Gene expression profiling in the hippocampus of learned helpless and nonhelpless rats.

In the learned helplessness (LH) animal model of depression, failure to attempt escape from avoidable environmental stress, LH, indicates behavioral despair, whereas nonhelpless (NH) behavior reflects behavioral resilience to the effects of environmental stress. Comparing hippocampal gene expression with large-scale oligonucleotide microarrays, we found that stress-resilient (NH) rats, although behaviorally indistinguishable from controls, showed a distinct gene expression profile compared to LH, sham stressed, and naïve control animals. Genes that were confirmed as differentially expressed in the NH group by quantitative PCR strongly correlated in their levels of expression across all four animal groups. Differential expression could not be confirmed at the protein level. We identified several shared degenerate sequence motifs in the 3' untranslated region (3'UTR) of differentially expressed genes that could be a factor in this tight correlation of expression levels among differentially expressed genes.

Cloning, expression, and regulation of a glucocorticoid-induced receptor in rat brain: effect of repetitive amphetamine.

Behavioral sensitization to psychostimulants involves neuroadaptation of stress-responsive systems. We have identified and sequenced a glucocorticoid-induced receptor (GIR) cDNA from rat prefrontal cortex. The full-length GIR cDNA encodes a 422 amino acid protein belonging to G-protein-coupled receptor superfamily. Although the ligand for GIR is still unknown, the dendrogram construction indicates that GIR may belong to peptide receptor subfamily (e.g., substance P receptor), with more distant relationship to subfamilies of glycoprotein hormone receptors (e.g., thyrotropin receptor) and biogenic amine receptors (e.g., dopamine receptor). GIR shares 31-34% amino acid identity to the tachykinin receptors (substance P receptor, neurokinin A receptor, and neurokinin B receptor). GIR mRNA is expressed preferentially in brain, and its neuronal expression is relegated to limbic brain regions, particularly in forebrain. GIR transcript levels are increased significantly and persistently in prefrontal cortex for 7 d after discontinuation of chronic amphetamine exposure. The induction of GIR expression by amphetamine is associated with augmented behavioral activation. These findings suggest that modulation of GIR expression may be involved in behavioral sensitization, and GIR may play a role at the interface between stress and neuroadaptation to psychostimulants.

Olanzapine treatment for post-traumatic stress disorder: an open-label study.

Post-traumatic stress disorder (PTSD) is a common and increasingly diagnosed mental illness. Recent pharmacotherapeutic research on treatments for this condition has focused on antidepressant drugs with serotonergic actions. However, the presence of intrusive, psychotic-like symptoms in a substantial portion of PTSD patients raises the possibility that antipsychotics with serotonergic properties might also prove useful in treating PTSD. We conducted an open-label 8-week study of olanzapine treatment in veterans with combat-induced PTSD. Primary outcome measures in this study were the Clinician Administered PTSD Scale (CAPS) and the Clinical Global Impressions Improvement scale. Secondary outcome measures included the Hamilton Rating Scales for Depression (HRSD) and Anxiety (HRSA). Forty-eight patients enrolled in the study, and 30 completed the 8-week trial. Results of intent-to-treat and completer analyses demonstrated that all outcome measures improved significantly during treatment. Secondary analyses indicate that improvement in the intrusive symptom cluster of the CAPS was independent of improvement on the HRSD and HRSA. In conclusion, the study indicates that olanzapine treatment is useful in alleviating the symptoms of combat-induced PTSD.

The influence of gender and the estrous cycle on learned helplessness in the rat.

Although the etiology of clinical depression is unknown, women are more likely to suffer from major depressive disorder than men. In addition, in some women, there is a clear association between depression and specific phases of the menstrual cycle. Surprisingly little research has examined gender differences and the influences of the estrous cycle in this and other animal behavioral models of clinical depression. Learned helplessness is a valid animal model of stress-induced behavioral depression in which prior exposure to inescapable stress produces deficits in escape testing. Learned helplessness was studied in rats using an inescapable tail shock stress followed by a shuttle box test to determine escape latencies. Animals with mean escape latencies of >or=20 s after shuttle-box testing are defined as learned helpless. Males and normal cycling female rats in the estrus and diestrus II phases were studied. Female rats in the diestrus II phase had significantly higher escape latencies and exhibited a more helpless behavior than female rats in the estrus phase. Male rat escape latencies were intermediate between the two female phases. These results suggest a role for gonadal hormones in the development of stress-induced behavioral depression or 'learned helplessness.'

Use of structural equation modeling to test the construct validity of a case definition of Gulf War syndrome: invariance over developmental and validation samples, service branches and publicity.

To attempt to replicate the syndrome-like structure identified by exploratory factor analysis of symptom reports from 249 Gulf War veterans of a Naval reserve battalion (the developmental sample), we administered Haley's original symptom questionnaire to 335 Gulf War veterans who served primarily in active-duty US Army units living in North Texas (the validation sample). On the basis of recently validated goodness-of-fit criteria (SRMRor=0.95), a structural equation model (Model 1) with four symptom scales loading on each of three first-order latent syndrome factors fit both the developmental and validation samples well and was invariant across both samples. Additional models validated a higher-order latent factor (a single Gulf War syndrome) explaining the variances and covariances of the first-order factors, four additional symptom scales loading on the higher-order factor, and four possible secondary factor loadings that also fit the data well. All structural models were invariant across cohorts of the validation sample surveyed before and after intense publicity following publication of the case definition. These findings suggest that the apparent syndrome structure of a single Gulf War syndrome with three variants may be found widely and justify a confirmatory sample survey of Gulf War-era veterans.

Plasma GABA levels correlate with aggressiveness in relatives of patients with unipolar depressive disorder.

Plasma gamma-aminobutyric acid (GABA) levels are decreased in some patients with depression, mania and alcoholism. Medications which increase plasma GABA improve symptoms of mood disorders and can decrease aggression. We examined the relationship between plasma GABA and aggressiveness on the Buss-Durkee Hostility Inventory in 77 psychiatrically healthy adults. In subjects selected for having a first-degree relative with primary unipolar depressive disorder (FH+, n=33), plasma GABA was negatively correlated with aggressiveness (beta=-0.338, P=0.036), as was age (beta=-0.483, P=0.005). A relationship between plasma GABA levels and aggressiveness was not observed in subjects with no such family history (FH-, n=44). Moreover, FH+ subjects had significantly lower plasma GABA concentrations than FH- subjects. These data suggest that low GABA levels may correlate with some aspects of aggressiveness and may be genetically regulated.

Activation of skeletal muscle afferents evokes release of glutamate in the subretrofacial nucleus (SRF) of cats.

The subretrofacial nucleus (SRF) is a region of the rostral ventrolateral medulla known to play a crucial role in sympathoexcitation. SRF neurons send direct projections to the intermediolateral cell columns of the spinal cord where they form synaptic contact with preganglionic sympathetic motor neurons. Activation of this neural pathway increases sympathetic outflow to the heart and blood vessels affecting cardiac function and vasomotor tone. Previous studies utilizing electrophysiological recording techniques and c-Fos expression have established that the activity of SRF neurons is increased during skeletal muscle contraction. However, the excitatory neurotransmitter mediating this increased activity remains in question. In the present study, static contraction of the triceps surae was induced by electrical stimulation of L7 and S1 ventral roots in anesthetized cats (n=12). Endogenous release of glutamate (Glu) from the SRF was recovered by microdialysis and measured by HPLC. Static muscle contraction for 4 min increased mean arterial pressure (MAP) 38+/-4 mmHg from a control level of 102+/-12 mmHg (P< 0.05). During muscle contraction the extracellular concentration of Glu recovered from the SRF increased from 623+/-117 to 1078+/-187 nM (P<0.05). To determine the effect of muscle contraction on Glu release in the absence of synaptic input from other reflexogenic areas, contraction was repeated following acute sinoaortic denervation and vagotomy. Following this denervation, muscle contraction increased MAP 41+/- 4 mmHg (P < 0.05) and Glu concentration from 635+/-246 to 1106+/-389 nM (P < 0.05). Muscle paralysis prevented the increases in MAP and Glu concentration during ventral root stimulation. These results suggest that: (i) Glu is released in the SRF during activation of contraction-sensitive skeletal muscle afferent fibers in the cat; and (ii) synaptic input from other reflexogenic areas appears to be ineffective in modulating the release of Glu in the SRF during static muscle contraction.

Structure of mania: depressive, irritable, and psychotic clusters with different retrospectively-assessed course patterns of illness in randomized clinical trial participants.

BACKGROUND: We investigated the structure of manic episodes by determining whether there was evidence for distinct groups of patients differing in clinical characteristics and course of illness. METHODS: The subjects were 162 patients hospitalized for manic episodes who underwent comprehensive evaluations of behavior, symptoms, and history before a treatment study. Pretreatment behavior ratings (Schedule for Affective Disorders and Schizophrenia, rated by clinicians, and Affective Disorder Rating Scale, rated by nurses) entered a principal components factor analysis, followed by a cluster analysis of the subjects based on their factor scores. Members of the resulting clusters were compared with respect to clinical characteristics and history of illness. RESULTS: The six factors were impulsivity, hyperactivity, anxious pessimism, distressed appearance, hostility, and psychosis. The four clusters were characterized as depressive, with high anxious pessimism (n=22), delusional, with high psychosis (n=39), classic (n=72), and irritable, with high distressed appearance and hostility (n=29). Depressive manics had the earliest onset of illness and the highest density of episodes/year, while irritable manics had later onset and the fewest previous episodes. LIMITATIONS: The number of subjects was smaller than ideal for multivariate analysis, subjects were limited to those able to consent and meet criteria for a randomized clinical trial, and course of illness was determined retrospectively. CONCLUSIONS: Manic episodes have a dimensional structure but appear to fall naturalistically into types that differ with respect to previous history, symptoms, and clinical characteristics. Whether these are distinct clinical subtypes will require further research.

Pharmacotherapy for post-traumatic stress disorder: a comprehensive review.

Significant advances have been made in the past 5 years in defining efficacious treatments for post-traumatic stress disorder (PTSD). Currently, sertraline is the first and only FDA-approved medication for this complex and often chronic illness. Other serotonergic antidepressants, such as paroxetine, fluoxetine and nefazodone, have well-controlled or replicated open-label evidence of efficacy. Anticonvulsants are also being studied as potential alternatives to treatment. Finally, atypical antipsychotic medications have shown promise in open-label trials. Clearly, more controlled studies are needed. This is especially true in males and in combat trauma-induced PTSD, where the effects of pharmacotherapy are less robust than in females or civilian trauma-induced PTSD. Also, there are virtually no data on pharmacotherapy for acute stress reaction or for PTSD in children. Future directions for research may focus on combination treatment in the more treatment-resistant patient populations.

Effect of basal ganglia injury on central dopamine activity in Gulf War syndrome: correlation of proton magnetic resonance spectroscopy and plasma homovanillic acid levels.

BACKGROUND: Many complaints of Gulf War veterans are compatible with a neurologic illness involving the basal ganglia. METHODS: In 12 veterans with Haley Gulf War syndrome 2 and in 15 healthy control veterans of similar age, sex, and educational level, we assessed functioning neuronal mass in both basal ganglia by measuring the ratio of N-acetyl-aspartate to creatine with proton magnetic resonance spectroscopy. Central dopamine activity was assessed by measuring the ratio of plasma homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenlyglycol (MHPG). RESULTS: The logarithm of the age-standardized HVA/MHPG ratio was inversely associated with functioning neuronal mass in the left basal ganglia (R(2) = 0.56; F(1,27) = 33.82; P<.001) but not with that in the right (R(2) = 0. 04; F(1,26) = 1.09; P =.30). Controlling for age, renal clearances of creatinine and weak organic anions, handedness, and smoking did not substantially alter the associations. CONCLUSIONS: The reduction in functioning neuronal mass in the left basal ganglia of these veterans with Gulf War syndrome seems to have altered central dopamine production in a lateralized pattern. This finding supports the theory that Gulf War syndrome is a neurologic illness, in part related to injury to dopaminergic neurons in the basal ganglia.

Effects of learned helplessness on brain GABA receptors.

GABA is involved in both clinical depression and in animal models of depression; however, the roles of GABA(A) and GABA(B) receptors in specific brain regions are not clear. Changes in densities of both GABA(A) and GABA(B) receptors have been reported with the learned helplessness animal model of depression and with chronic antidepressant drug treatment. However, some of these findings are discrepant. Thus, we used quantitative autoradiography to study the GABA(A) and GABA(B) receptors in learned helplessness and we used an experimental paradigm that allows non-specific effects of stress to be differentiated from learned helplessness. Densities of GABA binding were measured in prefrontal cortex, septum, hippocampus, hypothalamus and amygdala. In the septum, learned helpless rats had increased densities of GABA(A) receptors and rats that did not become helpless after inescapable stress had decreased GABA(B) receptor densities. No significant group differences of GABA(A) or GABA(B) receptor densities were observed in any other brain region studied. These results suggest a unique role for the septum in modulating GABA in the learned helplessness animal model of depression.

Posttraumatic stress disorder, dissociation, and trauma exposure in depressed and nondepressed veterans.

Increasing evidence indicates that exposure to traumatic events predisposes individuals to depressive symptoms as well as to emotional and psychophysiological symptoms covered under the diagnostic criteria of posttraumatic stress disorder (PTSD). Trauma exposure history and PTSD symptoms would, therefore, be expected to be more common in a depressed population than in a nondepressed group. To examine the association between trauma exposure (trauma load), dissociation, and depression, we administered clinical interviews and an assessment package derived from existing instruments (including the Dissociative Experiences Scale; DES) to 101 veteran patients with histories of clinically significant depression and a comparison group of 49 medical patients with no history of depression. The depression group had experienced significantly higher numbers of traumatic incidents, had higher average DES scores, and more frequently met diagnostic criteria for PTSD. The findings support the argument for a causal or predisposing effect of trauma in the expression of clinically significant depression.

Brain abnormalities in Gulf War syndrome: evaluation with 1H MR spectroscopy.

PURPOSE: To test for neuronal brain damage in the basal ganglia and brainstem in Gulf War veterans by using magnetic resonance (MR) spectroscopy. MATERIALS AND METHODS: Twenty-two Gulf War veterans with one of three factor analysis-derived syndromes (case patients); 18 well veterans matched for age, sex, and education level (control subjects); and six Gulf War veterans with syndrome 2 from a different population (replication sample) underwent long echo time (272 msec) proton (hydrogen 1) MR spectroscopy on a 4 x 2 x 2-cm voxel in the basal ganglia bilaterally and a 2 x 2 x 2-cm voxel in the pons. Syndromes 1-3 are described as "impaired cognition," "confusion-ataxia," and "central pain," respectively. RESULTS: The N-acetylaspartate-to-creatine (NAA/Cr) ratio, which reflects functional neuronal mass, was significantly lower in the basal ganglia and brainstem of Gulf War veterans with the three syndromes than in those structures of the control subjects (P =.007). The finding was corroborated in the replication sample (P =.002). Veterans with syndrome 2 (the most severe clinically) had evidence of decreased NAA/Cr in both the basal ganglia and the brainstem; those with syndrome 1, in the basal ganglia only; and those with syndrome 3, in the brainstem only. CONCLUSION: Veterans with different Gulf War syndromes have biochemical evidence of neuronal damage in different distributions in the basal ganglia and brainstem.

Increased septal 5-HIAA efflux in rats that do not develop learned helplessness after inescapable stress.

Learned helplessness is a behavioral deficit that can be induced by exposure to inescapable stress. Previous studies have implicated the lateral septum in mediating this phenomenon, and in this brain region, serotonin plays an important role in the development, maintenance, prevention, and reversal of learned helplessness behavior. Using the technique of in vivo microdialysis, we measured the efflux of serotonin (5-HT), dopamine (DA), and their respective metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 3, 4-dihydroxyphenylacetic acid (DOPAC), from the lateral septum of rats that either developed or did not develop learned helplessness. During the microdialysis session all rats were subjected to restraint stress. Control groups included naïve, home cage rats as well as tested control rats that were subjected to the identical handling, restraint, and shuttlebox testing as the rats that received inescapable shock. Overall, levels of 5-HIAA were significantly higher in non-helpless rats. There were no significant effects of restraint or differences in levels of 5-HT, DA, or DOPAC. We propose that this increase in 5-HIAA is indicative of an overall increase in serotonin metabolism in the lateral septum of rats that do not become helpless after inescapable stress. This increased serotonin metabolism in the lateral septum may protect the animal from adverse behavioral consequences of inescapable stress. J. Neurosci. Res. 61:101-106, 2000. Published 2000 Wiley-Liss, Inc.

A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.

BACKGROUND: Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. METHODS: A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. RESULTS: The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. CONCLUSIONS: The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

Stressful manipulations that elevate corticosterone reduce blood-brain barrier permeability to pyridostigmine in the Rat.

Pyridostigmine bromide (PB), a reversible inhibitor of acetylcholinesterase (AChE), is used for the treatment of myasthenia gravis. PB has also been provided to military personnel for preexposure protection against potential soman release. The entry of PB into the brain is typically minimal, but recently published data in mice suggest that a brief forced swim stress increases the permeability of the blood-brain barrier to PB. From these results, PB administered under stressful conditions was proposed to induce long-lasting central cholinergic deficits, potentially explaining the neurological and neuropsychological symptoms presented by some Gulf War veterans. In undertaking to replicate these results in the Long-Evans rat, no evidence of a stress-potentiated central effect of PB, administered at doses up 5.0 mg/kg ip, was found. Three stress protocols were used: restraint, forced swim, or a combined restraint/forced swim. Wistar rats were also tested in some of the protocols to ensure that the results were generalizable across rat strains, and plasma corticosterone levels were measured to test the effectiveness of the stressors employed. In contrast to the previously reported findings in the mouse, stress significantly reduced the entry of PB into rat brain, as measured by reduced inhibition of AChE activity: a 12.5% reduction in whole brain AChE activity after treatment with 5.0 mg/kg PB under control conditions declined to 9% after stress exposure. It is apparent, therefore, that the interaction between stress and PB requires further study, and previous data should be reassessed before they are used as a basis for interpreting symptoms presented by veterans.

Nefazodone treatment for chronic posttraumatic stress disorder: an open trial.

Currently, there is no standard treatment for posttraumatic stress disorder (PTSD) because of a deficit of systematic treatment trials. The symptom overlap with other mood and anxiety disorders that respond to antidepressants and the results of a limited number of antidepressant trials indicate promise for psychopharmacologic treatment. Several open trials and one controlled trial with selective serotonin reuptake inhibitors have reported improvement in the symptomatology of PTSD. In this study, a relatively new serotonergic antidepressant, nefazodone, was tested as a treatment for PTSD. Veterans with chronic PTSD (N = 36) were enrolled in an 8-week open-label trial of nefazodone. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Thirty-one patients completed at least 4 weeks of treatment, which was considered to be an adequate trial, and 26 patients completed the 8-week study. During treatment, there was a significant decrease in the total CAPS score and in each of three CAPS subscale scores, with most of the improvement occurring during the first 4 weeks. Comparable improvements were also seen on the Hamilton Rating Scales for Anxiety and for Depression. Nefazodone treatment was well tolerated by this patient population, with only four patients discontinuing because of adverse effects. In summary, nefazodone treatment improved the symptoms of PTSD, including the core symptoms. Placebo-controlled studies should be undertaken to further elucidate the efficacy of nefazodone in the treatment of PTSD.

Acute stress does not alter 5-HT1A receptor density.

Previous research suggests that 5-HT1A receptors are altered with exposure to chronic stress. No previous studies have examined the effect of acute stress on 5-HT1A. Using receptor autoradiography it was observed that there were no differences in [3H]-8-OH-DPAT binding between control rats and rats that received 20 minutes of restraint stress 2 hours prior to sacrifice. This study suggests that the changes in 5-HT1A receptor density associated with chronic stress develop over the course of repeated stress.

The psychiatric sequelae of civilian trauma.

Much of the literature on the psychiatric consequences of stress has focused on wartime combat trauma. However, traumatic events also frequently occur in civilian life. Controlled studies on the psychiatric effects of noncombat trauma were reviewed and a meta-analysis of these data was conducted. Generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), substance abuse, phobia, and major depressive disorder (MDD) were significantly elevated compared with a pooled control group, whereas panic disorder and dysthymic disorder were not significantly increased. These data suggest that the psychiatric effects of civilian trauma include both anxiety and depressive disorders. The results are strikingly similar to those reported in combat veterans, suggesting that severe trauma, even in very different populations, may be associated with similar psychopathology.