Associate Professor - Med Center Line, Psychiatry and Behavioral Sciences
Director of Outpatient Mental Health, VA Palo Alto HCS (2008 - Present)
My scholarly, clinical, and teaching activities apply interdisciplinary training in neuroscience/pharmacology and medicine/psychiatry to advance health and mental health care for psychiatric patients with disorders related to chronic and severe stress. As Director of Outpatient Mental Health for the VHA Palo Alto HCS, my work focuses on psychiatric disorders in military veterans. The goal is maximizing the use of evidence-based practices and reducing unnecessary medical burden of psychiatric treatments for stress-related disorders. I have conducted basic science research on the adverse effects of the stress hormone cortisol and applied research on the efficacy of medication treatments for posttraumatic stress disorder (PTSD). Currently, we are conducting research on the efficacy of innovative treatment approaches for PTSD and developing electronic medical records software tools that foster the use of evidence-based treatments and continuous monitoring of clinical outcomes and adverse effects. Clinically, we are developing and implementing clinical programs that improve access to mental health care and foster evidenced-based care.
VA Cooperative Study CSP #591 is designed to compare the effectiveness of two types of psychotherapy, Prolonged Exposure and Cognitive Processing Therapy, for treating posttraumatic stress disorder (PTSD) in male and female Veterans. Despite solid evidence that both treatments are effective in Veterans and non-Veterans, there is a lack of evidence about the effectiveness of these treatments compared with one another. The sample will include 900 male and female Veterans with PTSD due to any traumatic military event. Veterans who are eligible and agree to participate in the study will be randomly assigned (by chance) to receive Prolonged Exposure or Cognitive Processing Therapy. The standard "dose" of treatment is 12 weekly sessions but Veterans who improve more rapidly may finish in fewer sessions and Veterans who improve more slowly may have additional sessions. The primary outcome is improvement in PTSD symptoms after treatment. The outcome will be measured at regular follow-up visits that will occur at the middle and at the end of treatment and then 3 and 6 months later. The investigators will measure other outcomes, including additional mental health problems, functioning, quality of life, and use of treatments for mental and physical problems. The investigators also will measure Veterans' treatment preference and examine whether Veterans who get the treatment they prefer do better than Veterans who get the less-preferred treatment. As a large multi-site trial with men and women, CSP #591 is designed to provide conclusive information about whether one treatment is better than the other, overall and for different types of patients-for example, men vs. women, combat Veterans vs. Veterans who experienced military sexual trauma, and older vs. younger Veterans. Regardless of the outcome, patients will have more information to help them make an informed decisions about which treatment to choose and VA will have stronger evidence to help make care Veteran-centered.
Medications like olanzapine have been associated with the development of weight gain and diabetes in some patients. It is not known if the increased risk of developing diabetes is a direct effect on insulin or simply related to weight gain. We hope to learn in this study whether or not olanzapine directly slows down insulin secretion from the pancreas, thereby increasing the risk of developing diabetes.
Implementation planning typically incorporates stakeholder input. Quality improvement efforts provide data-based feedback regarding progress. Participatory system dynamics modeling (PSD) triangulates stakeholder expertise, data and simulation of implementation plans prior to attempting change. Frontline staff in one VA outpatient mental health system used PSD to examine policy and procedural "mechanisms" they believe underlie local capacity to implement evidence-based psychotherapies (EBPs) for PTSD and depression. We piloted the PSD process, simulating implementation plans to improve EBP reach. Findings indicate PSD is a feasible, useful strategy for building stakeholder consensus, and may save time and effort as compared to trial-and-error EBP implementation planning.
View details for PubMedID 27480546
This study assessed whether adding telephone care management to usual outpatient mental health care improved treatment attendance, medication compliance, and clinical outcomes of veterans with posttraumatic stress disorder (PTSD).In a multisite randomized controlled trial, 358 veterans were assigned to either usual outpatient mental health treatment (N=165) or usual care plus twice-a-month telephone care management (TCM) and support in the first three months of treatment (N=193). Treatment utilization and medication refills were determined from U.S. Department of Veterans Affairs administrative data. PTSD, depression, quality of life, aggressive behavior, and substance use were assessed with self-report questionnaires at intake, four months, and 12 months.Telephone care managers reached 95% of TCM participants (N=182), completing an average 5.1 of 6.0 planned telephone calls. During the three-month intervention period, TCM participants completed 43% more mental health visits (M±SD=5.9±6.8) than did those in usual care (4.1±4.2) (incident rate ratio=1.36, χ(2)=6.56, df=1, p<.01). Treatment visits in the nine-month follow-up period and medication refills did not differ by condition. Only 9% of participants were scheduled to receive evidence-based psychotherapy. Slopes of improvement in PTSD, depression, alcohol misuse, drug problems, aggressive behavior, and quality of life did not differ by condition or treatment attendance.TCM improved PTSD patients' treatment attendance but not their outcomes. TCM can enhance treatment engagement, but outcomes depend on the effectiveness of the treatments that patients receive.
View details for PubMedID 27745535
View details for Web of Science ID 000348623500008
Apparent psychotic symptoms are often associated with posttraumatic stress disorder (PTSD), but these symptoms are poorly understood. In a sample of 30 male Vietnam combat veterans with severe and chronic PTSD, we conducted detailed assessments of psychotic symptom endorsement, insight, symptom severity, neurocognitive function, and feigning. Two thirds of the subjects endorsed a psychotic item but did not believe that the experiences were real. Those endorsing psychotic items were higher in PTSD severity, general psychopathology, and dissociation but not depression, functional health, cognitive function, or feigned effort. Severity of psychotic symptoms correlated with dissociation, combat exposure, and attention but not PTSD, depression, or functional health. Those endorsing psychotic items scored higher on a screen but not on a detailed structured interview for malingering. Endorsement of psychotic experiences by combat veterans with PTSD do not seem to reflect psychotic symptoms or outright malingering.
View details for DOI 10.1097/NMD.0000000000000077
View details for PubMedID 24469519
C-reactive protein (CRP) is an inflammatory marker associated with obesity, insulin resistance, and cardiovascular disease. A recent study found CRP levels to be higher in individuals treated with certain antipsychotic medications such as olanzapine; however, it is not clear whether this is associated directly with drug intake or indirectly with drug-associated weight gain and insulin resistance. The objective of this study was to explore the potential predictors of CRP including insulin resistance, components of the metabolic syndrome, psychiatric diagnosis, and antipsychotic medication in patients treated with antipsychotics. Sixty-four outpatients without diabetes being treated with a single second generation antipsychotic medication had direct measurements of insulin resistance at the end of a 180-min infusion of glucose, insulin, and octreotide (insulin suppression test) as well as components of the metabolic syndrome. Insulin resistance was the strongest predictor of CRP (r=0.52, P<0.001). When adjusted for insulin resistance, there was no significant relationship between CRP and any of the components of the metabolic syndrome criteria, specific drug treatment or psychiatric diagnoses. In conclusion, insulin resistance is strongly associated with CRP levels and likely contributes to earlier associations between CRP and certain antipsychotic treatments.
View details for DOI 10.1097/YIC.0b013e3283400cd3
View details for Web of Science ID 000285083700005
View details for PubMedID 20861740
View details for DOI 10.1080/21507716.2011.629640
Second generation antipsychotics (SGAs) can increase weight gain and weight-induced insulin resistance. Recent studies have suggested weight-independent effects of certain SGAs on insulin resistance; however the magnitude of these effects and the relationship between BMI and insulin resistance in patients on SGAs are not established. To evaluate, the relationship between body mass index (BMI) and insulin resistance in 54 patients being stably treated with olanzapine (n=19), risperidone (n=16), or aripiprazole (n=19) was compared with data from a large reference population (n=201) not on SGAs. Insulin resistance was directly quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. The relationship between BMI and SSPG was similar between the SGA (r=0.58) and the reference population (r=0.50). When SSPG was standardized based on expected values for the reference population, patients on olanzapine had a higher degree of insulin resistance (mean z-score+/-SD, 0.68+/-0.9) than expected for level of BMI compared with those on aripiprazole (-0.25+/-1) and risperidone (-0.3+/-0.9), F(2,51)=6.28 (p=0.004). Thus, olanzapine group was 0.76 SD above the reference population or in the 78 percentile for insulin resistance. SSPG was correlated with fasting plasma insulin concentration (0.78 (0.64-0.87), p<0.001) but not fasting glucose concentration (0.15 (-0.13-0.40), p=0.29). In conclusion, BMI contributes a quarter to a third of the variance in insulin resistance in the SGA population similar to the reference population. Olanzapine also appears to have an independent effect on insulin resistance that is above and beyond obesity.
View details for DOI 10.1016/j.jpsychires.2009.11.007
View details for Web of Science ID 000278653500002
View details for PubMedID 19962157
Identifying factors that influence mental health outcomes in veterans can aid in the redesign of programs to maximize the likelihood of early resolution of problems. To that end, we examined demographic and clinical process data from 2,684 veterans who scored positive on a mental health screen. We investigated this data set for patterns and possible predictors of mental health referral acceptance and attendance. The majority of patients had not received mental health treatment within the last two years (76%). Veterans of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) were more likely to accept a mental health referral for depression but were equally likely to attend a mental health visit as other era veterans. Decreased acceptance was associated with provider type and contact method, clinic location, depression only, and specific age ranges (65-74). Among those who accepted a referral, decreased attendance was associated with clinic location, depression only, and retirement. No variables predicted OEF/OIF acceptance/attendance. In conclusion, our findings illustrate the importance of close, continual monitoring of clinical process data to help reveal targets for improving mental health care for veterans.
View details for DOI 10.1111/j.1749-6632.2010.05692.x
View details for Web of Science ID 000284742000014
View details for PubMedID 20955332
Neuropsychiatric disorders often involve considerable psychological stress and elevated cortisol activity. Glucocorticoid receptors have relatively low affinity for cortisol and are found distributed throughout the brain, particularly in the frontal cortex and hippocampus. In recent years, glucocorticoid receptors antagonists have been actively studied in both animal models of several disorders as well as a potential treatment in specific types of neuropsychiatric patients. Data from these various studies are reviewed with an emphasis on seven clinical disorders or problems: major depression with psychotic features, bipolar disorder, schizophrenia, cognitive disorders, (e.g., Alzheimer's disease and mild cognitive impairment), cognitive side effects of electroconvulsive therapy, and weight gain with atypical antipsychotic agents. Potential benefits and limitations are discussed.
View details for DOI 10.1016/j.ejphar.2008.01.001
View details for Web of Science ID 000254923600018
View details for PubMedID 18339372
Topiramate, a novel anticonvulsant, has been reported to rapidly reduce symptoms of posttraumatic stress disorder (PTSD) in an open-label trial. The present study was designed as a test of topiramate's efficacy as adjunctive therapy in a 7-week, randomized, double-blind, placebo-controlled trial.Forty male veterans with PTSD in a residential treatment program were randomized to flexible-dose topiramate or placebo augmentation. The primary outcome measures were PTSD symptom severity and global symptom improvement.Baseline Clinician-Administered PTSD Scale scores were 62.1 +/- 13.9 for placebo and 61.0 +/- 22.2 for topiramate. There was a high dropout rate from the study (55% topiramate; 25% placebo), with 40% of topiramate and 10% of placebo dropping because of adverse events (AEs). No significant treatment effects of topiramate versus placebo were observed for the primary treatment outcomes. Subjects reporting central nervous system-related AEs and with higher baseline severity of depression were more likely to discontinue because of AEs.Primary outcome measures failed to demonstrate a significant effect for topiramate over placebo; however, high dropout rate in the treatment group prohibits definitive conclusions about the efficacy of topiramate in this population.
View details for DOI 10.1097/jcp.0b013e31815a43ee
View details for Web of Science ID 000251181600017
View details for PubMedID 18004136
Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and investigate whether novelty seeking behavior is associated with differences in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the dopamine metabolite homovanillic acid (HVA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the neuropeptide corticotrophin-releasing factor (CRF). Monkeys were randomized early in life to either mild intermittent stress (IS) or no stress (NS) conditions, and subsequently presented with opportunities to interact with a familiar or novel object in a test box that was connected to each monkey's home cage. To further minimize the potentially stressful nature of the test situation, monkeys were acclimated to the test procedures prior to study initiation. Post-test plasma levels of cortisol in IS and NS monkeys did not differ significantly from baseline levels measured in undisturbed conditions. During testing, more IS than NS monkeys voluntarily left the home cage, and IS monkeys spent more time in the test box compared to NS monkeys. More IS than NS monkeys engaged in object exploration in the test box, and IS monkeys preferred to interact with the novel vs. familiar object. Novelty seeking was not associated with differences in 5HIAA, HVA, MHPG, or CRF, but correlated with differences in object exploration observed in a different test situation at an earlier age. These trait-like differences in novelty seeking appear to reflect mild early stress-induced adaptations that enhance curiosity and resilience.
View details for DOI 10.1016/j.psyneuen.2007.05.008
View details for Web of Science ID 000249510200003
View details for PubMedID 17604913
View details for PubMedCentralID PMC2716798
The s allele variant of the serotonin transporter gene (5-HTT) has recently been observed to moderate the relationship of stress to depression and anxiety. To date no study has considered interactive effects of 5-HTT genotype, stress and hypothalamic-pituitary-adrenal (HPA) function on cognition in healthy, older adults, which may reflect developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism. We investigated whether 5-HTT genotype interacts with cumulative life stress and HPA-axis measures of waking and diurnal cortisol slope to impact cognition in 154 non-depressed, older adults. Structural images of hippocampal volume were acquired on a subsample of 56 participants. The 5-HTT s allele was associated with both significantly lower delayed recall and higher waking cortisol levels. Presence of the s allele interacted with higher waking cortisol to negatively impact memory. We also observed a significant interaction of higher waking cortisol and the s allele on lower hippocampal volume. Smaller hippocampi and higher cortisol were associated with lower delayed recall only in s allele carriers. No impact or interactions of cumulative life stress with 5-HTT or cortisol were observed. This is the first investigation to identify an association of the 5-HTT s allele with poorer memory function in older adults. The interactive effects of the s allele and waking cortisol levels on reduced hippocampal volume and lower memory suggest that the negative effect of the serotonin polymorphism on memory is mediated by the HPA axis. Further, given the significant association of the s allele with higher waking cortisol in our investigation, future studies may be needed to evaluate the impact of the serotonin transporter polymorphism on any neuropsychiatric or behavioral outcome which is influenced by HPA axis function in older adults.
View details for DOI 10.1038/sj.mp.4001978
View details for Web of Science ID 000246906200003
View details for PubMedID 17353910
The authors report an 8-week, double-blind, randomized controlled trial of guanfacine versus placebo for posttraumatic stress disorder (PTSD).Veterans with chronic PTSD who were medication-free or receiving stable pharmacotherapy were randomly assigned to guanfacine (N=29) versus placebo (N=34).Guanfacine had no effect on PTSD symptoms, subjective sleep quality, or general mood disturbances. Guanfacine was associated with a number of side effects.These results do not support the use of alpha 2 agonists in veterans with chronic PTSD.
View details for Web of Science ID 000242626000029
View details for PubMedID 17151174
We previously reported changes in DA neurochemical estimates after sustained corticosterone (CORT) administration or adrenalectomy (ADX) that are consistent with glucocorticoid-induced inhibition of DA metabolism. The present investigation measured monoamine oxidase type A (MAO-A), type B (MAO-B) and catechol-o-methyltransferase (COMT) activity by enzymatic assay and levels of gene expression by real-time quantitative polymerase chain reaction (rt-PCR) in tissues from sham, ADX, or ADX+CORT-replaced Lewis rats. One week of ADX had no significant effect on either enzyme activity or gene expression for any of the three enzymes examined in the medial prefrontal cortex, striatum, or liver. One week of CORT administration (100mg-21 day release pellet) in ADX rats produced statistically significant decreases in MAO-A enzyme activity and MAO-B gene expression in the liver but no significant changes for any of the three enzymes in either activity or gene expression in the medial prefrontal cortex or striatum. The results do not support inhibition of DA metabolism as a mechanism by which glucocorticoids influence DA-mediated behaviors.
View details for DOI 10.1016/j.psyneuen.2005.03.007
View details for Web of Science ID 000229842300007
View details for PubMedID 15919584
Posttraumatic stress disorder (PTSD) has been associated with lower concentrations of cortisol and enhanced suppression of cortisol by dexamethasone, although discrepancies exist among reports. The objective of the study was to determine the pattern of cortisol responses in patients seeking treatment for PTSD resulting from a variety of traumatic experiences and to test whether cortisol responses are significantly related to childhood trauma, severity of symptoms, or length of time since trauma.Salivary cortisol was measured at 8 AM, 4 PM, and 10 PM on 2 consecutive days before and after a 10 PM dose of .5 mg dexamethasone in 17 psychotropic medication and substance-free subjects with PTSD and 17 matched control subjects.Repeated-measures analysis of variance (ANOVA) of the baseline salivary cortisol concentrations demonstrated a significant effect for group with higher concentrations in the PTSD group but no significant differences in responses to dexamethasone. The presence of childhood abuse did not significantly affect salivary cortisol concentrations, and there was no correlation between predexamethasone cortisol and either the severity of PTSD symptoms or the time since the index trauma.Neither low basal concentrations nor enhanced suppression of cortisol are consistent markers of a PTSD diagnosis.
View details for DOI 10.1016/j.biopsych.2003.12.021
View details for Web of Science ID 000220922100009
View details for PubMedID 15110738
The authors compared young and older adults with panic disorder (PD) to investigate differences in panic-associated phenomenology, psychiatric comorbidity, and risk factors.Patients in the older group (age 60 and above) were further subdivided into early- and late-onset groups and compared. Phenomenology (number of panic symptoms, severity of anxiety, physiological symptoms, panic-associated cognitions, and overall severity of PD); comorbidity (depressive and anxiety disorders); and risk factors (family history of anxiety and life stressors) were assessed in 167 outpatients with PD.Older patients reported fewer panic symptoms, less anxiety and arousal, less severe PD, lower levels of depression, and higher levels of functioning. Furthermore, within the older-patient group, late-onset patients were found to report less distress during panic attacks in relation to body sensations and panic-related cognitions and emotions. Multiple-regression analysis of the entire sample showed that chronological age and age at onset of PD distinctly predicted different domains of panic phenomenology.PD was consistently less severe in older patients across multiple domains, and a later age at onset was associated with less distress due to body sensations, cognitions, and emotions during panic attacks.
View details for Web of Science ID 000188001000014
View details for PubMedID 14729565
The effects of alterations in peripheral corticosterone levels on multiple dopamine neurochemical estimates were examined in inbred Fischer and Lewis inbred rat strains. 2x2 ANOVA's (treatment x strain) showed a main effect for treatment (1 week CORT versus placebo) on the concentrations of the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid in the medial prefrontal cortex, with lower levels after treatment, but no significant treatment versus strain interaction. There was no effect of CORT treatment on DA metabolites in the nucleus accumbens shell or dorsal striatum. DOPA accumulation in any terminal region examined and tyrosine hydroxylase protein content in the ventral tegmental area were also not affected by 1 week of corticosterone in either strain. One week after adrenalectomy, homovanillic acid but not dihydroxyphenylacetic acid concentrations were significantly increased in the medial prefrontal cortex, dorsal striatum, and nucleus accumbens shell in the Lewis but not the Fischer strain, with a significant treatment x strain interaction only in the dorsal striatum. Based on these findings, the effect of adrenalectomy on DOPA accumulation and extracellular DA concentrations was examined in the Lewis strain only. Adrenalectomy produced a decrease in DOPA accumulation in the dorsal striatum with no significant change in the other regions. Adrenalectomy did not alter estimates of extracellular dopamine concentrations determined by in vivo no net flux microdialysis but did significantly increase in vivo dopamine recovery in the dorsal striatum. The findings indicate a pattern of changes in neurochemical measurements consistent with a small magnitude inhibition of basal dopamine metabolism, but not with a change neuronal activity, release or reuptake.
View details for Web of Science ID 000180087300022
View details for PubMedID 12470878
Recent data suggest that the presence of psychotic symptoms in patients suffering from posttraumatic stress disorder (PTSD) may represent an underrecognized and unique subtype of PTSD. Among combat veterans with PTSD, 30% to 40% report auditory or visual hallucinations and/or delusions. The presence of psychotic symptoms in PTSD is associated with a more severe level of psychopathology, similar to that of chronic schizophrenia. In this review, the differential diagnosis of psychotic symptoms in PTSD is discussed, including possible comorbid schizophrenia, psychotic depression, substance-induced psychosis, and personality disorder. A recent biologic study supporting the existence of a unique subtype of PTSD with psychotic features is also addressed, as are the similarities between PTSD with psychotic features and psychotic depression disorder. Finally, data on the treatment implications of psychotic symptoms in PTSD are presented. The intriguing recent findings on psychotic symptoms in PTSD need further investigation in noncombat-related PTSD populations before findings can be generalized to all individuals with PTSD.
View details for PubMedID 17637580
Multiple neurochemical estimates were used to examine peripheral corticosterone (CORT) effects in dopaminergic terminal regions. Acute CORT administration, which elevated plasma CORT (5 h), slightly decreased dihydroxyphenylacetic acid (DOPAC) to dopamine (DA) ratios in the striatum but not in other regions examined. Two weeks of adrenalectomy (ADX) increased both medial prefrontal cortex DOPAC/DA and homovanillic acid (HVA)/DA and striatal HVA/DA. A reciprocal pattern of changes was observed with CORT replacement in ADX animals. In contrast, CORT replacement in ADX animals did not significantly influence tyrosine hydroxylase content, basal dihydroxyphenylalanine (DOPA) accumulation after NSD 1015 treatment or the decline in DA after alpha-methyl-para-tyrosine, suggesting that neither DA neuronal activity nor release are altered by CORT. Moreover, neither gamma-hydroxybutyric acid lactone-induced increases in DOPA accumulation or stress-induced increases in DA utilization were influenced by CORT replacement, indicating that neither autoreceptor regulation of DA synthesis nor acute stress regulation of DA utilization are changed by CORT. The findings are most consistent with direct inhibition of basal DA metabolism in the medial prefrontal cortex and striatum. The possible physiological and behavioral significance of this inhibition is being further explored.
View details for Web of Science ID 000081926400008
View details for PubMedID 10457537
Differences in the behavioral responses of Lewis and Fischer (F344) inbred rat strains to stress and psychoactive drugs have been related to differences in the expression of various regulatory proteins in regions containing mesolimbic dopamine (DA) neurons. The present study compared basal and stimulated neurochemical estimates of DA utilization and synthesis in mesocortical, mesolimbic and nigrostriatal DA terminal regions of these two strains. In unstressed control animals, the Lewis strain had lower DA concentrations in the dorsal striatum (ST; 80.3% of F344) and lower basal dihydroxyphenylalanine (DOPA) accumulation after m-hydroxybenzylhydrazine (NSD 1015) treatment in the medial prefrontal cortex (mPfx; 75.3% of F344). Similar differences were observed in vehicle-injected animals. No strain differences in basal neurochemistry were apparent in the nucleus accumbens shell (NAs) or core (NAc). In response to restraint stress, dihydroxyphenylacetic acid (DOPAC) to DA ratios in the mPfx, NAs and ST increased in the F344 but not the Lewis strain. However, restraint stress did not significantly increase DOPA accumulation in the F344 strain. This latter finding was not due to a deficit in synthesis capacity, as gamma-hydroxybutyric acid lactone (GBL) increased DOPA accumulation significantly more in F344 than Lewis animals. Finally, haloperidol increased DA utilization similarly in the two strains. Together these findings suggest that the inbred, behaviorally divergent F344 and Lewis rats have selective differences in mesocortical, nigrostriatal and mesolimbic DA neuronal regulation.
View details for Web of Science ID 000081066800017
View details for PubMedID 10375661
When separated from groups, squirrel monkeys respond with significant increases in plasma cortisol and adrenocorticotropic hormone (ACTH). While cortisol remains elevated above pre-separation levels, significant reductions occur in ACTH. Monkeys that respond with greater increases in cortisol subsequently exhibit greater reductions in ACTH, which suggests that reductions in ACTH are mediated by corticosteroid feedback. Monkeys that respond with greater increases in cortisol also tend to exhibit greater cerebrospinal fluid levels of the dopamine metabolite HVA, but not the norepinephrine metabolite MHPG, or corticotropin-releasing factor (CRF). Attenuation of corticosteroid feedback with metyrapone results in significant increases in circulating ACTH, and in older monkeys increases plasma HVA. Similar findings in humans have been reported in clinical studies of hypercortisolism and major depression.
View details for Web of Science ID 000078796300001
View details for PubMedID 10101722
The ability of sodium butyrate and dexamethasone to promote adrenergic differentiation in PC12 cells was examined using the gene encoding the epinephrine biosynthetic enzyme, phenylethanolamine N-methyltransferase (PNMT), as a marker. Sodium butyrate and dexamethasone independently stimulated expression of PNMT mRNA in PC12 cells, and the combined action of these drugs led to synergistic activation of the PNMT gene. Despite the induction of the PNMT gene, epinephrine is not produced in these cells, in part due to the absence of a corresponding induction in PNMT enzymatic activity. Another contributing factor appears to be a reduction in the precursor catecholamines, norepinephrine and dopamine, in the presence of sodium butyrate. Thus, while sodium butyrate and dexamethasone can induce PNMT gene expression, treatment of PC12 cells with these drugs appears insufficient for full acquisition of the adrenergic phenotype.
View details for Web of Science ID A1997XH21400003
View details for PubMedID 9221898
The purpose of the present study was to provide neurochemical and endocrinological evidence that dopamine (DA) neurons terminating in the intermediate lobe of the rat pituitary originate in the periventricular nucleus of the hypothalamus. One week following surgical separation of the periventricular nucleus from the mediobasal hypothalamus, DA and 3,4-dihydroxyphenyl-acetic acid (DOPAC) concentrations in the intermediate lobe were reduced by 50%, and this was accompanied by an increase in plasma alpha-melanocyte-stimulating hormone (alpha-MSH) concentrations. In contrast, this procedure had no effect on concentrations of prolactin in the plasma, or DA or DOPAC in the median eminence, the region of the mediobasal hypothalamus containing terminals of tuberoinfundibular DA neurons. Electrical stimulation of the periventricular nucleus increased the ratio of DOPAC/DA in the intermediate lobe and reduced the concentrations of alpha-MSH in the plasma, whereas in these same animals the DOPAC/DA ratio in the median eminence and concentrations of prolactin in the plasma were unaltered. These results indicate that approximately 50% of all the DA neurons terminating in the intermediate lobe of the rat pituitary originate in or project through the periventricular nucleus of the hypothalamus, and that these DA neurons regulate the secretion of alpha-MSH from intermediate lobe melanotrophs.
View details for Web of Science ID A1992JC21600014
View details for PubMedID 1322505
The relative roles of dopaminergic and beta-adrenergic receptors in mediating the stress-induced increase in the secretion of alpha-melanocyte-stimulating hormone (alpha-MSH) from the intermediate lobe of the pituitary were determined in the male rat. Thirty minutes of physical immobilization (restraint stress) increased the circulating concentrations of alpha-MSH and decreased the 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio in the intermediate lobe of the pituitary, reflecting a decrease in the tuberohypophysial dopaminergic neuronal activity. Pretreatment with the beta-adrenergic antagonist propranolol reduced the stress-induced increase in the circulating levels of alpha-MSH, but had no effect on the basal plasma concentrations of this hormone or the stress-induced decrease in DOPAC/DA in the intermediate lobe. If the dopaminergic tone during stress was maintained by administration of the DA agonist apomorphine, the stress-induced increase in alpha-MSH secretion was prevented. In nonstressed animals the administration of the beta 2-adrenergic agonist metaproterenol increased the plasma levels of alpha-MSH, and the effect of this drug was augmented if the inhibitory dopaminergic tone on alpha-MSH secretion was blocked by the administration of the DA antagonist haloperidol. Severing neurons in the retrochiasmatic region of the hypothalamus blocked the stress-induced decrease in DOPAC/DA in the intermediate lobe and attenuated the stress-induced increase in plasma concentrations of alpha-MSH. Taken together, these results indicate that a decrease in tuberohypophysial dopaminergic neuronal inhibitory tone and an increase in beta-adrenergic stimulation are both necessary for the full expression of the stress-induced increase in secretion of alpha-MSH from melanotrophs in the intermediate lobe of the rat pituitary.
View details for Web of Science ID A1990DP32700008
View details for PubMedID 2168526
The effect of alpha-melanocyte-stimulating hormone (alpha MSH) on the activity of different central dopaminergic neurons in the male rat was determined by measuring the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) and the accumulation of 3,4-dihydroxyphenylalanine (DOPA) following the administration of a decarboxylase inhibitor in brain regions that contain terminals of nigrostriatal (striatum), mesolimbic (nucleus accumbens), tuberoinfundibular (median eminence) and tuberohypophysial (neural and intermediate lobe of the pituitary) dopaminergic neurons. Intracerebroventricular (i.c.v.) administration of alpha MSH caused a prompt (within 30 min) increase in the concentration of DOPAC and the accumulation of DOPA in the median eminence, but was without effect in the other brain regions. The alpha MSH-induced increase in tuberoinfundibular dopaminergic neuronal activity was temporally related to a decrease in circulating concentrations of prolactin. Twelve hours after the i.c.v. administration of prolactin DOPA accumulation increased in the median eminence but not in the neural or intermediate lobes of the pituitary. DOPA accumulation was not altered in any brain region 12 h after the i.c.v. administration of alpha MSH. These results suggest that alpha MSH acts acutely to selectively activate tuberoinfundibular dopaminergic neurons and thereby cause the secretion of prolactin from the anterior pituitary to decrease.
View details for Web of Science ID A1990CX12900004
View details for PubMedID 2161087
Tuberohypophysial dopamine (DA) neurons terminate in the intermediate and neural lobes of the posterior pituitary. The objective of this study was to determine if concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a major metabolite of DA in these regions, reflect the activity of tuberohypophysial DA neurons. The concentrations of DOPAC and DA in the intermediate lobe were approximately twice those in the neural lobe, so that the ratios of DOPAC/DA were similar between lobes. The administration of a monoamine oxidase inhibitor pargyline produced a rapid decline (by 5 min) of DOPAC concentrations in both the intermediate and neural lobes. The administration of nomifensine, an inhibitor of DA uptake at the nerve terminal, produced a modest 33% decline in DOPAC concentrations in the intermediate lobe, but was without effect in the neural lobe. Activation of tuberohypophysial DA neurons by electrical stimulation of the pituitary stalk increased both the rate of DA synthesis (accumulation of dihydroxyphenylalanine (DOPA) after administration of the decarboxylase inhibitor NSD 1015) and the concentrations of DOPAC in the intermediate and neural lobes. Administration of the DA antagonist haloperidol increased, and the DA agonist apomorphine decreased both the rate of DOPA accumulation and DOPAC concentrations in the intermediate lobe but not the neural lobe. The results of the present study demonstrate that: (1) elimination of DOPAC from the intermediate lobe and neural lobe is rapid and alterations in DOPAC concentrations reflect dynamic changes in metabolism of DA; (2) DA which is released and recaptured is a minor contributor to DOPAC concentrations; and (3) alterations in the activity of tuberohypophysial DA neurons are accompanied by corresponding changes in DOPAC concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1990CH58000019
View details for PubMedID 2302550
Administration of gamma-butyrolactone (GBL), an anesthetic which reduces dopaminergic neuronal activity, decreased the concentration of the dopamine (DA) metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the intermediate lobe of the pituitary gland, and increased alpha-melanocyte stimulating hormone (alpha MSH) concentrations in the serum of male rats. Bilateral electrical stimulation of the rostral arcuate nucleus, which contains perikarya of tuberohypophysial DA neurons, increased DOPAC concentrations in the intermediate lobe and decreased alpha MSH concentrations in the serum of GBL-anesthetized rats. Administration of the DA antagonist haloperidol prevented the decline in serum alpha MSH levels following arcuate nucleus stimulation, but had no effect on serum alpha MSH concentrations in sham-stimulated GBL-treated rats. These results indicate that GBL-induced decreases or stimulation-induced increases in the activity of tuberohypophysial DA neurons are accompanied by corresponding changes in the metabolism of DA in the intermediate lobe of the rat pituitary gland, and by reciprocal changes in the secretion of alpha MSH.
View details for Web of Science ID A1988P332700006
View details for PubMedID 2839845
The activity of nigrostriatal dopaminergic neurons has been estimated biochemically by measuring the rates of dopamine (DA) synthesis (accumulation of dihydroxyphenylalanine (DOPA) after NSD 1015) and turnover (decline of DA concentrations after alpha-methyltyrosine) in the striatum. It has been assumed that the activities of tuberoinfundibular dopaminergic (TIDA) and tuberohypophysial dopaminergic (THDA) neurons can also be estimated by making the same measurements in the terminals of these neurons in the median eminence and the posterior pituitary, respectively. In the present study, this assumption was tested directly by measuring the rates of DA synthesis and turnover in the median eminence and posterior pituitary following electrical stimulation of TIDS and THDA cell bodies in the arcuate nucleus. Electrical stimulation of the arcuate nucleus increased the rate of DOPA accumulation and the alpha-methyltyrosine-induced decline of DA concentrations in the median eminence and in the neural and intermediate lobes of the posterior pituitary. gamma-Butyrolactone (GBL), an anesthetic that selectively inhibits DA impulse flow, reduced the rates of DA synthesis and turnover in the median eminence. GBL also increased prolactin secretion which is tonically inhibited by DA released from TIDA neurons. Serum prolactin levels were significantly decreased by arcuate nucleus stimulation in GBL-anesthetized rats. These results indicate that the rates of DA synthesis and turnover within the median eminence and posterior pituitary reflect the activities of TIDA and THDA neurons, respectively.
View details for Web of Science ID A1987K689000020
View details for PubMedID 3119157
Previous work indicated that immature oocytes of Xenopus were incapable of assembling microtubules but that competence was achieved during maturation. We report here that small numbers of microtubules do exist in immature oocytes. Consistent with this finding, ultrastructural observations indicate that brain microtubules injected into immature oocytes persist in large numbers for at least 30 min. We report that the tubulin dimers of mature and immature oocytes are equally capable of assembling with brain tubulin in vitro. We confirmed previous results that injection of taxol into immature oocytes has no effect when assayed by light microscopy. However, ultrastructural observations suggest that some microtubule assembly is stimulated by taxol. We tested for the ability of immature oocytes to elongate microtubules from 'seeds' by injecting deciliated pellicles of Tetrahymena. No elongation was observed either by light or electron microscopic observation. We conclude that the immature oocyte is capable of very limited microtubule assembly and that a marked increase in assembly competence occurs during maturation. Our data suggest that the change in assembly competence during maturation is due to the release, activation or synthesis of a stimulatory co-factor.
View details for Web of Science ID A1985AVU3200010
View details for PubMedID 2868018
Several workers have found that axonal microtubules have a uniform polarity orientation. It is the "+" end of the polymer that is distal to the cell body. The experiments reported here investigate whether this high degree of organization can be accounted for on the basis of structures or mechanisms within the axon. Substantial depolymerization of axonal microtubules was observed in isolated, postganglionic sympathetic nerve fibers of the cat subjected to cold treatment; generally less than 10% of the original number of microtubules/micron 2 remained in cross section. The number of cold stable MTs that remained was not correlated with axonal area and they were also found within Schwann cells. Microtubules were allowed to repolymerize and the polarity orientation of the reassembled microtubules was determined. In fibers from four cats, a majority of reassembled microtubules returned with the original polarity orientation. However, in no case was the polarity orientation as uniform as the original organization. The degree to which the original orientation returned in a fiber was correlated with the number of cold-stable microtubules in the fiber. We suggest that stable microtubule fragments serve as nucleating elements for microtubule assembly and play a role in the spatial organization of neuronal microtubules. The extremely rapid reassembly of microtubules that we observed, returning to near control levels within the first 5 min, supports microtubule elongation from a nucleus. However, in three of four fibers examined this initial assembly was followed by an equally rapid, but transient decline in microtubule number to a value that was significantly different than the initial peak. This observation is difficult to interpret; however, a similar transient peak has been reported upon repolymerization of spindle microtubules after pressure induced depolymerization.
View details for Web of Science ID A1984TM94800013
View details for PubMedID 6480693