Prazosin Reduces Alcohol Intake in an Animal Model of Alcohol Relapse

BACKGROUND: Many alcoholics and heavy drinkers undergo repeated cycles of alcohol abstinence followed by relapse to alcohol drinking; a pattern that contributes to escalated alcohol intake over time. In rodents, alcohol drinking that is interspersed with periods of alcohol deprivation (imposed abstinence) increases alcohol intake during reaccess to alcohol. This is termed the "alcohol deprivation effect" or "ADE" and is a model of alcohol relapse in humans. We have previously reported that prazosin reduces alcohol drinking during both brief and prolonged treatment in rats selectively bred for alcohol preference ("P" rats). This study explores whether prazosin prevents alcohol "relapse" in P rats, as reflected by a reduced or abolished ADE. METHODS: Adult male P rats were given 24-hour access to food and water and scheduled access to alcohol (15 and 30% v/v solutions presented concurrently) for 2 h/d. After 5 weeks, rats underwent imposed alcohol deprivation for 2 weeks, followed by alcohol reaccess for 2 weeks, and this pattern was repeated for a total of 3 cycles. Rats were injected with prazosin (0, 0.5, 1.0, or 2.0 mg/kg body weight, intraperitoneally) once a day for the first 5 days of each alcohol reaccess cycle. RESULTS: Alcohol intake increased on the first day of each alcohol reaccess cycle, demonstrating the formation of an ADE. The ADE was short-lived, lasting only 1 day, during each of the 3 cycles. Prazosin, in all doses tested, prevented the expression of an ADE in all 3 alcohol reaccess cycles. CONCLUSIONS: Prazosin decreases alcohol intake in P rats even in a situation that would be expected to increase alcohol drinking, namely following periods of alcohol deprivation. This suggests that prazosin may be effective in reducing alcohol relapse that often occurs during attempts to achieve permanent alcohol abstinence in treatment-seeking alcoholics and heavy drinkers

Alcohol Drinking and Blood Alcohol Concentration Revisited

Background It is widely assumed that the amount of alcohol in the blood reflects the amount of alcohol consumed. However, several factors in addition to amount of alcohol consumed can influence blood alcohol concentration (BAC). This study examines the effect of alcohol dose, concentration, and volume on BAC in rats with a high-alcohol-drinking (HAD) phenotype. Methods Study 1 examined the relationship between the amount of alcohol consumed and BAC. Alcohol-naïve, male, HAD rats (N = 7) were given access to alcohol for 2 h/d for 9 consecutive days with food and water ad libitum. Alcohol intake and BAC were measured at 30, 60, and 90 minutes after onset of access. Study 2 examined the effects of altering alcohol dose, concentration, and volume on BAC (as measured by area under the curve). Alcohol-naïve, male, HAD rats (N = 39) were infused, via an intragastric cannulus, with 1.16, 2.44, or 3.38 g alcohol/kg body weight (BW), produced by varying alcohol volume while holding concentration constant or by holding volume constant while varying concentration. Other rats were infused with 10, 15, or 20% v/v alcohol solutions while holding dose constant. Results BAC was more strongly correlated with the ratio of alcohol intake (g/kg BW) to total fluid intake (mls) (R = 0.85 to 0.97, p < 0.05 to p < 0.001) than it was with the amount of alcohol consumed (g/kg BW) (R = 0.70 to 0.81, p < 0.05). No effect of alcohol dose was seen during the first hour following the onset of an alcohol infusion regardless of whether dose was achieved by altering alcohol volume or concentration. After 1 hour, higher alcohol doses were predictive of greater BACs. Conclusions The fact that a 3-fold difference in alcohol dose did not result in significant differences in BACs during the first 30 minutes after ingestion of alcohol has potentially important implications for interpretation of studies that measure alcohol-sensitive end points during this time

Tumour necrosis factor (TNF) and interleukin-1 (IL-1) induce muscle proteolysis through different mechanisms

The purpose of this study was to test the hypothesis that muscle proteolysis induced by TNF or IL-1 is mediated by glucocorticoids. Rats were treated with 300 μg kg−1 of recombinant human preparations of IL-1α (rIL-1α) or TNFα (rTNFα) divided into three equal intraperitoneal doses given over 16 h. Two hours before each cytokine injection, rats were given 5 mg kg−1 of the glucocorticoid receptor blocker mifepristone RU 38486, by gavage or were gavaged with the vehicle. Eighteen hours after the first cytokine injection, total and myofibrillar protein breakdown rates were determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Total and myofibrillar proteolytic rates were increased following injection of rIL-1α or rTNFα. Proteolysis induced by rIL-1α was not altered by treatment with RU 38486. In contrast, the glucocorticoid receptor blocker inhibited the proteolytic effect of rTNFα. The results suggest that the proteolytic effect of TNF is mediated by glucocorticoids and that IL-1 induces muscle proteolysis through a glucocorticoid independent pathway

Germination of Silene regia Seeds from Four Sites in Lawrence County, Illinois, Following Scarification or Stratification

Silene regia Sims is an endangered prairie forb in Illinois where small isolated colonies are scattered. In La·wrence County, two sites (Allison Prairie and Chauncey Marsh) have fewer plants (6-23) than two other sites (Cmmty Road and Cemetery) with 26-45 plants. Information on seed germination in these isolated colonies is needed. Our goal was to evaluate seed germination of S. regia from colonies in Lawrence County, illinois. S. regia fruits were collected from these four sites on August 9 and 19, 1999. Seeds were scarified by cutting the seed coat, or they were stratified at 2 C for 12 or 15 weeks. Seeds from Chaun.cey Marsh weighed less than those from other sites. With the exception of seeds from Chauncey Marsh, scariiication increased gemrination within each site. When significant germination differences occurred due to site, they were apparent on stratified seed, where frequently Allison Prairie was highest and Chauncey Marsh was lowest. Germination clifferences between stratified and control seeds were inconsistent, although stratified seeds had up to 67% higher gemrination than control seeds when significant differences occurred. These increases in seed germination were most evident in seeds collected on August 9th and stratified for 12 weeks. Seed that was neither scarified nor stratified gemrinated after storage, indicating that scarification and stratification are not absolute gemrination requirements with after-ripened seeds. Seed germination at different sites did not correspond directly with population sizes, and multiple mechanisms were present for breaking seed donnancy in S. regia

Germination of Silene regia Seeds from Four Sites in Lawrence County, Illinois, Following Scarification or Stratification

Silene regia Sims is an endangered prairie forb in Illinois where small isolated colonies are scattered. In La·wrence County, two sites (Allison Prairie and Chauncey Marsh) have fewer plants (6-23) than two other sites (Cmmty Road and Cemetery) with 26-45 plants. Information on seed germination in these isolated colonies is needed. Our goal was to evaluate seed germination of S. regia from colonies in Lawrence County, illinois. S. regia fruits were collected from these four sites on August 9 and 19, 1999. Seeds were scarified by cutting the seed coat, or they were stratified at 2 C for 12 or 15 weeks. Seeds from Chaun.cey Marsh weighed less than those from other sites. With the exception of seeds from Chauncey Marsh, scariiication increased gemrination within each site. When significant germination differences occurred due to site, they were apparent on stratified seed, where frequently Allison Prairie was highest and Chauncey Marsh was lowest. Germination clifferences between stratified and control seeds were inconsistent, although stratified seeds had up to 67% higher gemrination than control seeds when significant differences occurred. These increases in seed germination were most evident in seeds collected on August 9th and stratified for 12 weeks. Seed that was neither scarified nor stratified gemrinated after storage, indicating that scarification and stratification are not absolute gemrination requirements with after-ripened seeds. Seed germination at different sites did not correspond directly with population sizes, and multiple mechanisms were present for breaking seed donnancy in S. regia

Combining Varenicline (Chantix) with Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in a Rodent Model of Alcoholism

Background This study examined whether varenicline (VAR), or naltrexone (NTX), alone or in combination, reduces alcohol drinking in alcohol-preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake. Methods Alcohol-experienced P rats that had been drinking alcohol (15% v/v) for 2 h/d for 4 weeks were fed either vehicle (VEH), VAR alone (0.5, 1.0, or 2.0 mg/kg body weight [BW]), NTX alone (10.0, 15.0, or 20.0 mg/kg BW), or VAR + NTX in 1 of 4 dose combinations (0.5 VAR + 10.0 NTX, 0.5 VAR + 15.0 NTX, 1.0 VAR + 10.0 NTX, or 1.0 VAR + 15.0 NTX) at 1 hour prior to alcohol access for 10 consecutive days, and the effects on alcohol intake were assessed. Results When administered alone, VAR in doses of 0.5 or 1.0 mg/kg BW did not alter alcohol intake but a dose of 2.0 mg/kg BW decreased alcohol intake. This effect disappeared when drug treatment was terminated. NTX in doses of 10.0 and 15.0 mg/kg BW did not alter alcohol intake but a dose of 20.0 mg/kg BW decreased alcohol intake. Combining low doses of VAR and NTX into a single medication reduced alcohol intake as well as did high doses of each drug alone. Reduced alcohol intake occurred immediately after onset of treatment with the combined medication and continued throughout prolonged treatment. Conclusions Low doses of VAR and NTX, when combined in a single medication, reduce alcohol intake in a rodent model of alcoholism. This approach has the advantage of reducing potential side effects associated with each drug. Lowering the dose of NTX and VAR in a combined treatment approach that maintains efficacy while reducing the incidence of negative side effects may increase patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake

The Functions of Auxilin and Rab11 in Drosophila Suggest That the Fundamental Role of Ligand Endocytosis in Notch Signaling Cells Is Not Recycling

Notch signaling requires ligand internalization by the signal sending cells. Two endocytic proteins, epsin and auxilin, are essential for ligand internalization and signaling. Epsin promotes clathrin-coated vesicle formation, and auxilin uncoats clathrin from newly internalized vesicles. Two hypotheses have been advanced to explain the requirement for ligand endocytosis. One idea is that after ligand/receptor binding, ligand endocytosis leads to receptor activation by pulling on the receptor, which either exposes a cleavage site on the extracellular domain, or dissociates two receptor subunits. Alternatively, ligand internalization prior to receptor binding, followed by trafficking through an endosomal pathway and recycling to the plasma membrane may enable ligand activation. Activation could mean ligand modification or ligand transcytosis to a membrane environment conducive to signaling. A key piece of evidence supporting the recycling model is the requirement in signaling cells for Rab11, which encodes a GTPase critical for endosomal recycling. Here, we use Drosophila Rab11 and auxilin mutants to test the ligand recycling hypothesis. First, we find that Rab11 is dispensable for several Notch signaling events in the eye disc. Second, we find that Drosophila female germline cells, the one cell type known to signal without clathrin, also do not require auxilin to signal. Third, we find that much of the requirement for auxilin in Notch signaling was bypassed by overexpression of both clathrin heavy chain and epsin. Thus, the main role of auxilin in Notch signaling is not to produce uncoated ligand-containing vesicles, but to maintain the pool of free clathrin. Taken together, these results argue strongly that at least in some cell types, the primary function of Notch ligand endocytosis is not for ligand recycling

Emerging Scholarly Practitioners

The purpose of this research project was to explore doctoral student learning and development as scholarly practitioners through one innovative method: a course-based self-study. This self-study empowered doctoral candidates in three key forms of data collection: 1) two project-based course assignments; 2) a survey on course-based student learning; and 3) a self-reflection on learning in the self-study. Results indicate positive impacts in addressing real-life problems and in connecting students to cohort members. The application of skills and knowledge in a course-embedded self-study connects to the Carnegie Project on the Education Doctorate (CPED) principles of creating scholarly practitioners and also developing activist leaders who build coalitions and focus on researching real life social justice issues. This study can serve as an exemplar for similar EdD programs who are developing scholarly practitioners