinatal exposure to diazepam.

Alterations in a low affinity form of the GABAA receptor were examined with [3H]bicuculline methylchloride in the adult rat following perinatal exposure to diazepam. Perinatal exposure resulted in a significant reduction in [3H]bicuculline binding in the cingulate cortex. A significant decrease in the ability of GABA to displace bound [3H]bicuculline was observed only in the hypothalamus. The results suggest that the effects of perinatal exposure to diazepam are regionally specific and that benzodiazepine receptors and low affinity GABAA receptors are functionally linked during the perinatal period.

The effects of perinatal diazepam exposure on stress-induced activation of the mesotelencephalic dopamine system.

The effects of perinatal diazepam exposure of rats on stress-induced metabolic activation of the mesotelencephalic dopamine (DA) system were examined. Footshock stress parameters were selected such that DA turnover was increased in the prefrontal cortex and certain mesolimbic dopaminergic regions; a stress-induced activation of striatum was not observed. Perinatal treatment with the anxiolytic benzodiazepine diazepam (days E8 through the first week after gestation) did not alter basal dopamine turnover in the prefrontal cortex or striatum, or in any of the mesolimbic sites examined except for the nucleus accumbens and ventral tegmental area (in which turnover was decreased). However, perinatal exposure to diazepam significantly reduced the magnitude of the stress-elicited increase in prefrontal cortical dopamine turnover, and conversely resulted in a stress-induced enhancement of turnover in the striatum. These data suggest that although perinatal exposure to diazepam may alter basal dopaminergic function in some regions, certain enduring changes in dopamine function in other mesotelencephalic DA sites are revealed only under conditions that result in perturbation of central dopamine neurons, such as environmental stress. These data also suggest that perinatal benzodiazepine exposure may be reflected in the adult in a decreased ability to cope with stress.

Centrality and individual differences in the meaning of daily hassles.

In this study we introduce the concept of centrality in an attempt to assess individual differences in the meaning underlying daily hassles. Central hassles are defined as those which reflect important ongoing themes or problems in the person's life. The characteristics of central hassles, and their role in psychological and somatic health, were assessed in a sample of 150 community-residing men and women. The results indicate that central hassles vary in content from person to person and touch more on problems with personal needs and deficits in coping skills compared to noncentral hassles. The dimension of centrality was found to play a significant role in the prediction of psychological symptoms. Although the empirical case for the importance of centrality in the stress-illness relationship is inconclusive due to problems of confounding and a cross-sectional rather than longitudinal design, the ideas presented appear promising and provide a basis for further research on psychological vulnerability to stress.

Dynamics of a stressful encounter: cognitive appraisal, coping, and encounter outcomes.

Despite the importance that is attributed to coping as a factor in psychological and somatic health outcomes, little is known about actual coping processes, the variables that influence them, and their relation to the outcomes of the stressful encounters people experience in their day-to-day lives. This study uses an intraindividual analysis of the interrelations among primary appraisal (what was at stake in the encounter), secondary appraisal (coping options), eight forms of problem- and emotion-focused coping, and encounter outcomes in a sample of community-residing adults. Coping was strongly related to cognitive appraisal; the forms of coping that were used varied depending on what was at stake and the options for coping. Coping was also differentially related to satisfactory and unsatisfactory encounter outcomes. The findings clarify the functional relations among appraisal and coping variables and the outcomes of stressful encounters.

Appraisal, coping, health status, and psychological symptoms.

In this study we examined the relation between personality factors (mastery and interpersonal trust), primary appraisal (the stakes a person has in a stressful encounter), secondary appraisal (options for coping), eight forms of problem- and emotion-focused coping, and somatic health status and psychological symptoms in a sample of 150 community-residing adults. Appraisal and coping processes should be characterized by a moderate degree of stability across stressful encounters for them to have an effect on somatic health status and psychological symptoms. These processes were assessed in five different stressful situations that subjects experienced in their day-to-day lives. Certain processes (e.g., secondary appraisal) were highly variable, whereas others (e.g., emotion-focused forms of coping) were moderately stable. We entered mastery and interpersonal trust, and primary appraisal and coping variables (aggregated over five occasions), into regression analyses of somatic health status and psychological symptoms. The variables did not explain a significant amount of the variance in somatic health status, but they did explain a significant amount of the variance in psychological symptoms. The pattern of relations indicated that certain variables were positively associated and others negatively associated with symptoms.