Splenic artery aneurysm: a rare complication of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of renal dysfunction. It is the most common genetic disorder leading to end-stage kidney disease requiring dialysis. ADPKD is a multisystem disease and is linked to several extra renal abnormalities. Splenic artery aneurysms are rare in the general population. ADPKD is associated with cerebral artery aneurysms. However, splenic artery aneurysms are not a well-recognised complication of ADPKD. We report an unusual case of a splenic artery aneurysm found incidentally on abdominal CT imaging of a woman with known ADPKD.

Cancer Treatment-Related Ovarian Dysfunction in Women of Childbearing Potential: Management and Fertility Preservation Options.

PURPOSE: To review the complex concerns of oncofertility created through increased cancer survivorship and the long-term effects of cancer treatment in young adults. DESIGN: Review chemotherapy-induced ovarian dysfunction, outline how fertility may be addressed before treatment initiation, and discuss barriers to oncofertility treatment and guidelines for oncologists to provide this care to their patients. CONCLUSION: In women of childbearing potential, ovarian dysfunction resulting from cancer therapy has profound short- and long-term implications. Ovarian dysfunction can manifest as menstrual abnormalities, hot flashes, night sweats, impaired fertility, and in the long term, increased cardiovascular risk, bone mineral density loss, and cognitive deficits. The risk of ovarian dysfunction varies between drug classes, number of received lines of therapy, chemotherapy dosage, patient age, and baseline fertility status. Currently, there is no standard clinical practice to evaluate patients for their risk of developing ovarian dysfunction with systemic therapy or means to address hormonal fluctuations during treatment. This review provides a clinical guide to obtain a baseline fertility assessment and facilitate fertility preservation discussions.

Naltrexone-bupropion combinations do not affect cocaine self-administration in humans.

The FDA has not yet approved a pharmacotherapy for cocaine use disorder despite nearly four decades of research. This study determined the initial efficacy, safety, and tolerability of naltrexone-bupropion combinations as a putative pharmacotherapy for cocaine use disorder. Thirty-one (31) non-treatment seeking participants with cocaine use disorder completed a mixed-design human laboratory study. Participants were randomly assigned to the naltrexone conditions (i.e., 0, 50 mg/day; between-subject factor) and maintained on escalating doses of bupropion (i.e., 0, 100, 200, 400 mg/day; within-subject factor) for at least four days prior to the conduct of experimental sessions. Cocaine self-administration (IN, 0, 40, 80 mg) was then determined using a modified progressive ratio and relapse procedure. Subjective and cardiovascular effects were also measured. Cocaine produced prototypical dose-related increases in self-administration, subjective outcomes (e.g., "Like Drug"), and cardiovascular indices (e.g., heart rate, blood pressure) during placebo maintenance. Naltrexone and bupropion alone, or in combination, did not significantly decrease self-administration on either procedure. Low doses of bupropion (i.e., 100 mg) blunted the effects of the cocaine on subjective measures of "Like Drug" and "Stimulated". No unexpected adverse effects were observed with naltrexone and bupropion, alone and combined, in conjunction with cocaine. Together, these results do not support the use of these bupropion-naltrexone combinations for the treatment of cocaine use disorder. Future research should determine if novel drug combinations may decrease cocaine self-administration.

Topiramate-phentermine combinations reduce cocaine self-administration in humans.

RATIONALE: Cocaine use disorder is an unrelenting public health concern. Despite nearly four decades of research, an FDA approved medication is not yet available. OBJECTIVES: The objective of this human laboratory study was to demonstrate the initial efficacy, safety and tolerability of topiramate-phentermine combinations for cocaine use disorder. METHODS: Thirty-one (31) participants with cocaine use disorder completed this mixed-model inpatient laboratory study. Participants were maintained on topiramate (0 [N = 11], 50 [N = 9] or 100 [N = 11] mg/day). Each topiramate group was concurrently maintained on phentermine (0, 15, 30 mg). Drug self-administration, subjective responses and cardiovascular effects following acute doses of intranasal cocaine (0, 40, 80 mg) were determined during separate experimental sessions after at least seven (7) days of maintenance on each condition. RESULTS: The three groups of participants were well matched demographically and generally did not differ significantly in their responses to a range of doses of intranasal cocaine (0, 10, 20, 40, 80 mg) during a medical safety session. Maintenance on topiramate and phentermine alone significantly decreased cocaine self-administration although these effects were modest in magnitude. Combining topiramate and phentermine robustly decreased cocaine self-administration. Topiramate and phentermine were well tolerated alone and combined, as well as in conjunction with cocaine. CONCLUSIONS: The results of the present study support advancing topiramate-phentermine combinations as a putative pharmacotherapeutic for cocaine use disorder.

History and development of national burden of disease assessment in Australia.

Australia's 1996 national burden of disease (BoD) study was one of the first in the world and updates have continued over the following two decades with the fifth study now underway. The studies adapt the global framework most recently implemented by the Global Burden of Disease Study and the World Health Organization to suit Australia's specific needs, producing estimates of fatal and non-fatal burden via the Disability Adjusted Life Year (DALY) metric, as well as attribution of the burden to many risk factors. Detailed Australian data are used with minimal reliance on modelling to fill data gaps. Comprehensive estimates are produced, including for the Indigenous population, for each of the eight states and territories, the five remoteness areas and five socioeconomic quintiles. A number of method developments have been made as part of these studies, including redistribution of deaths data and a detailed quality framework for describing the robustness of the underlying data and methods. Data and methods continue to be refined as part of the studies, and developments in global studies and other national studies are incorporated where appropriate.

The Role of GnRH Receptor Autoantibodies in Polycystic Ovary Syndrome.

OBJECTIVE: Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? DESIGN AND METHODS: We retrospectively screened sera from 40 patients with PCOS and 14 normal controls (NCs) with regular menses using enzyme-linked immunosorbent assay (ELISA) for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified immunoglobulin (Ig)G using a cell-based GnRHR bioassay. RESULTS: The mean ELISA value in the PCOS group was markedly higher than the NC (P = .000036) and the OIC (P = .0028) groups. IgG from a sample of 5 PCOS subjects, in contrast to a sample of 5 OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. The GnRHR antagonist cetrorelix significantly suppressed (P < .01) the elevated GnRHR activity induced by IgG from 7 PCOS patients while the IgG activity level from 7 OIC subjects was unchanged. Five other OIC subjects had relatively high ELISA values at or above the 95% confidence limits. On further study, 3 had normal or low activity while 2 had elevated IgG-induced GnRHR activity. One suppressed with cetrorelix while the other did not. The copresence of PCOS IgG increased the responsiveness to GnRH and shifted the dosage response curve to the left (P < .01). CONCLUSIONS: GnRHR-ECL2-AAb are significantly elevated in patients with PCOS compared with NCs. Their presence raises important etiological, diagnostic, and therapeutic implications.

Human Drug Discrimination: Elucidating the Neuropharmacology of Commonly Abused Illicit Drugs.

Drug-discrimination procedures empirically evaluate the control that internal drug states have over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs in vivo. As a result, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This chapter provides a basic overview of human drug-discrimination procedures and reviews the extant literature concerning the use of these procedures to elucidate the underlying neuropharmacological mechanisms of commonly abused illicit drugs (i.e., stimulants, opioids, and cannabis) in humans. This chapter is not intended to review every available study that used drug-discrimination procedures in humans. Instead, when possible, exemplary studies that used a stimulant, opioid, or Δ9-tetrahydrocannabinol (the primary psychoactive constituent of cannabis) to assess the discriminative-stimulus effects of drugs in humans are reviewed for illustrative purposes. We conclude by commenting on the current state and future of human drug-discrimination research.

Exploring the effects of transfers and readmissions on trends in population counts of hospital admissions for coronary heart disease: a Western Australian data linkage study.

OBJECTIVES: To develop a method for categorising coronary heart disease (CHD) subtype in linked data accounting for different CHD diagnoses across records, and to compare hospital admission numbers and ratios of unlinked versus linked data for each CHD subtype over time, and across age groups and sex. DESIGN: Cohort study. DATA SOURCE: Person-linked hospital administrative data covering all admissions for CHD in Western Australia from 1988 to 2013. MAIN OUTCOME: Ratios of (1) unlinked admission counts to contiguous admission (CA) counts (accounting for transfers), and (2) 28-day episode counts (accounting for transfers and readmissions) to CA counts stratified by CHD subtype, sex and age group. RESULTS: In all CHD subtypes, the ratios changed in a linear or quadratic fashion over time and the coefficients of the trend term differed across CHD subtypes. Furthermore, for many CHD subtypes the ratios also differed by age group and sex. For example, in women aged 35-54 years, the ratio of unlinked to CA counts for non-ST elevation myocardial infarction admissions in 2000 was 1.10, and this increased in a linear fashion to 1.30 in 2013, representing an annual increase of 0.0148. CONCLUSION: The use of unlinked counts in epidemiological estimates of CHD hospitalisations overestimates CHD counts. The CA and 28-day episode counts are more aligned with epidemiological studies of CHD. The degree of overestimation of counts using only unlinked counts varies in a complex manner with CHD subtype, time, sex and age group, and it is not possible to apply a simple correction factor to counts obtained from unlinked data.

Broad-spectrum protein kinase inhibition by the staurosporine analog KT-5720 reverses ethanol withdrawal-associated loss of NeuN/Fox-3.

Chronic, intermittent ethanol (CIE) exposure is known to produce neuroadaptive alterations in excitatory neurotransmission that contribute to the development of dependence. Although activation of protein kinases (e.g., cyclic AMP [cAMP]-dependent protein kinase) is implicated in the synaptic trafficking of these receptors following CIE exposure, the functional consequences of these effects are yet to be fully understood. The present study sought to delineate the influence of protein kinase in regulating cytotoxicity following CIE exposure, as well as to examine the relative roles of ethanol exposure and ethanol withdrawal (EWD) in promoting these effects. Rat hippocampal explants were exposed to a developmental model of CIE with or without co-application of broad-spectrum protein kinase inhibitor KT-5720 (1 µM) either during ethanol exposure or EWD. Hippocampal cytotoxicity was assessed via immunofluorescence (IF) of neuron-specific nuclear protein (NeuN) with thionine staining of Nissl bodies to confirm IF findings. Concomitant application of ethanol and KT-5720 restored the loss of NeuN/Fox-3 IF in pyramidal CA1 and granule DG cell layers produced by CIE, but there was no restoration in CA3. Application of KT-5720 during EWD failed to significantly alter levels of NeuN IF, implying that ethanol exposure activates protein kinases that, in part, mediate the effects of EWD. KT-5720 application during EWD also restored thionine staining in CA1, suggesting kinase regulation of both neurons and non-neuronal cells. These data demonstrate that CIE exposure alters protein kinase activity to promote ethanol withdrawal-associated loss of NeuN/Fox-3 and highlight the influence of kinase signaling on distinct cell types in the developing hippocampus.

Buspirone maintenance does not alter the reinforcing, subjective, and cardiovascular effects of intranasal methamphetamine.

BACKGROUND: Medications development efforts for methamphetamine-use disorder have targeted central monoamines because these systems are directly involved in the effects of methamphetamine. Buspirone is a dopamine autoreceptor and D3 receptor antagonist and partial agonist at serotonin 1A receptors, making it a logical candidate medication for methamphetamine-use disorder. Buspirone effects on abuse-related behaviors of methamphetamine have been mixed in clinical and preclinical studies. Experimental research using maintenance dosing, which models therapeutic use, is limited. This study evaluated the influence of buspirone maintenance on the reinforcing effects of methamphetamine using a self-administration procedure, which has predictive validity for clinical efficacy. The impact of buspirone maintenance on the subjective and cardiovascular response to methamphetamine was also determined. METHODS: Eight research participants (1 female) reporting recent illicit stimulant use completed a placebo-controlled, crossover, double-blind protocol in which the pharmacodynamic effects of intranasal methamphetamine (0, 15, and 30mg) were assessed after at least 6days of buspirone (0 and 45mg/day) maintenance. RESULTS: Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like subjective (e.g., increased ratings of Good Effects and Like Drug) and cardiovascular (e.g., elevated blood pressure) effects. These effects of methamphetamine were similar under buspirone and placebo maintenance conditions. Maintenance on buspirone was well tolerated and devoid of effects when administered alone. CONCLUSIONS: These data suggest that buspirone is unlikely to be an effective pharmacotherapy for methamphetamine-use disorder. Given the central role of monoamines in methamphetamine-use disorder, it is reasonable for future studies to continue to target these systems.

Is the incidence of heart attack still decreasing in Australia? Developing reliable methods for monitoring trends in myocardial infarction and coronary heart disease (AUS-MOCHA): a study protocol.

INTRODUCTION: Accurate monitoring of acute coronary heart disease (CHD) is essential for understanding the effects of primary and secondary prevention and for planning of healthcare services. The ability to reliably monitor acute CHD has been affected by new diagnostic tests for myocardial infarction (MI) and changing clinical classifications and management of CHD. Our study will develop new and reliable methods for monitoring population trends in incidence, outcomes and health service usage for acute CHD and chest pain. METHODS AND ANALYSIS: The study cohort of all CHD will be identified from the Western Australian Data Linkage System using state-wide data sets for emergency department presentation, hospitalisations and mortality data for 2002-2014. This core linked data set will be supplemented with data from hospital medical record reviews, pathology data and hospital pharmacy dispensing databases. The consistency over time of the coding of the different subgroups of CHD/chest pain (ST-elevation MI, non-ST elevation MI, unstable angina, stable angina, other CHD, non-CHD chest pain) in linked data will be assessed using these data sources, and an algorithm developed detailing groups in which temporal trends can be reliably measured. This algorithm will be used for measurement of trends in incidence and outcomes of acute CHD, and to develop further methods for monitoring acute CHD using unlinked and linked data with varying availability of hospitalisation history. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Human Research Ethics Committees of the WA Department of Health (#2016/23) and The University of Western Australia (RA/4/1/7230). Findings will be disseminated via publication in peer-reviewed journals, and presentation at national and international conferences. There will also be a strong platform for dissemination of new monitoring methods via collaboration with the Australian Institute of Health and Welfare which will assist with promotion of these methods at state and national levels.

Human drug discrimination: A primer and methodological review.

Drug-discrimination procedures empirically evaluate the control that internal drug states exert over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs. Historically, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have also been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This review gives some general history and background concerning the major theoretical concepts and principles of drug-discrimination research as well as its relevance to substance-use disorders. This article also provides a procedural overview and discusses key methodological issues that must be considered when designing and conducting a human drug-discrimination study. Although drug discrimination is unequivocally one of the most sophisticated and useful behavioral assays to investigate the underlying neuropharmacology of drugs in vivo, enthusiasm for its use has steadily declined in the last decade and a half. We conclude by commenting on the current state of drug-discrimination research and suggest potential avenues for future drug-discrimination research. (PsycINFO Database Record

Ethanol Stimulates Endoplasmic Reticulum Inositol Triphosphate and Sigma Receptors to Promote Withdrawal-Associated Loss of Neuron-Specific Nuclear Protein/Fox-3.

BACKGROUND: Prior studies demonstrate that ethanol (EtOH) exposure induces the release of intracellular calcium (CA(2+) ) in modulation of γ-aminobutyric acid-ergic tone and produces concomitant alterations in sigma (σ)-1 protein expression that may contribute to the development EtOH dependence. However, the influence of CA(2+) released from endoplasmic reticulum (ER)-bound inositol triphosphate (IP3) and σ-1 receptors in regulating hippocampal function has yet to be delineated. METHODS: Rat hippocampal explants were subjected to chronic intermittent EtOH (CIE) exposure with or without the addition of IP3 inhibitor xestospongin C (0 to 0.5 µM) or σ-1 receptor antagonist BD-1047 (0 to 80 µM). Hippocampal viability was assessed via immunohistochemical labeling of neuron-specific nuclear protein (NeuN)/Fox-3 in CA1, CA3, and dentate gyrus (DG) subregions. RESULTS: Exposure to CIE produced consistent and significant decreases of NeuN/Fox-3 in each primary cell layer of the hippocampal formation. Co-exposure to xestospongin reversed these effects in the CA1 subregion and significantly attenuated these effects in the CA3 and DG regions. Xestospongin application also significantly increased NeuN/Fox-3 immunofluorescence in EtOH-naïve hippocampi. Co-exposure to 20 µM BD-1047 also reversed the loss of NeuN/Fox-3 during CIE exposure in each hippocampal cell layer, whereas exposure to 80 µM BD-1047 did not alter NeuN/Fox-3 in EtOH-treated hippocampi. By contrast, 80 µM BD-1047 application significantly increased NeuN/Fox-3 immunofluorescence in EtOH-naïve hippocampi in each subregion. CONCLUSIONS: These data suggest that EtOH stimulates ER IP3 and σ-1 receptors to promote hippocampal loss of NeuN/Fox-3 during CIE.

Regulation of cocaine craving by cognitive strategies in an online sample of cocaine users.

Emphasis on the negative consequences of drug use is a critical component of cognitive-behavioral therapy (CBT) skills to regulate craving. Despite the relative success of CBT for treating substance use disorders, effective human laboratory models of CBT are lacking. Recent reports have indicated that the regulation of craving (ROC) task provides a valid model of craving regulation for nicotine, alcohol, and methamphetamine use. The present study examined ROC in an online sample of regular cocaine users (n = 44) recruited from Amazon.com's Mechanical Turk. In the ROC task, cognitive regulation strategies were manipulated by instructing participants to think about either the positive or negative consequences of consuming cocaine. Participants were then presented with cocaine images while engaging in each cognitive regulation strategy and asked to report current craving that was then compared to neutral look conditions. Food images served as a control. A cocaine purchase task was also completed to assess economic demand for cocaine and its relationship with cocaine craving. The use of negative appraisal strategies that model those used in CBT significantly attenuated craving for cocaine. Cocaine craving was also stimulus-specific, with greater smoked cocaine craving reported by individuals with a history of smoked cocaine use. This online extension of the ROC task provides converging evidence for its use as a model of CBT cocaine-craving regulation. Futures studies can use this model to examine the mechanisms underlying the effectiveness of CBT for cocaine use and the relationship between craving regulation and drug-use behavior. (PsycINFO Database Record

Female Japanese quail with high levels of estradiol demonstrate cocaine-induced conditioned place preference.

Preclinical research has indicated that females may be more sensitive to the rewarding properties of cocaine. However, the majority of this research has been done in rodent species. Environmental cues associated with human drug-taking behavior tend to be visual. Because rodents do not rely on the visual system as their primary sense modality, the use of a visually oriented species may add to our understanding of cue-elicited drug cravings and relapse. The present study examined the potential role of the steroid hormone, estradiol, in the rewarding properties of cocaine in female Japanese quail using a conditioned place preference (CPP) procedure. In the current experiment, female quail were housed on either an 8L:16D (light:dark) or 16L:8D (light:dark) cycle for 21 days to induce photoregression or photostimulation, respectively. They then received 10, 20, or 30 mg/kg cocaine, or saline during conditioning. Conditioning trials were carried out for 8 days, once per day for 30 min, for a total of 4 cocaine and 4 saline alternating conditioning trials. Results indicated that female quail housed in long-light conditions (16L:8D) had significantly higher levels of estradiol than short-cycle females. Additionally, photostimulated female quail developed a CPP to 10 and 20 mg/kg cocaine. Short-cycle females did not show cocaine-induced CPP to any dose tested. Results indicate that cocaine is dose-dependently rewarding to photostimulated female Japanese quail. Furthermore, the current findings suggest that estradiol may enhance the rewarding properties of cocaine in female quail. (PsycINFO Database Record

Corticosterone enhances N-methyl-D-aspartate receptor signaling to promote isolated ventral tegmental area activity in a reconstituted mesolimbic dopamine pathway.

Elevations in circulating corticosteroids during periods of stress may influence activity of the mesolimbic dopamine reward pathway by increasing glutamatergic N-methyl-D-aspartate (NMDA) receptor expression and/or function in a glucocorticoid receptor-dependent manner. The current study employed organotypic co-cultures of the ventral tegmental area (VTA) and nucleus accumbens (NAcc) to examine the effects of corticosterone exposure on NMDA receptor-mediated neuronal viability. Co-cultures were pre-exposed to vehicle or corticosterone (CORT; 1 µM) for 5 days prior to a 24 h co-exposure to NMDA (200 µM). Co-cultures pre-exposed to a non-toxic concentration of corticosterone and subsequently NMDA showed significant neurotoxicity in the VTA only. This was evidenced by increases in propidium iodide uptake as well as decreases in immunoreactivity of the neuronal nuclear protein (NeuN). Co-exposure to the NMDA receptor antagonist 2-amino-7-phosphonovaleric acid (APV; 50 µM) or the glucocorticoid receptor (GR) antagonist mifepristone (10 µM) attenuated neurotoxicity. In contrast, the combination of corticosterone and NMDA did not produce any significant effects on either measure within the NAcc. Cultures of the VTA and NAcc maintained without synaptic contact showed no response to CORT or NMDA. These results demonstrate the ability to functionally reconstitute key regions of the mesolimbic reward pathway ex vivo and to reveal a GR-dependent enhancement of NMDA receptor-dependent signaling in the VTA.

Group 1 mGlu-family proteins promote neuroadaptation to ethanol and withdrawal-associated hippocampal damage.

BACKGROUND: Group 1 mGlu-family proteins (i.e., mGlu) consist of mGlu1 and mGlu5 and their activity may influence voluntary ethanol intake. The present studies sought to examine the influence of these receptors on the development of ethanol dependence using in vitro and in vivo models of chronic, intermittent ethanol (CIE). METHODS: Rat hippocampal explants were exposed to CIE with or without the addition of mGlu1 antagonist (7-hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt; 0.5, 1, and 3µM) or mGlu5 antagonist (E)-2-methyl-6-styryl-pyridine (SIB-1893; 20, 100, and 200µM) to assess sparing of withdrawal-induced cytotoxicity. In a separate study, adult male rats were administered CIE with or without the addition of oral administration of group 1 mGlu antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 3mg/kg). Blood ethanol levels (BELs) were determined at 0930h on Day 2 of Weeks 1, 2, and 3. Withdrawal behavior was monitored during Day 6 of the third consecutive withdrawal. RESULTS: CIE produced significant hippocampal cytotoxicity. These effects were attenuated by co-exposure to CPCCOEt (3µM) with ethanol in the CA3. By contrast, these effects were blocked by SIB-1893 (20µM) in each primary cell layer. Oral administration of MPEP with ethanol significantly attenuated behavioral effects of subsequent withdrawal and reduced BELs. CONCLUSIONS: These data demonstrate that ethanol activates group 1 mGlu-family proteins to promote withdrawal-associated cytotoxicity in vitro and physical dependence in vivo. These findings suggest that group 1 mGlu-family proteins may be therapeutic targets for treatment of alcohol use disorders.

Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic-pituitary-adrenal axis activation.

BACKGROUND: The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. METHODS: Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 11:00hours on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60mg/kg/i.g.) or a placebo and withdrawal was monitored. RESULTS: Peak BELs of 225.52mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g., aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. CONCLUSIONS: The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence.

Terfestatins B and C, New p-Terphenyl Glycosides Produced by Streptomyces sp. RM-5-8.

Terfestatins B (1) and C (2), new p-terphenyls bearing a novel unsaturated hexuronic acid (4-deoxy-α-L-threo-hex-4-enopyranuronate), a unique ß-D-glycosyl ester of 5-isoprenylindole-3-carboxylate (3) and the same rare sugar, and two new hygromycin precursors, were characterized as metabolites of the coal mine fire isolate Streptomyces sp. RM-5-8. EtOH damage neuroprotection assays using rat hippocampal-derived primary cell cultures with 1, 2, 3 and echoside B (a terfestatin C-3'-ß-D-glucuronide from Streptomyces sp. RM-5-8) revealed 1 as potently neuroprotective, highlighting a new potential application of the terfestatin scaffold.