of the original article: Aversive experiences have been thought to provoke or exacerbate clinical depression. The present review provides a brief survey of the stress-depression literature and suggests that the effects of stressful experiences on affective state may be related to depletion of several neurotransmitters, including norepinephrine, dopamine, and serotonin. A major element in determining the neurochemical changes is the organism's ability to cope with the aversive stimuli through behavioral means. Aversive experiences give rise to behavioral attempts to cope with the stressor, coupled with increased utilization and synthesis of brain amines to contend with environmental demands. When behavioral coping is possible, neurochemical systems are not overly taxed, and behavioral pathology will not ensue. However, when there can be no behavioral control over the stressful 368 THE BEHAVIORAL AND BRAIN SCIENCES (1985) 8:2 Continuing Commentary stimuli, or when the aversive experience is perceived as uncontrollable, increased emphasis is placed on coping through endogenous neuroehemical mechanisms. Amine utilization increases appreciably and may exceed synthesis, resulting in a net reduction of amine stores, which in turn promotes or exacerbates affective disorder. The process governing the depletions may be subject to sensitization or conditioning, such that exposure to traumatic experiences may have long-term repercussions when the organism subsequently encounters related stressful stimuli. With continued uncontrollable stimulation, adaptation occurs in the form of increased activity of synthetic enzymes, and levels of amines approach basal values. It is suggested that either the initial amine depletion provoked by aversive experiences or a dysfunction of the adaptive processes, resulting in persistent amine depletion, contributes to behavioral depression. Aside from the contribution of behavioral coping, several organismic, experiential, and environmental variables will influence the effects of aversive experiences on neuroehemical activity, and may thus influence vulnerability to depression. Learned helplessness, human depression, and perhaps endorphins?

Differentially expressed clones from subtracted cDNA libraries of a pair of monozygotic twins discordant for schizophrenia have been reported in the literature. The clones were expressed in lymphocytes from the healthy twin, but not from the schizophrenic twin. In the current study, we assessed the expression of one of these clones, oksc12b, in 10 normal controls and in 10 patients who met DSM-IV criteria for schizophrenia and had never received neuroleptic medication. We hypothesized that this clone would be differentially expressed in normal controls and in the schizophrenic patients, and that its expression could be a peripheral marker of the disease. Lymphocytes were isolated and total RNA was purified, reverse-transcribed, and quantified by two PCR methods. In the first PCR assay, oksc12b expression was measured relative to beta-actin gene expression. The second PCR assay consisted of a competitive procedure using a heterologous DNA internal standard. Neither method confirmed any difference in oksc12b expression between schizophrenic patients and normal controls. Subtypes of schizophrenia or the general heterogeneity of this syndrome may explain the discrepancy found. It is also possible that the differentially expressed clones are present in discordant monozygotic twins, but not in other patients.

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.

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.

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.

The role of the transcription factor AP-1 in regulating D2 receptor transcriptional activity was investigated in D2 receptor expressing neuroblastoma cells, NB41A3, and in non-D2 receptor expressing CHO cells. Deletion of a region containing the putative AP-1 binding site resulted in a significant reduction in the activity in CHO cells; while the activity in NB41A3 cells was increased suggesting that the AP-1 site may differentially regulate D2 gene expression in these distinct cell types. However, both cell lines were found to express significant and similar levels of the transcription factors AP-1. Analysis of phosphorylated proteins in each of the cell lines provided evidence that AP-1 is phosphorylated in NB41A3 cells, but not in CHO cells. This result suggests that differential regulation of D2 gene expression may be related to AP-1 phosphorylation.

Background: Neuroleptics are considered the mainstay of treatment in Tourette's disorder, and haloperidol is deemed the treatment of choice by many. Factors such as treatment efficacy and the side effects that appear in response to neuroleptic administration have been implicated in affecting medication compliance. However, a detailed evaluation of these factors has yet to be undertaken in Tourette's disorder.Method: Of 51 consecutive referrals to a Tourette's disorder clinic, 48 met DSM-III-R criteria for Tourette's disorder. Of these 48, 28 had previously received neuroleptics. In this set of 28 patients, 24 (16 male, 8 female) had initially received treatment with haloperidol, and they made up the present sample; their ages ranged from 10.4 to 47.9 years (mean = 27.1), and age at onset ranged from 2 to 16 years. Each patient completed an evaluation consisting of a Tourette Syndrome Questionnaire and a clinical interview with the patient and involved family members. Charts were also reviewed to gather information concerning side effects and other factors that led to haloperidol discontinuation and/or noncompliance.Results: Duration of treatment ranged from 3 days to 14 years (mean = 3.6 years). In this sample, 12.5% (3/24) of the subjects continued medication without interruption (mean +/- SD = 8.4 +/- 5.1 years of medication). Of the 21 patients who discontinued haloperidol, 66.7% (14/21) did so because they experienced intolerable side effects, 9.5% (2/21) because the medication became ineffective, 9.5% (2/21) because of the fear of experiencing certain side effects, and 14.3% (3/21) because of a combination of these factors. The principal side effects that led to discontinuation included dysphoric reactions, akathisia, nervousness, sedation, dystonic reactions, and cognitive dulling/feeling drugged.Conclusion: Careful monitoring of side effects and efficacy is essential to continued compliance with haloperidol. In addition, psychoeducation about potential consequences of medication administration may help promote compliance in those patients who develop fears of possible adverse reactions.

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 purpose of this paper is to assess how 29 different environmental factors affected Tourette symptomatology in 14 children and adolescents (6.6-14.5 years; mean 10.3) who had never received any medication for their disorder. Assessment was based on patients' responses to the Tourette Syndrome (TS) Questionnaire. Eleven different factors were associated with a decrease in symptoms and included doctor visits, talking to friends, and reading for pleasure. The 10 factors reported to have no impact on Tourette symptomatology included various foods, weather, and living away from home. Seventeen factors associated with an increase in Tourette symptoms included events causing anxiety, emotional trauma, and social gatherings.

Plasma homovanillic acid concentration was assessed in 60 young schizophrenic patients, with and without first-degree relatives with schizophrenia, before treatment, and 3 days after starting haloperidol treatment. The baseline concentration of homovanillic acid in plasma was no different in the two groups before treatment; it was, however, significantly higher in the patients with relatives than in those without relatives diagnosed of schizophrenia after 3 days of haloperidol treatment.

Rates of spontaneous and drug-induced repetitive jaw movements (RJM) in rats vary widely. Low and high RJM responders were isolated and genetically selected. At each generation mean RJM responses (spontaneous or SKF 38393-induced) of the two types of rats were found to differ significantly, whereas neither apomorphine-induced stereotypic responses nor D1 and D2 receptor numbers and affinities differed. A significant increase in cAMP production was evident in SKF 38393-stimulated striatal homogenates of high RJM responders as compared with low responders. Animals subjected to 8-months exposure to fluphenazine exhibited RJM that were about twice as great as that of controls, 2 months after the last treatment, with a prevalence of about 75%. Similarities between RJM observed in rats and neuroleptic-induced tardive dyskinesia suggest that the two are strongly related.

Plasma dihydroxyphenylacetic acid (pDOPAC) was determined in 48 young patients with schizophrenia before and during four weeks of treatment with haloperidol. We have not observed any clear effects of haloperidol on the levels of pDOPAC. We did not find any correlation between basal values of DOPAC or changes in the concentrations of DOPAC and clinical outcome.

Naturalistic and laboratory stress has been shown to lead to alterations in plasma cortisol, norepinephrine (NE), and negative emotion, and it has been suggested that dysfunctional attitudes (i.e., rigid, distorted, peffectionistic cognitions) limit an individual's ability to respond to stress adaptively. Stress-induced alterations in plasma glucocorticoids are thought to buffer the effects of stress. The present study then, was designed to examine the relationship between dysfunctional attitudes, and stress-induced alterations in plasma cortisol, NE, and emotion. Subjects: 28 females were divided into 3 groups: controls (n-10); depression in remission subjects (n-9); and actively depressed subjects (n,,,9), ages ranged from 20 to 41 (mean, 27), all healthy and medication free for at least 2 weeks. Methods: Subjects completed the Dysfunctional Attitudes Scale (DAS), re. ceived a physical examination and laboratory workup, and were diagnosed using the SCID. Subjects were then exposed to an induced-failure stressor. Blood samples and mood ratings were obtained at baseline, during stress exposure, and 40 minutes later. Plasma was analyzed for cortisol and NE by HPLC. Statistics: Change in plasma NE, conisol, and emotion were assessed using MANOVA. Relationships between the DAS and stress-induced changes in cortisol, NE, and emotion were assessed using partial correlations. Result: I) induced.failure stress led to a significant increase in both plasma NE and negative emotion during stress egposure. A significant decrease in cortisol was observed 40 minutes after egposure; 2) Dysfunctional attitudes were significantly and negatively correlated with plasma cortisol and significantly and positively correlated with negative emotion during stress exposure. Dysfunctional attitudes were significantly and positively correlated with plasma NE 40 minutes after stress exposure. The data support the concept that dysfunctional attitudes play a role in shaping stress-induced alterations in biochemistry and emotion.

In an investigation of cation transport in bipolar affective disorder, we have measmed parameters related to Na,K-ATPase, the enzyme that carties out active transport of sodium and potassium, in lymphoblastoid cells cultured from patients with bipolar affective disorder, age-matched nonaffected family relatives, and unrelated controls. Patients and their relafives were from well.characterized pedigrees of Old Order Amish. The use of iymphoblastoid cell lines largely eliminated possible effects of factom such as clinical state or recent drug treatment. Patients had lower ion mmsport per cell (271:1:40 pmol/10 e cells-min for patients vs 490 + 107 for related controls and 396 + 79 for unrelated controls; pc 0.001 by Kmskal-Wallis test) and per mmsport enzyme site (reduced by about 35% in patients, pc 0.02) than did related or unrelated controls. These data suggest that abnormally regulated ion transport may be associated with bipolar affective disorder independently of clinical state.