Rapid disintegration and weakening of ice shelves in North Greenland.

The glaciers of North Greenland are hosting enough ice to raise sea level by 2.1 m, and have long considered to be stable. This part of Greenland is buttressed by the last remaining ice shelves of the ice sheet. Here, we show that since 1978, ice shelves in North Greenland have lost more than 35% of their total volume, three of them collapsing completely. For the floating ice shelves that remain we observe a widespread increase in ice shelf mass losses, that are dominated by enhanced basal melting rates. Between 2000 and 2020, there was a widespread increase in basal melt rates that closely follows a rise in the ocean temperature. These glaciers are showing a direct dynamical response to ice shelf changes with retreating grounding lines and increased ice discharge. These results suggest that, under future projections of ocean thermal forcing, basal melting rates will continue to rise or remain at high level, which may have dramatic consequences for the stability of Greenlandic glaciers.

Environmental factors in the pathogenesis of primary Sjögren's syndrome.

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease in which exocrine organs, primarily the salivary and lacrimal glands, are targets of chronic inflammation, leading to severe dryness of eyes and mouth. Fatigue and arthralgia are also common, and extraglandular manifestations involving the respiratory, nervous and vascular systems occur in a subset of patients. Persistent activation of the type I interferon system, and autoreactive B and T cells with production of disease-associated autoantibodies are central to the pathogenesis. Genetic polymorphisms that associate with an increased risk of SS have been described, though the risk-increase contributed by the respective variant is generally low. It is thus becoming increasingly clear that genetics cannot alone account for the development of SS and that other, presumably exogenous, factors must play a critical role. Relatively few studies have investigated exposure to potential risk factors prior to SS disease onset. Rather, many factors have been studied in prevalent cases. In this review, we summarize current literature on exogenous factors in the pathogenesis of SS including infections, hormones, smoking, solvents and additional compounds. We delineate for which factors there is current evidence of increased disease risk, and for which our present knowledge is confined to suggesting their role in SS pathogenesis. Finally, we outline future perspectives in the continued search for environmental risk factors for SS, a research area of great importance considering the possibilities for preventive measures.

Concomitant Ro/SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembolism and cerebral infarction in primary Sjögren's syndrome.

BACKGROUND: To assess the risk of incident cardiovascular disease in patients with primary Sjögren's syndrome, overall and stratified by Ro/SSA and La/SSB autoantibody status. METHODS: A cohort of patients with primary Sjögren's syndrome in Sweden (n = 960) and matched controls from the general population (n = 9035) were included, and data extracted from the National Patient Register to identify events of myocardial infarction, cerebral infarction and venous thromboembolism. Hazard ratios were estimated using cox proportional hazard regressions. RESULTS: During a median follow-up of 9.5 years, the overall hazard ratio (HR) was 1.6 (95% CI 1.2-2.1) for myocardial infarction, 1.2 (95% CI 0.9-1.7) for cerebral infarction and 2.1 (95% CI 1.6-2.9) for venous thromboembolism. Patients positive for both Ro/SSA and La/SSB autoantibodies had a substantially higher risk of cerebral infarction (HR 1.7, 95% CI 1.0-2.9) and venous thromboembolism (HR 3.1, 95% CI 1.9-4.8) than the general population. These risks were not significantly increased in Ro/SSA- and La/SSB-negative patients. Among autoantibody-positive patients, the highest HR of cerebral infarction was seen after ≥10 years disease duration (HR 2.8, 95% CI 1.4-5.4), while the HR for venous thromboembolism was highest 0-5 years after disease diagnosis (HR 4.7, 95% CI 2.3-9.3) and remained high throughout disease duration. CONCLUSIONS: Primary Sjögren's syndrome is associated with a markedly increased risk of cardiovascular disease and the presence of Ro/SSA and La/SSB autoantibodies identify the subgroup of patients carrying the highest risk. These findings suggest that monitoring and prevention of cardiovascular disease in this patient group should be considered.

Infections increase the risk of developing Sjögren's syndrome.

OBJECTIVE: Environmental factors have been suggested in the pathogenesis of rheumatic diseases. We here investigated whether infections increase the risk of developing primary Sjögren's syndrome (pSS). METHODS: Patients with pSS in Sweden (n = 945) and matched controls from the general population (n = 9048) were included, and data extracted from the National Patient Register to identify infections occurring before pSS diagnosis during a mean observational time of 16.0 years. Data were analysed using conditional logistic regression models. Sensitivity analyses were performed by varying exposure definition and adjusting for previous health care consumption. RESULTS: A history of infection associated with an increased risk of pSS (OR 1.9, 95% CI 1.6-2.3). Infections were more prominently associated with the development of SSA/SSB autoantibody-positive pSS (OR 2.7, 95% CI 2.0-3.5). When stratifying the analysis by organ system infected, respiratory infections increased the risk of developing pSS, both in patients with (OR 2.9, 95% CI 1.8-4.7) and without autoantibodies (OR 2.1, 95% CI 1.1-3.8), whilst skin and urogenital infections only significantly associated with the development of autoantibody-positive pSS (OR 3.2, 95% CI 1.8-5.5 and OR 2.7, 95% CI 1.7-4.2). Furthermore, a dose-response relationship was observed for infections and a risk to develop pSS with Ro/SSA and La/SSB antibodies. Gastrointestinal infections were not significantly associated with a risk of pSS. CONCLUSIONS: Infections increase the risk of developing pSS, most prominently SSA/SSB autoantibody-positive disease, suggesting that microbial triggers of immunity may partake in the pathogenetic process of pSS.

FoxP3+ CXCR5+ CD4+ T cell frequencies are increased in peripheral blood of patients with primary Sjögren's syndrome.

We recently explored the expression of CXCR5 on T and B cells from peripheral blood of patients with primary Sjögren's syndrome (SS). Here we investigated the frequency of CD25+ FoxP3+ CD4+ regulatory T cells (Tregs ) among CXCR5+ CD4+ follicular cells in the same cohort of patients. We confirm that the frequency of Tregs among follicular T cells is increased in SS patients and also provide novel data showing an increased frequency of PD-1 expressing cells among CXCR5+ FoxP3+ CD4+ T cells.

Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden.

The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.

Vulnerability of Southeast Greenland Glaciers to Warm Atlantic Water From Operation IceBridge and Ocean Melting Greenland Data.

We employ National Aeronautics and Space Administration (NASA)'s Operation IceBridge high-resolution airborne gravity from 2016, NASA's Ocean Melting Greenland bathymetry from 2015, ice thickness from Operation IceBridge from 2010 to 2015, and BedMachine v3 to analyze 20 major southeast Greenland glaciers. The results reveal glacial fjords several hundreds of meters deeper than previously thought; the full extent of the marine-based portions of the glaciers; deep troughs enabling warm, salty Atlantic Water (AW) to reach the glacier fronts and melt them from below; and few shallow sills that limit the access of AW. The new oceanographic and topographic data help to fully resolve the complex pattern of historical ice front positions from the 1930s to 2017: glaciers exposed to AW and resting on retrograde beds have retreated rapidly, while glaciers perched on shallow sills or standing in colder waters or with major sills in the fjords have remained stable.

Transcription profiling of peripheral B cells in antibody-positive primary Sjögren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature.

B cells play a key role in the pathogenesis of primary Sjögren's syndrome (pSS). The aim of this study was to analyse the transcriptome of CD19+ B cells from patients with pSS and healthy controls to decipher the B cell-specific contribution to pSS. RNA from purified CD19+ B cells from 12 anti-SSA antibody-positive untreated female patients with pSS and 20 healthy blood donors was subjected to whole transcriptome sequencing. A false discovery rate corrected significance threshold of α < 0.05 was applied to define differential gene expression. As validation, gene expression in B cells from 17 patients with pSS and 16 healthy controls was analysed using a targeted gene panel. RNA-sequencing identified 4047 differentially expressed autosomal genes in pSS B cells. Upregulated expression of type I and type II interferon (IFN)-induced genes was observed, establishing an IFN signature in pSS B cells. Among the top upregulated and validated genes were CX3CR1, encoding the fractalkine receptor involved in regulation of B-cell malignancies, CCL5/RANTES and CCR1. Increased expression of several members of the TNF superfamily was also identified; TNFSF4/Ox40L, TNFSF10/TRAIL, TNFSF13B/BAFF, TNFRSF17/BCMA as well as S100A8 and -A9/calprotectin, TLR7, STAT1 and STAT2. Among genes with downregulated expression in pSS B cells were SOCS1 and SOCS3, CD70 and TNFAIP3/A20. We conclude that B cells from patients with anti-SSA antibody-positive pSS display immune activation with upregulated expression of chemokines, chemokine receptors and a prominent type I and type II IFN signature, while suppressors of cytokine signalling are downregulated. This adds insight into the autoimmune process and suggests potential targets for future functional studies.

Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing.

Genetic investigations of Sjögren's syndrome (SS) have identified a susceptibility locus at p23.3 of chromosome 11, which contains the CXCR5 gene. C-X-C motif chemokine receptor 5 (CXCR5) is a chemokine receptor expressed on B and T cell subsets, and binds the chemotactic ligand C-X-C motif chemokine ligand 13 (CXCL13). In this study we aimed to link the genetic association with functional effects and explore the CXCR5/CXCL13 axis in SS. Expression quantitative trait loci analysis of the 11q23.3 locus was performed using B cell mRNA expression data from genotyped individuals. Lymphocyte surface markers were assessed by flow cytometry, and CXCL13 levels by a proximity extension assay. CXCR5+ and CXCL13+ cells in minor salivary glands were detected using immunohistochemistry. Our results demonstrated that SS-associated genetic polymorphisms affected the expression of CXCR5 (P < 0·01). Notably, a decreased percentage of CXCR5+ cells, with lower CXCR5 expression, was observed for most circulating B and T cell subsets in SS patients, reaching statistical significance in CD19+ CD27+ immunoglobulin (Ig)D+ marginal zone (P < 0·001), CD19+ CD27+ IgD- memory (P < 0·05) and CD27-IgD double-negative (P < 0·01) B cells and CD4+ CXCR3- CCR6+ Th17 cells (P < 0·05). CXCL13 levels were increased in patient plasma (P < 0·001), and immunohistochemical staining revealed expression of CXCL13 and higher numbers of CXCR5+ cells (P < 0·0001) within focal infiltrates and interstitially in salivary glands of SS patients. In conclusion, we link a genetic susceptibility allele for SS to a functional phenotype in terms of decreased CXCR5 expression. The decrease of CXCR5+ cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS.

Geographic distribution of blood collections in Haiti before and after the 2010 earthquake.

BACKGROUND: The January 2010 Haiti earthquake destroyed the National Blood Transfusion Center and reduced monthly national blood collections by > 46%. Efforts to rapidly scale-up blood collections outside of the earthquake-affected region were investigated. STUDY DESIGN AND METHODS: Blood collection data for 2004-2014 from Haiti's 10 administrative departments were grouped into four regions: Northern, Central, Port-au-Prince and Southern. Analyses compared regional collection totals during the study period. RESULTS: Collections in Port-au-Prince accounted for 52% of Haiti's blood supply in 2009, but fell 96% in February 2010. Haiti subsequently increased blood collections in the North, Central and Southern regions to compensate. By May 2010, national blood collections were only 10·9% lower than in May 2009, with 70% of collections coming from outside of Port-au-Prince. By 2013 national collections (27 478 units) had surpassed 2009 levels by 30%, and Port-au-Prince collections had recovered (from 11 074 units in 2009 to 11 670 units in 2013). CONCLUSION: Haiti's National Blood Safety Program managed a rapid expansion of collections outside of Port-au-Prince following the earthquake. Annual collections exceeded pre-earthquake levels by 2012 and continued rising annually. Increased regional collections provided a greater share of the national blood supply, reducing dependence on Port-au-Prince for collections.

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes.

Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH(-/-) MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH(+/+) littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration.

LIFEHOPE.EU: lifestyle and healthy outcome in physical education.

ACCESSIBLE SUMMARY: ● People with severe mental illnesses (SMIs) suffer from health inequities and have a higher mortality rate, resulting from a sedentary lifestyle and a high prevalence of undiagnosed and untreated metabolic and cardiovascular risk factors. Cognitive deficits due to SMI symptoms may affect their ability to engage in a healthier lifestyle. ● Programmes for a healthier lifestyle with physical activity components may improve mental and physical health for people with SMIs. In order to increase physical activity among this population, a new approach was developed as an integrated part of daily care. ● This programme included a cognitive support in the shape of cognitive adaptation training (CAT) in order to address cognitive impairments, and provided education and individualized support in natural nursing environments to help individuals engage in physical activity (PHYS) and dietary changes (PHYS/CAT). ABSTRACT: People with severe mental illness (SMIs) are more prone to physical illnesses, increased mortality and cognitive impairments, all of which negatively influence their daily lives. Physical activity (PHYS) programmes have helped alleviate SMI. LIFEHOPE is an ongoing research project with the purpose of developing a sustainable lifestyle intervention for physical and mental health. PHYS/cognitive adaptation training (CAT) is a newly created lifestyle intervention that provides group education and is based on CAT. It provides individualized support for PHYS and dietary change in a natural nursing environment. The aim of this study was to obtain further knowledge for developing a sustainable lifestyle programme by exploring psychiatric clients' experiences with PHYS and lifestyle habits, which we did by interviewing a local reference group, community mental healthcare users and community mental healthcare workers. Then, we developed a lifestyle programme for people with SMI using information obtained from these focus group interviews. Our results suggest that there is a need for support and education, as well as active interventions, in carrying out PHYS and dietary changes among people with SMIs, and the PHYS/CAT may be a useful strategy.

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer.

BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for >or=4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of >or=50% was noted in two patients. The median time to PSA progression (>25%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.

Haplotypes of the interleukin-4 receptor alpha chain gene associate with susceptibility to and severity of atopic asthma.

BACKGROUND: Development of asthma is likely to depend on a complex interaction between environmental and genetic factors. Several groups have suggested the gene of the IL-4 receptor alpha chain (IL4R) as a candidate gene for the development of asthma, although association with single polymorphisms has shown contradicting results. OBJECTIVE: We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes. METHODS: IL4R gene haplotypes were analysed, based on the three markers C-3223T, Q551R and I50V, using the expectation-maximization algorithm, in 170 atopic asthma patients and 350 controls, all adult Swedish Caucasians. RESULTS: Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthma patients compared with controls (P<0.0001). Furthermore, we showed a significant association between the IL4R haplotype containing the alleles T-3223, V50 and R551 (TVR) of the IL4R gene, and susceptibility to atopic asthma, with a frequency of 6.5% in the patients compared with 1% in the controls (P<0.0005). A subgroup of patients with heterozygous or homozygous state for the T-3223, V50 and R551 alleles, also had lower levels of sIL-4R in their circulation compared with patients with homozygous state in the C-3223, I50 and Q551 alleles (P<0.05) and showed less severe asthma according to lung function test (P<0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P<0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing, P<0.01; coughing, P<0.05 and breathing difficulties, P<0.01). CONCLUSION: Our data suggest that asthmatic patients with low levels of sIL-4 receptor may represent a genetically distinct subgroup of atopic asthma. TVR haplotype analyses confirm the importance of IL4R as a candidate gene for susceptibility to asthma. This finding may have implications for the understanding of the pathogenesis of asthma and possibly for the development of more specific therapies.

Inhibition of autoimmune disease by the immunomodulator linomide correlates with the ability to activate macrophages.

Linomide is a potent immunomodulator that has been shown to inhibit autoimmunity in several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis (EAE). Linomide's mechanism of action is unknown, however, it has been suggested to modulate the function of antigen presenting cells (APC) and that this may account for the inhibition of autoimmune disease. In this study we have been able to show that Linomide treatment of SJL/N mice upregulates the cell surface expression of several activation markers on macrophages and B cells. Thus, we found the following markers, expressed as a % of control, to be significantly upregulated following Linomide treatment; MHC class II (260%), Ly-6A/E (520%), CD11a (280%), CD54 (190%) and CD80 (200%) on macrophages and Ly-6A/E (250%) and CD11a (150%) on B cells. The duration and dosage of Linomide required to obtain these effects is similar to those required for EAE inhibition. Several Linomide analogues were made by the introduction of structural modifications into the Linomide molecule, resulting in a number of compounds with varying effects on EAE. We found a linear relationship between the compound's ability to inhibit EAE and its ability to upregulate MHC class II on macrophages (p<0.001), such that compounds which were able to inhibit EAE also upregulated MHC class II expression, whereas those that did not inhibit EAE were unable to do so. These results suggest that drug-mediated activation of distinct APC functions may be protective in autoimmunity.

Measurements of ECP in serum and the impact of plasma coagulation.

Serum measurement of ECP (eosinophil cationic protein) is used as an indication of eosinophil activation in diseases such as asthma. The levels are dependent on sample handling, since a certain amount of ECP is released during storage. The mechanisms that induce this in vitro release are not known, but are supposed to be related to the coagulation process. The aim of this study was to investigate this further. ECP was measured in EDTA plasma and serum at 22 and 37 degrees C from healthy individuals and patients with asthma and allergy. The serum levels of ECP increased with temperature. Recalcification of citrated plasma in the presence of granulocytes with increasing concentrations of Ca(2+) showed a dissociation between the levels of ECP and the occurrence of coagulation. Further experiments indicated that plasma coagulation is not of any importance for the degranulation of eosinophils, nor did the addition of platelets or mononuclear cells affect the ECP levels. Incubations of granulocytes with fresh or frozen plasma and Ca(2+) suggested the existence of a freezing labile factor in plasma, necessary for the degranulation of healthy eosinophils, but not for allergic/asthmatic eosinophils. Further experiments with pure eosinophils indicated the existence of factors in serum and plasma which facilitate ECP secretion of an active, temperature-dependent nature. We conclude that the raised ECP levels in serum, as compared to EDTA plasma, are unrelated to the coagulation process, but are due to the continuous secretion ex vivo of ECP from active eosinophils. This process is time and temperature dependent and may be facilitated by eosinophil-activating components in the extracellular environment.

Interaction of the novel antipsychotic drug amperozide and its metabolite FG5620 with central nervous system receptors and monoamine uptake sites: relation to behavioral and clinical effects.

Behavioral, biochemical, and electrophysiological studies suggest that amperozide affects mesolimbic and mesocortical dopamine neurotransmission. The receptor binding profile of amperozide is discussed and related to behavioral and clinical, i.e., antipsychotic, effects of the drug. As previously reported, amperozide displayed high affinity for serotonin 5-HT2A receptors (Ki = 16 nmol/L), and moderate affinity for striatal dopamine D2 (Ki = 540 nmol/L) and cortical alpha 1-adrenergic receptors (Ki = 172 nmol/L). In the present study amperozide displayed low affinity for several serotonin receptor subtypes as well as for the dopamine D4 receptor transfected in COS7 cells (Ki D4.2 = 769 nmol/L and Ki D4.4 = 384 nmol/L). Amperozide was very weak or did not interact with several other receptor species including adrenergic, histaminergic, muscarinic, benzodiazepine, gamma-aminobutyric acid, amino acid, opiate, and Ca channels; however, amperozide was found to compete for [3H]paroxetine binding for the serotonin transporter in the nanomolar range (Ki = 49 nmol/L). In vitro and in vivo binding potency of amperozide correlates best with behavioral effects, indicating 5-HT2A antagonism, although serotonin uptake inhibition may contribute to the effects of amperozide on dopamine neurotransmission. The metabolite of amperozide, FG5620, displayed 5-10 times lower pharmacologic activity than amperozide. These properties of amperozide may suggest that the antipsychotic effects of amperozide are mediated by 5-HT2A receptors, although 5-HT uptake inhibition and alpha 1-adrenergic receptor-mediated effects may be considered, particularly at higher doses.

The mixed 5-HT 1A/2A receptor drug FG5938 suppresses alcohol drinking while enhancing feeding in P rats.

The neurotransmitter serotonin (5-HT) has long been implicated in the etiology of aberrant consumption of alcohol. Several compounds thought to possess a potential therapeutic value to counteract drinking have high affinities for 5-HT1A and 5-HT2A receptors in the brain. For example, amperozide and FG5865 significantly reduce the volitional intake of alcohol, without altering food intake, both in rats genetically predisposed or chemically induced to drink alcohol. The present study was undertaken in the alcohol-preferring (P) rat to determine whether an amperozide like drug. FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate). exerts an action on the volitional drinking of alcohol as well as on the intakes of food and water. In 11 male P rats, the pattern of preference for different concentrations of alcohol was determined by an 11-day test for water vs. 3 to 30% alcohol solutions. After maximally preferred alcohol concentrations, i.e., 9 to 15% had stabilized for 4 days, saline or FG5938 was injected subcutaneously at 1600 and 2200 h in a dose of 2.5, 5.0, or 10.0 mg/kg over 4 consecutive days. Following treatment, preference testing for the same concentrations of alcohol was continued for 5 additional days. FG5938 caused a significant suppression in alcohol drinking in terms of both absolute g/kg and proportion to total fluid intake. During its administration, FG5938 also enhanced the ingestion of food and water of the P animals significantly, with the largest intake occurring on the initial day, while body weights increased. After FG5938 injections, food and water intakes returned to predrug levels. The saline control vehicle had no significant effect on the intakes of alcohol, food, or water of the P rats. Overall, these results show that FG5938 acts to attenuate alcohol preference while simultaneously increasing the ingestion of food paradoxically. To our knowledge, this is the first known drug to possess this unique property. Finally, these findings support the view that a compound having affinities to both 5-HT1A and 5-HT2A receptors may be useful as a therapeutic agent in the treatment of alcoholism.

Differential efficacy of serotonergic drugs FG5974, FG5893, and amperozide in reducing alcohol drinking in P rats.

Amperozide (FG5606), a 5-HT2 receptor antagonist, is well known to suppress alcohol consumption in different rat models of drinking. The present study compared the efficacy of three drugs, FG5974, FG5893, and amperozide, which have differential affinities for 5-HT1A and 5-HT2A receptors, on alcohol drinking in the genetic alcohol-preferring (P) rat. After preference for alcohol vs. water was determined over 10 days when concentrations of alcohol were increased from 3% to 30%, the maximal concentration of alcohol preferred by each animal was selected for drug testing. A 4-day predrug preference test was followed by SC injection of the saline control vehicle or doses of 1.0 and 2.5 mg/kg FG5974, FG5893, or amperozide given at 1600 and 2200 h for 4 days. Alcohol preference testing concluded with a final 4-day interval. A total daily dose of 5.0 mg/kg FG5974 reduced absolute g/kg intake of alcohol and proportional intakes of the P rats significantly; the lower dose of FG5974 also reduced alcohol drinking significantly following treatment. The mixed 5-HT1A agonist/5-HT2A antagonist, FG5893, which suppresses drinking in cyanamide-treated rats, was without effect on alcohol ingested by the P rats. However, amperozide caused a dose-dependent decline in both absolute intakes and proportion of alcohol that was more intense than that of FG5974. The control vehicle failed to alter alcohol drinking and, like the FG compounds, did not affect food intake or body weight. Although the inhibition of alcohol drinking by amperozide corresponds precisely with previous findings, the effect of FG5974 contrasts to results obtained with a structurally analogous drug FG5893. Thus, the genetic strain of rat as well as the nature of the chemical characteristics of a 5-HT agonist/antagonist will determine the differential efficacy of a drug in influencing the volitional drinking of alcohol.