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1.  Allopregnanolone Levels are Reduced in Temporal Cortex in Patients with Alzheimer’s Disease Compared to Cognitively Intact Control Subjects 
Biochimica et biophysica acta  2010;1801(8):951-959.
The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimer’s disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers.
Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects).
Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n= 40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r= −0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04).
Neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. The APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.
PMCID: PMC2907131  PMID: 20488256
2.  GABAergic neuroactive steroids: a new frontier in bipolar disorders? 
Neurosteroids are synthesized in the brain and modulate brain excitability. There is increasing evidence of their sedative, anesthetic and antiseizure properties, as well as their influence on mood. Currently neurosteroids are classified as pregnane neurosteroids (allopregnanolone and allotetrahydrodeoxycorticosterone), androstane neurosteroids (androstanediol and etiocholanone) or sulfated neurosteroids (pregnenolone sulfate and dehydroepiandrosterone sulfate). Both preclinical and clinical findings indicate that progesterone derivative neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone play a role in mood disorders. Clozapine and olanzapine, which were shown to be effective in stabilizing bipolar disorder, elevate pregnenolone levels in rat hippocampus, cerebral cortex, and serum. In lithium-treated mice, the blood levels of allopregnanolone and pregnenolone were elevated compared to control levels. Women diagnosed with bipolar disorder typically show symptomatic exacerbation in relation to the menstrual cycle, and show vulnerability to the onset or recurrence of mood disorders immediately after giving birth, when the levels of neurosteroid derivatives of progesterone drop. Whereas in women who had recovered from bipolar disorder, the plasma concentration of allopregnanolone was elevated compared to either healthy controls or women with major depressive disorder during the premenstrual period. During depressive episodes, blood level of allopregnanolone is low. Treatment with fluoxetine tends to stabilize the levels of neurosteroids in depression. These findings converge to suggest that these steroids have significant mood-stabilizing effect. This hypothesis is consistent with the observation that a number of anticonvulsants are effective therapies for bipolar disorder, a finding also consistent with the antiseizure properties of neurosteroids. Further exploration of action of neuroactive steroids is likely to open new frontiers in the investigation of the etiology and treatment of mood disorders, particularly bipolar disorders.
PMCID: PMC3573983  PMID: 23253178
3.  Psychiatric Diagnoses and Neurobehavioral Symptom Severity Among OEF/OIF VA Patients with Deployment-Related Traumatic Brain Injury: A Gender Comparison 
Traumatic brain injury (TBI) has substantial negative implications for the post-deployment adjustment of Veterans who served in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF); however, most research on Veterans has focused on males. This study investigated gender differences in psychiatric diagnoses and neurobehavioral symptom severity among OEF/OIF Veterans with deployment-related TBI.
This population-based study examined psychiatric diagnoses and self-reported neurobehavioral symptom severity from administrative records for 12,605 United States OEF/OIF Veterans evaluated as having deployment-related TBI. Men (n = 11,951) and women (n = 654) who were evaluated to have deployment-related TBI during a standardized comprehensive TBI evaluation in Department of Veterans Affairs (VA) facilities were compared on the presence of psychiatric diagnoses and severity of neurobehavioral symptoms.
Posttraumatic stress disorder (PTSD) was the most common psychiatric condition for both genders, although women were less likely than men to have a PTSD diagnosis. In contrast, relative to men, women were 2 times more likely to have a depression diagnosis, 1.3 times more likely to have a non-PTSD anxiety disorder, and 1.5 times more likely to have PTSD with comorbid depression. Multivariate analyses indicated that blast exposure during deployment may account for some of these differences. Additionally, women reported significantly more severe symptoms across a range of neurobehavioral domains.
Although PTSD was the most common condition for both men and women, it is also critical for providers to identify and treat other conditions, especially depression and neurobehavioral symptoms, among women Veterans with deployment-related TBI.
PMCID: PMC3132395  PMID: 21724143
traumatic brain injury; Veterans; women; gender; psychiatric conditions; neurobehavioral symptoms; post-deployment adjustment
4.  Gender Differences in Rates of Depression, PTSD, Pain, Obesity, and Military Sexual Trauma Among Connecticut War Veterans of Iraq and Afghanistan 
Journal of Women's Health  2010;19(2):267-271.
The current wars in Iraq and Afghanistan have led to an increasing number of female veterans seeking medical and mental healthcare in the Department of Veterans Affairs (VA) healthcare system. To better understand gender differences in healthcare needs among recently returned veterans, we examined the prevalence of positive screenings for depression, posttraumatic stress disorder (PTSD), military sexual trauma (MST), obesity, and chronic pain among female and male veterans of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) receiving care at the VA Connecticut Healthcare System.
We performed a retrospective, cross-sectional data analysis of OEF/OIF veterans at VA Connecticut who received services in either Primary Care or the Women's Health Clinic between 2001 and 2006.
In this study, 1129 electronic medical records (1032 men, 197 women) were examined. Female veterans were more likely to screen positive for MST (14% vs. 1%, p < 0.001) and depression (48% vs. 39%, p = 0.01) and less likely to screen positive for PTSD (21% vs. 33%, p = 0.002). There was no significant gender difference in clinically significant pain scores. Men were more likely than women to have body mass index (BMI) >30 kg/m2 (21% vs. 13%, p = 0.008).
These results suggest that important gender differences exist in the prevalence of positive screenings for MST, depression, obesity, and PTSD. As the VA continues to review and improve its services for women veterans, clinicians, researchers, and senior leaders should consider innovative ways to ensure that female veterans receive the health services they need within the VA system.
PMCID: PMC3052274  PMID: 20109115
5.  A retrospective cohort study of U.S. service members returning from Afghanistan and Iraq: is physical health worsening over time? 
BMC Public Health  2012;12:1124.
High rates of mental health disorders have been reported in veterans returning from deployment to Afghanistan (Operation Enduring Freedom: OEF) and Iraq (Operation Iraqi Freedom: OIF); however, less is known about physical health functioning and its temporal course post-deployment. Therefore, our goal is to study physical health functioning in OEF/OIF veterans after deployment.
We analyzed self-reported physical health functioning as physical component summary (PCS) scores on the Veterans version of the Short Form 36 health survey in 679 OEF/OIF veterans clinically evaluated at a post-deployment health clinic. Veterans were stratified into four groups based on time post-deployment: (1Yr) 0 – 365 days; (2Yr) 366 – 730 days; (3Yr) 731 – 1095 days; and (4Yr+) > 1095 days. To assess the possibility that our effect was specific to a treatment-seeking sample, we also analyzed PCS scores from a separate military community sample of 768 OEF/OIF veterans evaluated pre-deployment and up to one-year post-deployment.
In veterans evaluated at our clinic, we observed significantly lower PCS scores as time post-deployment increased (p = 0.018) after adjusting for probable post-traumatic stress disorder (PTSD). We similarly observed in our community sample that PCS scores were lower both immediately after and one year after return from deployment (p < 0.001) relative to pre-deployment PCS. Further, PCS scores obtained 1-year post-deployment were significantly lower than scores obtained immediately post-deployment (p = 0.02).
In our clinical sample, the longer the duration between return from deployment and their visit to our clinic, the worse the Veteran’s physical health even after adjusting for PTSD. Additionally, a decline is also present in a military community sample of OEF/OIF veterans. These data suggest that, as time since deployment length increases, physical health may deteriorate for some veterans.
PMCID: PMC3543837  PMID: 23272950
Veterans; Military personnel; Veterans health; Quality of life; Operation enduring freedom; Operation iraqi freedom; Health surveys
6.  Neurosteroid regulation of CNS development 
Pharmacology & therapeutics  2007;116(1):107-124.
Neurosteroids are a relatively new class of neuroactive compounds, brought to prominence in the past two decades. Despite knowing of their presence in the nervous system of various species for over twenty years and knowing of their functions as GABAA and NMDA ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of four distinct neurosteroids – pregnenolone, progesterone, allopregnanolone and dehydroepiandrosterone.
PMCID: PMC2386997  PMID: 17651807
Pregnenolone; Progesterone; Allopregnanolone; Dehydroepiandrosterone; neurogenesis; neurotoxicity; neurodegeneration; Niemann Pick Type C
7.  Feedback from recently returned veterans on an anonymous web-based brief alcohol intervention 
Veterans of Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) are at increased risk for alcohol misuse, and innovative methods are needed to improve their access to alcohol screening and brief interventions (SBI). This study adapted an electronic SBI (e-SBI) website shown to be efficacious in college students for OEF/OIF veterans and reported findings from interviews with OEF/OIF veterans about their impressions of the e-SBI.
Outpatient veterans of OEF/OIF who drank ≥3 days in the past week were recruited from a US Department of Veterans Affairs (VA) Deployment Health Clinic waiting room. Veterans privately pretested the anonymous e-SBI then completed individual semistructured audio-recorded interviews. Their responses were analyzed using template analysis to explore domains identified a priori as well as emergent domains.
During interviews, all nine OEF/OIF veterans (1 woman and 8 men) indicated they had received feedback for risky alcohol consumption. Participants generally liked the standard-drinks image, alcohol-related caloric and monetary feedback, and the website’s brevity and anonymity (a priori domains). They also experienced challenges with portions of the e-SBI assessment and viewed feedback regarding alcohol risk and normative drinking as problematic, but described potential benefits derived from the e-SBI (emergent domains). The most appealing e-SBIs would ensure anonymity and provide personalized transparent feedback about alcohol-related risk, consideration of the context for drinking, strategies to reduce drinking, and additional resources for veterans with more severe alcohol misuse.
Results of this qualitative exploratory study suggest e-SBI may be an acceptable strategy for increasing OEF/OIF veteran access to evidenced-based alcohol SBI.
PMCID: PMC3507636  PMID: 23186354
Internet; Alcohol; Brief intervention; Feedback; Iraq war; Veteran
8.  Self Reported Incidence and Morbidity of Acute Respiratory Illness among Deployed U.S. Military in Iraq and Afghanistan 
PLoS ONE  2009;4(7):e6177.
Historically, respiratory infections have had a significant impact on U.S. military missions. Deployed troops are particularly at high risk due to close living conditions, stressful work environments and increased exposure to pathogens. To date, there are limited data available on acute respiratory illness (ARI) among troops deployed in support of ongoing military operations, specifically Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF).
Using self-report data from two sources collected from troops deployed to Iraq, Afghanistan and the surrounding region, we analyzed incidence and risk factors for ARI. Military personnel on mid-deployment Rest & Recuperation (R&R) or during redeployment were eligible to participate in the voluntary self-report survey.
Overall, 39.5% reported having at least one ARI. Of these, 18.5% sought medical care and 33.8% reported having decreased job performance. The rate of self-reported ARI was 15 episodes per 100 person-months among those taking the voluntary survey, and 24.7 episodes per 100 person-months among those taking the clinic health questionnaire. Negative binomial regression analysis found female sex, Navy branch of service and lack of flush toilets to be independently associated with increased rates of ARI. Deployment to OIF, increasing age and higher rank were also positively associated with ARI risk.
The overall percentage of deployed military personnel reporting at least one acute respiratory illness decreased since earlier parts of OIF/OEF. However, the reported effect on job performance increased tremendously. The most important factors associated with increased respiratory infection are female sex, Navy branch of service, lack of improved latrine facilities, deployment to OIF, increasing age and higher rank.
PMCID: PMC2702682  PMID: 19584919
9.  Pregnancy and Mental Health Among Women Veterans Returning from Iraq and Afghanistan 
Journal of Women's Health  2010;19(12):2159-2166.
Veterans of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) may experience significant stress during military service that can have lingering effects. Little is known about mental health problems or treatment among pregnant OEF/OIF women veterans. The aim of this study was to determine the prevalence of mental health problems among veterans who received pregnancy-related care in the Veterans Health Administration (VHA) system.
Data from the Defense Manpower Data Center (DMDC) deployment roster of military discharges from October 1, 2001, through April 30, 2008, were used to assemble an administrative cohort of female OEF/OIF veterans enrolled in care at the VHA (n = 43,078). Pregnancy and mental health conditions were quantified according to ICD-9-CM codes and specifications. Mental healthcare use and prenatal care were assessed by analyzing VHA stop codes.
During the study period, 2966 (7%) women received at least one episode of pregnancy-related care, and 32% of veterans with a pregnancy and 21% without a pregnancy received one or more mental health diagnoses (p < 0.0001). Veterans with a pregnancy were twice as likely to have a diagnosis of depression, anxiety, posttraumatic stress disorder (PTSD), bipolar disorder, or schizophrenia as those without a pregnancy.
Women OEF/OIF veterans commonly experience mental health problems after military service. The burden of mental health conditions is higher among women with an identified instance of pregnancy than among those without. Because women do not receive pregnancy care at the VHA, however, little is known about ongoing concomitant prenatal and mental healthcare or about pregnancy outcomes among these women veterans.
PMCID: PMC3052271  PMID: 21039234
10.  Neurosteroid Replacement Therapy for Catamenial Epilepsy 
Perimenstural catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation, affects a high proportion of women of reproductive age with drug refractory epilepsy. Enhanced seizure susceptibility in perimenstrual catamenial epilepsy is believed to be due to the withdrawal of the progesterone-derived GABAA receptor modulating neurosteroid allopregnanolone as a result of the fall in progesterone at the time of menstruation. Studies in a rat pseudopregnancy model of catamenial epilepsy indicate that following neurosteroid withdrawal there is enhanced susceptibility to chemoconvulsant seizures. There is also a transitory increase in the frequency of spontaneous seizures in epleptic rats that had experienced pilocarpine-induced status epilepticus. In the catamenial epilepsy model, there is a marked reduction in the antiseizure potency of anticonvulsant drugs, including benzodiazepines and valproate, but an increase in the anticonvulsant potency and protective index of neurosteroids such as allopregnanolone and the neurosteroid analog ganaxolone. The enhanced seizure susceptibility and benzodiazepine-resistance following neurosteroid withdrawal may be related to reduced expression and altered kinetics of synaptic GABAA receptors and increased expression of GABAA receptor subunits (such as α4) that confer benzodiazepine insensitivity. The enhanced potency of neurosteroids may be due to a relative increase following neurosteroid withdrawal in the expression of neurosteroid-sensitive δ-subunit-containing perisynaptic/extrasynaptic GABAA receptors. Positive allosteric modulatory neurosteroids and synthetic analogs such as ganaxolone may be administered to prevent catamenial seizure exacerbations, which we refer to as “neurosteroid replacement therapy.”
PMCID: PMC2682439  PMID: 19332335
catamenial epilepsy; progesterone; neurosteroid; allopregnanolone; ganaxolone; GABAA receptor
11.  Patterns and Correlates of Prescription Opioid Use in OEF/OIF Veterans with Chronic Non-Cancer Pain 
Pain medicine (Malden, Mass.)  2011;12(10):1502-1509.
Little is known about the treatment Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans receive for chronic non-cancer pain (CNCP). We sought to describe the prevalence of prescription opioid use, types and doses of opioids received, and identify correlates of receiving prescription opioids for CNCP among OEF/OIF veterans.
Retrospective review of VA administrative data.
Ambulatory clinics within a VA regional healthcare network.
OEF/OIF veterans who had at least 3 elevated pain screening scores within a 12-month period in 2008. Within this group, those prescribed opioids (n=485) over the next 12 months were compared to those not prescribed opioids (n=277). In addition, patients receiving opioids short term (<90 days, n=284) were compared to patients receiving them long-term (≥90 consecutive days, n=201).
Of 762 OEF/OIF veterans with CNCP, 64% were prescribed at least one opioid medication over the 12 months following their index dates. Of those prescribed an opioid, 59% were prescribed opioids short-term and 41% were prescribed opioids long-term. The average morphine-equivalent opioid dose for short-term users was 23.7 mg (SD=20.5) compared with 40.8 mg (SD=36.1) for long-term users (p<0.001). Fifty-one percent of long-term opioid users were prescribed short-acting opioids only and one-third were also prescribed sedative-hypnotics. In adjusted analyses, diagnoses of low back pain, migraine headache, post-traumatic stress disorder, and nicotine use disorder were associated with an increased likelihood of receiving an opioid prescription.
Prescription opioid use is common among OEF/OIF veterans with CNCP and is associated with several pain diagnoses and medical conditions.
PMCID: PMC3724513  PMID: 21899715
Chronic pain; Opioids; Veteran; Pain/drug therapy
12.  Comparison of outpatient health care utilization among returning women and men Veterans from Afghanistan and Iraq 
The number of women serving in the United States military increased during Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), leading to a subsequent surge in new women Veterans seeking health care services from the Veterans Administration (VA). The objective of this study was to examine gender differences among OEF/OIF Veterans in utilization of VA outpatient health care services.
Our retrospective cohort consisted of 1,620 OEF/OIF Veterans (240 women and 1380 men) who enrolled for outpatient healthcare at a single VA facility. We collected demographic data and information on military service and VA utilization from VA electronic medical records. To assess gender differences we used two models: use versus nonuse of services (logistic regression) and intensity of use among users (negative binomial regression).
In our sample, women were more likely to be younger, single, and non-white than men. Women were more likely to utilize outpatient care services (odds ratio [OR] = 1.47, 95% confidence interval [CI]:1.09, 1.98), but once care was initiated, frequency of visits over time (intensity) did not differ by gender (incident rate ratio [IRR] = 1.07; 95% CI: 0.90, 1.27).
Recently discharged OEF/OIF women Veterans were more likely to seek VA health care than men Veterans. But the intensity of use was similar between women and men VA care users. As more women use VA health care, prospective studies exploring gender differences in types of services utilized, health outcomes, and factors associated with satisfaction will be required.
PMCID: PMC2910695  PMID: 20565985
13.  Anxiogenic Effects of Neurosteroid Exposure: Sex Differences and Altered GABAA Receptor Pharmacology in Adult Rats 
Acute exposure to progesterone or its neurosteroid derivative allopregnanolone (3α,5α-THP) is anxiolytic, consistent with the GABA modulatory effects of 3α,5α-THP at the GABAA receptor. However, continuous exposure to progesterone increases anxiety in association with increased expression of the benzodiazepine-insensitive GABAA receptor α4 subunit. Furthermore, negative mood symptoms and altered GABAA receptor pharmacology in patients with premenstrual dysphoric disorder occur in the early luteal phase in association with peak circulating levels of progesterone and 3α,5α-THP. Because sex differences have been reported in steroid-regulated anxiety responses, the present study investigated the role of sex and development in the regulation of anxiety after short-term exposure to 3α,5α-THP. To this end, we compared the effects of hormone administration in adult male, adult female, and juvenile female rats. Increased anxiety in the elevated plus maze was evident in all groups after 48-h exposure to either 3α,5α-THP or progesterone. At this time point, alterations in the anxiolytic profile of benzodiazepine agonists and antagonists were also observed in both adult males and females in the elevated plus maze. However, sex differences in the acoustic startle response were observed after short-term hormone treatment such that only female rats displayed an increased response indicative of higher anxiety levels. These results suggest that although neurosteroid exposure may influence both the pharmacological properties of the GABAA receptor and the manifestation of anxiety in both sexes, the effects of neurosteroids may be modulated in a sex- and task-specific manner.
PMCID: PMC2882102  PMID: 12606703
14.  Comparative Analysis of Gelsemine and Gelsemium sempervirens Activity on Neurosteroid Allopregnanolone Formation in the Spinal Cord and Limbic System 
Centesimal dilutions (5, 9 and 15 cH) of Gelsemium sempervirens are claimed to be capable of exerting anxiolytic and analgesic effects. However, basic results supporting this assertion are rare, and the mechanism of action of G. sempervirens is completely unknown. To clarify the point, we performed a comparative analysis of the effects of dilutions 5, 9 and 15 cH of G. sempervirens or gelsemine (the major active principle of G. sempervirens) on allopregnanolone (3α,5α-THP) production in the rat limbic system (hippocampus and amygdala or H-A) and spinal cord (SC). Indeed, H-A and SC are two pivotal structures controlling, respectively, anxiety and pain that are also modulated by the neurosteroid 3α,5α-THP. At the dilution 5 cH, both G. sempervirens and gelsemine stimulated [3H]progesterone conversion into [3H]3α,5α-THP by H-A and SC slices, and the stimulatory effect was fully (100%) reproducible in all assays. The dilution 9 cH of G. sempervirens or gelsemine also stimulated 3α,5α-THP formation in H-A and SC but the reproducibility rate decreased to 75%. At 15 cH of G. sempervirens or gelsemine, no effect was observed on 3α,5α-THP neosynthesis in H-A and SC slices. The stimulatory action of G. sempervirens and gelsemine (5 cH) on 3α,5α-THP production was blocked by strychnine, the selective antagonist of glycine receptors. Altogether, these results, which constitute the first basic demonstration of cellular effects of G. sempervirens, also offer interesting possibilities for the improvement of G. sempervirens-based therapeutic strategies.
PMCID: PMC3136435  PMID: 19628662
15.  The Case for Treating Depression in Military Spouses 
The increased operational tempo associated with current deployments to Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) is placing considerable strain on military families. Among other sequelae of OIF and OEF deployment, findings from recent studies suggest high rates of depression in spouses of service members. This review presents a rationale for targeting depression among military spouses. It examines how stressors relating to the deployment cycle may contribute to depression in spouses, and outlines the effects of spousal depression on the mental health of service members and their children. Mental health services currently available to military spouses as well as barriers to their care are also described. Considerations for the adaptation of treatment to their unique circumstances and needs are discussed.
PMCID: PMC3164322  PMID: 21842994
military spouses; depression; service members; deployment
16.  Neurosteroids: Endogenous Role in the Human Brian and Therapeutic Potentials 
Progress in brain research  2010;186:113-137.
This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone, and androstane neurosteroids, such as androstanediol and etiocholanone. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful antiseizure activity in diverse animal models. Neurosteroids increases both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-Areceptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.
PMCID: PMC3139029  PMID: 21094889
Allopregnanolone; androstanediol; deoxycorticosterone; epilepsy; ganaxolone; GABA-A receptor; sex differences; neurosteroid; progesterone; seizure susceptibility; testosterone
17.  A TSPO ligand is protective in a mouse model of multiple sclerosis 
EMBO Molecular Medicine  2013;5(6):891-903.
Local production of neurosteroids such as progesterone and allopregnanolone confers neuroprotection in central nervous system (CNS) inflammatory diseases. The mitochondrial translocator protein (TSPO) performs a rate-limiting step in the conversion of cholesterol to pregnenolone and its steroid derivatives. Previous studies have shown that TSPO is upregulated in microglia and astroglia during neural inflammation, and radiolabelled TSPO ligands such as PK11195 have been used to image and localize injury in the CNS. Recent studies have shown that modulating TSPO activity with pharmacological ligands such as etifoxine can initiate the production of neurosteroids locally in the injured CNS. In this study, we examined the effects of etifoxine, a clinically available anxiolytic drug, in the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis (MS). Our results showed that etifoxine attenuated EAE severity when administered before the development of clinical signs and also improved symptomatic recovery when administered at the peak of the disease. In both cases, recovery was correlated with diminished inflammatory pathology in the lumbar spinal cord. Modulation of TSPO activity by etifoxine led to less peripheral immune cell infiltration of the spinal cord, and increased oligodendroglial regeneration after inflammatory demyelination in EAE. Our results suggest that a TSPO ligand, e.g. etifoxine, could be a potential new therapeutic option for MS with benefits that could be comparable to the administration of systemic steroids but potentially avoiding the detrimental side effects of long-term direct use of steroids.
PMCID: PMC3779450  PMID: 23681668
autoimmune demyelination; etifoxine; mitochondria; multiple sclerosis; translocator protein
18.  Differential Anesthetic Activity of Ketamine and the GABAergic Neurosteroid Allopregnanolone in Mice Lacking Progesterone Receptor A and B subtypes 
Progesterone affects the function of the brain by multiple mechanisms. The physiological effects of progesterone are mediated by interaction of the hormone with progesterone receptors (PRs), which are widely expressed in the hypothalamus, hippocampus and limbic areas. The PR is composed of two protein isoforms, PR-A and PR-B, which are expressed from a single PR gene. In addition, progesterone influences neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABAA receptors. However, the role of PRs in the sedative-hypnotic action of neurosteroids is unclear. In this study, PR knockout (PRKO) mice were used as model to study the sedative-anesthetic actions of the progesterone-derived neurosteroid allopregnanolone and the non-competitive NMDA receptor antagonist ketamine. Mice were confirmed to be PR deficient by genotyping and immunohistochemistry of PR expression in the brain. Anesthetic potency was evaluated by the loss of the righting reflex paradigm. Allopregnanolone induced anesthetic activity was similar in PRKO mice and their wild-type littermates, suggesting that PRs are not involved in the anesthetic response to allopregnanolone. However, the non-competitive NMDA receptor antagonist ketamine has significantly reduced anesthetic potency in PRKO mice, suggesting a possible developmental plasticity of glutamate receptors. There was no marked gender-related difference to ketamine response in both genotypes. In conclusion, these results suggest that the neurosteroid allopregnanolone and ketamine produce differential anesthetic response in mice lacking PRs.
PMCID: PMC2561334  PMID: 18200328
Allopregnanolone; Anesthesia; Neurosteroid; Progesterone receptor
19.  Gender Differences Among Veterans Deployed in Support of the Wars in Afghanistan and Iraq 
Journal of General Internal Medicine  2013;28(Suppl 2):556-562.
The changing scope of women’s roles in combat operations has led to growing interest in women’s deployment experiences and post-deployment adjustment.
To quantify the gender-specific frequency of deployment stressors, including sexual and non-sexual harassment, lack of social support and combat exposure. To quantify gender-specific post-deployment mental health conditions and associations between deployment stressors and posttraumatic stress disorder (PTSD), to inform the care of Veterans returning from the current conflicts.
National mail survey of OEF/OIF Veterans randomly sampled within gender, with women oversampled.
The community.
In total, 1,207 female and 1,137 male Veterans from a roster of all Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans. Response rate was 48.6 %.
Deployment stressors (including combat and harassment stress), PTSD, depression, anxiety and alcohol use, all measured via self-report.
Women were more likely to report sexual harassment (OR = 8.7, 95% CI: 6.9, 11) but less likely to report combat (OR = 0 .62, 95 % CI: 0.50, 0.76). Women and men were equally likely to report symptoms consistent with probable PTSD (OR = 0 .87, 95 % CI: 0.70, 1.1) and symptomatic anxiety (OR  =  1.1, 9 5% CI: 0.86, 1.3). Women were more likely to report probable depression (OR = 1.3, 95 % CI: 1.1, 1.6) and less likely to report problematic alcohol use (OR  = 0 .59, 9 5% CI: 0.47, 0.72). With a five-point change in harassment stress, adjusted odds ratios for PTSD were 1.36 (95 % CI: 1.23, 1.52) for women and 1.38 (95 % CI: 1.19, 1.61) for men. The analogous associations between combat stress and PTSD were 1.31 (95 % CI: 1.24, 1.39) and 1.31 (95 % CI: 1.26, 1.36), respectively.
Although there are important gender differences in deployment stressors—including women’s increased risk of interpersonal stressors—and post-deployment adjustment, there are also significant similarities. The post-deployment adjustment of our nation’s growing population of female Veterans seems comparable to that of our nation’s male Veterans.
PMCID: PMC3695273  PMID: 23807065
veteran; women; sexual harassment; PTSD
20.  Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration 
Neuropharmacology  2012;63(4):555-564.
Recent evidence suggests that GABAA receptor ligands may regulate ethanol intake via effects at both synaptic and extrasynaptic receptors. For example, the endogenous neurosteroid, allopregnanolone (ALLO) has a similar pharmacological profile as ethanol, and it alters ethanol intake in rodent models. Additionally, recent evidence suggests that δ-subunit containing extrasynaptic GABAA receptors may confer high sensitivity to both ethanol and neurosteroids. The purpose of the present study was to determine the effects of ganaxolone (GAN; an ALLO analogue) and gaboxadol (THIP; a GABAA receptor agonist with selectivity for the extrasynaptic δ-subunit) on ethanol intake, drinking patterns, and bout characteristics in operant and limited access self-administration procedures. In separate studies, the effects of GAN (0 – 10 mg/kg) and THIP (2 – 16 mg/kg) were tested in C57BL/6J male mice provided with two-hour access to a two-bottle choice of water or 10% ethanol or trained to respond for 30 minutes of access to 10% ethanol. GAN had no overall significant effect on operant ethanol self-administration, but tended to decrease the latency to consume the first bout. In the limited-access procedure, GAN dose-dependently decreased ethanol intake. THIP dose-dependently decreased ethanol intake in both paradigms, altering both the consummatory and appetitive processes of operant self-administration as well as shifting the drinking patterns in both procedures. These results add to literature suggesting time-dependent effects of neurosteroids to promote the onset, and to subsequently decrease, ethanol drinking behavior, and they support a role for extrasynaptic GABAA receptor activation in ethanol reinforcement.
PMCID: PMC3656651  PMID: 22613838
21.  Veteran Perceptions of Virtual Reality to Assess and Treat Posttraumatic Stress Disorder 
Implementation of evidence-based treatments (EBT) is necessary to address posttraumatic stress disorder (PTSD) in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) military service personnel. Because virtual reality (VR) offers a promising tool for delivery of one type of EBT—exposure therapy—this study explored veterans' perceptions of VR as an assessment tool and treatment adjunct. We conducted semi-structured interviews with 14 OEF/OIF veterans being treated for PTSD after viewing two 3 minute VR scenarios as part of a larger research study. Veterans reported a capacity for immersion in VR in both combat and civilian environments, characterized by self-reported physiological reactivity, thoughts/behaviors similar to those experienced in Iraq, and triggered memories. Although participants were generally positive about VR, they expressed concerns about the possibility of negative reactions after viewing VR. Findings are discussed in the context of further development of VR aided interventions in veteran healthcare systems.
PMCID: PMC3624696  PMID: 23574368
22.  Neurosteroid Binding Sites on the GABAA Receptor Complex as Novel Targets for Therapeutics to Reduce Alcohol Abuse and Dependence 
Despite the prevalence of alcohol abuse and dependence in the US and Europe, there are only five approved pharmacotherapies for alcohol dependence. Moreover, these pharmacotherapeutic options have limited clinical utility. The purpose of this paper is to present pertinent literature suggesting that both alcohol and the neurosteroids interact at the GABAA receptor complex and that the neurosteroid sites on this receptor complex could serve as new targets for the development of novel therapeutics for alcohol abuse. This paper will also present data collected by our laboratory showing that one neurosteroid in particular, dehydroepiandrosterone (DHEA), decreases ethanol intake in rats under a variety of conditions. In the process, we will also mention relevant studies from the literature suggesting that both particular subtypes and subunits of the GABAA receptor play an important role in mediating the interaction of neurosteroids and ethanol.
PMCID: PMC3206502  PMID: 22110489
23.  Enhancing entrance into PTSD treatment for post-deployment veterans through collaborative/integrative care 
High rates of posttraumatic stress disorder (PTSD) among post-deployment veterans and the associated long-term consequences highlight the importance of early identification and treatment. The Veterans Health Administration (VHA)’s Primary Care Mental Health Integration (PCMHI) program aims to increase identification and access to care for veterans with mental illness, decrease stigma, improve continuity of care, and the efficiency of healthcare utilization. This project examines PCMHI’s progress towards these goals within the Operation Iraqi Freedom/Operation Enduring Freedom (OEF/OIF) population. We examined data from consults to the OEF/OIF PTSD clinic for 18 months. PCMHI placed 129 consults and 91 (70.5%) were completed. Veterans referred by PCMHI tended to have increased consult completion in specialty care, higher rates of confirmed PTSD, however, no significant differences in reported PTSD symptoms, or follow-up visits in the OEF/OIF PTSD clinic compared to Veterans referred from the hospital at large. PCMHI potentially preserve resources, increases continuity of care, and increases treatment access for OEF/OIF/OND veterans.
PMCID: PMC3717667  PMID: 24073084
Collaborative care; PTSD; Mental health; PCMHI
24.  Health Risk Behaviors of Afghanistan and Iraq War Veterans Attending College 
The population military veterans attending college is rapidly growing as veterans return from Operations Enduring Freedom and Iraqi Freedom (OEF/OIF). We sought to describe patterns of student veterans’ health-related behaviors and how they might differ from their non-veteran peers.
We analyzed data from the 2008 Boynton College Student Health Survey (CSHS).
CSHS participants completed an anonymous online survey.
The CSHS sampled students (n=8,651) attending public, private, two-, and four-year postsecondary educational institutions in Minnesota.
The CSHS included items on substance use (including alcohol and tobacco), safety, nutrition, and physical activity.
We described demographics of OEF/OIF veteran, non-OEF/OIF veteran, and non-veteran students and used poisson regression to compute adjusted relative risks (ARR) with 95% confidence intervals to characterize associations between veteran status and health behaviors.
After controlling for demographics, veteran students reported more safety-, tobacco-, and alcohol-related risk behaviors compared to non-veteran students. For instance, compared to the non-veteran reference group, the ARR for past year smokeless tobacco use and physical fighting among for OEF/OIF veterans was 1.76 [CI: 1.31–2.35] and 1.48 [CI: 1.22–1.79] respectively. Veteran and non-veteran students display similar weight-related behaviors, though OEF/OIF veteran students were more likely to engage in strengthening exercises.
There are specific health risk behaviors which are particularly relevant for veterans attending postsecondary institutions. As veterans enroll in postsecondary education there is a unique window of opportunity for health promotion in this population.
PMCID: PMC3579508  PMID: 22040391
Veterans; Young Adult; Tobacco; Substance Abuse; Obesity; Safety
Neuroscience  2010;166(1):5.
The neurosteroid allopregnanolone (ALLO) is a progesterone metabolite that is one of a family of neuroactive steroids (NAS) that are potent positive allosteric modulators of γ-aminobutyric acidA (GABAA) receptors. These GABAergic NAS are produced peripherally (in the adrenals and gonads) and centrally in the brain. Peripherally produced NAS modulate some effects of ethanol intoxication (e.g., anxiolytic, antidepressant, and anticonvulsant effects) in rodents. We have found that NAS also may be involved in the rebound neural hyperexcitability following a high ethanol dose. Removal of the adrenals and gonads (ADX/GDX) increased withdrawal severity following 4 g/kg ethanol, as measured by handling-induced convulsions (HICs) in male and female DBA/2J mice. NAS are produced through the metabolism of progesterone (PROG), deoxycorticosterone (DOC), or testosterone, which can be blocked with the administration of finasteride (FIN), a 5α-reductase enzyme inhibitor. The current investigation was undertaken to clarify the step(s) in the biosynthetic NAS pathway that were sufficient to restore the acute ethanol withdrawal profile in ADX/GDX mice to that seen in intact animals.
Male and female DBA/2J mice underwent ADX/GDX or SHAM surgery. After recovery, separate groups of animals were administered PROG, DOC, PROG+FIN, DOC+FIN, FIN, ALLO, ganaxalone (a synthetic ALLO derivative), corticosterone, or vehicle. Animals were then administered a 4 g/kg ethanol dose and allowed to undergo withdrawal. HICs were measured for 12 hours and again at 24 hours. The results indicate that replacement with PROG and DOC restored the withdrawal profile in ADX/GDX animals to SHAM levels, and that this effect was blocked with co-administration of FIN. Administration of FIN alone increased the withdrawal profile in both SHAM and ADX/GDX males. These findings indicate that the increase in acute withdrawal severity after ADX/GDX may be due to the loss of GABAergic NAS, providing insight into the contribution of endogenous GABAergic NAS to ethanol withdrawal severity.
PMCID: PMC2815158  PMID: 20004707
Neurosteroids; alcohol; allopregnanolone; progesterone; deoxycorticosterone; finasteride

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