Kelly H. Skelton

The neurobiology of urocortin.

Urocortin (UCN) is a recently isolated 40 amino acid-containing neuropeptide that is the second endogenous mammalian ligand for the corticotropin-releasing factor (CRF) receptors. While UCN and CRF both display a similar high affinity for the CRF(1) receptor, the affinity of UCN for the CRF(2) receptor is more than 10-fold higher than that of rat/human CRF. UCN mRNA expression is highest in the Edinger-Westphal nucleus and lateral superior olive, with the most prominent terminal fields found in the lateral septum. Because of the higher relative affinity of UCN for the CRF(2) receptor and the corresponding neuroanatomical distribution of the highest density of UCN expression and innervation to brain regions preferentially expressing the CRF(2) receptor subtype, it has been hypothesized that UCN is the preferred endogenous ligand for the CRF(2) receptor. Following central administration, UCN has been demonstrated to produce behavioral and physiological effects that are qualitatively similar to CRF. Quantitatively, however, UCN appears to be a more potent suppressor of ingestive behavior (food and water intake) and a less potent inducer of anxiogenic behavior than CRF.

More than military sexual trauma: Interpersonal violence, PTSD, and mental health in women veterans

Military sexual trauma (MST) is reported by 20-40% of female veterans. The purpose of this study of female veterans referred for MST treatment was to examine the relationships between lifetime trauma (physical, sexual, and psychological) and posttraumatic stress disorder (PTSD), depression, physical health, and quality of life using retrospective cross-sectional data from medical records. Of the 135 participants, 95.4% reported at least one trauma in addition to MST, most notably sexual abuse as adult civilians (77.0%) and as children (52.6%). PTSD, depression, and sleep difficulty rates were clinically significant. Chronic pain (66.4%) was associated with childhood abuse, physical health, sleep difficulties, and coping. Integrating mental and physical health treatment is necessary to treat MST and PTSD in female veterans.

Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population

OBJECTIVE Metabolic syndrome is associated with elevated risk for cardiovascular disease and diabetes and has increased prevalence in low-income African Americans, which constitutes a significant health disparity. The mechanisms responsible for this disparity remain unclear; the current study investigated the relationship between posttraumatic stress disorder (PTSD) and metabolic syndrome. METHOD We assessed childhood and adult trauma history, major depressive disorder, PTSD and the components of metabolic syndrome in an urban population. We recruited 245 low-socioeconomic-status, primarily African American subjects from general medical clinics in an inner-city hospital. RESULTS Trauma exposure was extremely prevalent, with 90.6% of subjects reporting at least one significant trauma and 18.8% of subjects meeting criteria for current PTSD. Metabolic syndrome was also prevalent in this population (33.2%), with significantly higher rates among patients with current PTSD (47.8%, P<.05). After controlling for demographics, smoking history, antipsychotic use, depression and exercise, current PTSD remained the only significant predictor of metabolic syndrome (P=.006). CONCLUSIONS PTSD is associated with increased rates of metabolic syndrome within a traumatized, impoverished urban population. Further studies should investigate if PTSD treatment may reduce the rates of metabolic syndrome, improve overall health outcomes and decrease health care disparities in minority populations.

Pain Symptomatology and Pain Medication Use in Civilian PTSD

Summary Participants with posttraumatic stress disorder (PTSD) had higher self‐reported pain and were significantly more likely to have used opioid analgesics for pain control compared to those without PTSD. Abstract The comorbidity of pain syndromes and trauma‐related syndromes has been shown to be high. However, there have been limited data, especially in civilian medical populations, on the role of trauma‐related disorders such as posttraumatic stress disorder (PTSD) on chronic pain and pain medication use. We analyzed 647 general hospital patients in primary care and obstetrics and gynecological waiting rooms for the experience of trauma and PTSD‐related stress disorders. PTSD symptoms were found to be significantly positively correlated with pain ratings (r = .282, P < 0.001) and pain‐related functional impairment (r = 0.303, P < 0.001). Those with a current PTSD diagnosis had significantly higher subjective pain and pain‐related impairment ratings than those with no PTSD. Furthermore, those with a current diagnosis of PTSD were significantly more likely to have used opioid analgesics for pain control compared to those without a diagnosis of PTSD (χ2 = 8.98, P = 0.011). When analyzing the separate PTSD symptom subclusters (re‐experiencing, avoidance, and hyperarousal), all symptom clusters were significantly related to pain and pain‐related impairment ratings, but only the avoidance cluster was significantly related to prior opioid pain medication use. We conclude that PTSD and trauma‐related disorders are common in impoverished medical populations and that their presence should be examined in patients with pain syndromes. Furthermore, these data suggest that PTSD and pain may share a vulnerability pathway, including the endogenous opioid neurotransmission systems.

The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal

RationaleCorticotropin-releasing factor (CRF) is the primary physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to globally coordinate the mammalian stress response. Hyperactivity of central nervous system CRF neurotransmission, acting primarily via the CRF1 receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, there is evidence of enhanced CRF transcription, release, and neuronal activity after the administration of and withdrawal from several drugs of abuse, including cannabis, cocaine, ethanol, and morphine. Treatment with CRF antagonists has been demonstrated to reduce the severity of certain drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed after abrupt drug discontinuation.Objectives/MethodsTo extend these findings, we investigated whether pretreatment with the selective CRF1 receptor antagonist R121919 decreases the behavioral and neuroendocrine activation observed after the precipitation of benzodiazepine (BZ) withdrawal in BZ-dependent rats.ResultsPretreatment with R121919 attenuated the subsequent HPA axis activation, behavioral measures of anxiety, and expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA, which occurs after flumazenil-precipitation of withdrawal from the BZ, lorazepam.ConclusionsThese results indicate that the activation of CRF neuronal systems may be a common neurobiological mechanism in withdrawal from drugs of abuse and moreover, that the CRF1 receptor subtype plays a major role in mediating the effects of CRF on neuroendocrine and behavioral responses during BZ withdrawal. Therefore, CRF1 receptor antagonists may be of therapeutic utility in the treatment of drug withdrawal syndromes.

Spontaneous Withdrawal from the Triazolobenzodiazepine Alprazolam Increases Cortical Corticotropin-Releasing Factor mRNA Expression

Corticotropin-releasing factor (CRF) is the major physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and plays a key role in coordinating the mammalian stress response. Substantial data implicates hyperactivity of CRF neuronal systems in the pathophysiology of depression and anxiety disorders. Enhanced CRF expression, release, and function have also been demonstrated during acute withdrawal from several drugs of abuse. Previous studies revealed that chronic administration of the anxiolytic alprazolam reduced indices of CRF and CRF1 receptor function. Conversely, measures of urocortin I and CRF2 receptor function were increased. To further scrutinize these findings, we sought to determine whether CRF neuronal systems are activated during spontaneous withdrawal from the triazolobenzodiazepine alprazolam in dependent rats and to characterize the time course, extent, and regional specificity of the patterns of activation. After 14 d of alprazolam administration (90 mg · kg-1 · d-1), spontaneous withdrawal produced activation of the HPA axis, as well as suppression of food intake and weight loss that peaked 24-48 hr after withdrawal. Remarkably, CRF mRNA expression in the cerebral cortex was markedly (>300%) increased over the same time period. Other indices of CRF-CRF1 and urocortin I-CRF2A function, altered by chronic alprazolam treatment as previously described, returned to pretreatment levels over 96 hr. The physiologic significance of this dramatic induction of cortical CRF mRNA expression, as well as whether this occurs during withdrawal from other drugs of abuse is yet to be determined. The marked increase in CRFergic neurotransmission is hypothesized to play a major role in benzodiazepine withdrawal.

Prevalence of childhood physical and sexual abuse in veterans with psychiatric diagnoses.

Abstract We examined the prevalence of childhood (⩽18 years) physical and sexual abuse reported among patients admitted to the psychiatric inpatient service and the differential rates of this abuse associated with psychiatric diagnoses. This study consisted of a retrospective chart review of 603 patients admitted to a psychiatric ward during a period of 1 year at Atlanta Veterans Affairs Medical Center who had data on childhood physical and sexual abuse. The prevalence of reported childhood physical or sexual abuse in this inpatient clinical population was 19.4% (117/603). The prevalence of reported physical abuse was 22.6% (19/84) in the women and 12.0% (62/519) in the men (p = 0.008); the prevalence of sexual abuse was 33.3% (28/84) in the women and 7.7% (40/519) in the men (p < 0.0001). More patients with depressive disorders reported sexual abuse than did those without these disorders. More patients with posttraumatic stress disorder (PTSD) reported physical and sexual abuse than did those without these disorders. Stratifying by race, sex, and diagnoses, multivariate analyses showed that the women with PTSD had a greater likelihood to report physical abuse (p = 0.03) and sexual abuse histories (p = 0.008) than did the women without PTSD. The men with substance-induced mood disorder (p = 0.01) were more likely to report physical abuse compared with the men without substance-induced mood disorder. Screening for abuse in patients with depressive disorders and PTSD is warranted to tailor individualized treatments for these patients. More research is needed to better understand the potential implications of childhood abuse on psychiatric diagnoses.

An Evolving Integrative Treatment Program for Military Sexual Trauma (MST) and One Veteran's Experience

Military sexual trauma (MST) increases the risk for Posttraumatic Stress Disorder (PTSD) and multiple other comorbidities, presenting substantial challenges for nurses and psychiatric and medical clinicians. A specialized VA Medical Center outpatient program is patterned after Hermans three-phased, empirically-supported, recovery treatments. We use a case example of a female veteran MST survivor to illustrate our treatment model. She presented to our program meeting diagnostic criteria for PTSD, Major Depressive Disorder, and a history of substance abuse. Post-treatment she demonstrated improved scores on measures of PTSD, quality of life, and socialization. This model shows promise for treatment of MST survivors with PTSD.

Psychological resilience is associated with more intact social functioning in veterans with post-traumatic stress disorder and depression

Patients with depression or post-traumatic stress disorder (PTSD), common sequelae among individuals exposed to stressful or traumatic events, often report impairment in social functioning. Resilience is a multidimensional construct that enables adaptive coping with life adversity. Relationship between resilience and social functioning among veterans with depression and PTSD is not entirely clear and is the focus of this report. Resilience was assessed in 264 veterans using the Connor-Davidson Resilience Scale, PTSD with the PTSD Symptom Scale, depression with the Beck Depression Inventory, and social functioning with the Short Form Health Survey. Higher resilience was associated with more intact social functioning after PTSD and depression severity, childhood maltreatment, physical health, gender, education, marital status, and employment were simultaneously adjusted for. Childhood maltreatment, gender, marital status, education, and employment did not predict social functioning; however, greater severity of PTSD, depression, or physical health problems was each significantly associated with more impaired social functioning. Our findings suggest that higher resilience was associated with more intact social functioning regardless of the severity of PTSD and depression. Given the importance of social functioning in depression and/or PTSD recovery, studies are needed to examine if enhancing resilience presents a complementary approach to alleviating impaired social functioning.

Urocortin, the CRF2 receptor and effects of anxiolytic drugs

Corticotropin-releasing factor (CRF) ts the major regulator of the HPA axis, and plays a key role in coordinatiig the mammalian stress.response. Recently, the existence of two distinct CRF receptor subtypes has been demonstrated CRF, and CRFs; the CRF: receptor also existing in multiple splice variants. Neuroanatomlc and pharmacologic data suggests that the novel ncuropeptide, urocortin, may be the endogenous CRF? hgand. While there is a considerable amount of data that supports a role for CRF in stress responses, depression and anxiety, and perhaps drug abuse, little is known about the role of urocortin and the CRFz receptor system m basic or stress ncumbiology We have previously demonstrated that chronic oral administration of the anviolytic benzodiazepine. alprazolam, to Sprague-Dawley rats decreases basal HPA axis activity, CRF mRNA espresslon in the central nucleus of the amygdala, and CRF, receptor mRNA and binding in the basolateral amygdala. Here we report that contrary to the downregulation of CRF and its CRF, receptor, chronic alprazolam treatment produced significant increases in urocottin mF3A cxpresion in the Edinger-Wcstphal nucleus and CWZreceptor binding m the lateral septum and vmtromedial hypothalamus (VMH). This increase in urocottin mRNA expression was still evident following both Ilumazcnd-precipitated and spontaneous alprazolam wlthdravval While available data suggests a role for urocortm and the CRF? receptor in the regulation of food and water balance, our data, as well as other recent studies demonstrating decreased CRFz, receptor mRNA express!on following maternal deptivatlon and mcreased immobility m a forced swim test following administration of CRI:: receptor antlscnse, Indicate that the urocortin-CRF2 receptor system may play a role m stress-coping behaviors. Additionally, it IS intrigumg to note that the CRF-CRF, and urocortin-CRFZ systems are mverscly modulated following chrome ansiolytic administration. A simdar antlparallel relationship between the CRF and CRF2 reqtor systems has been reported m an anxiety model In rats based on adverse early-life expmencc Supported hy NIH DA08705 and MH42088