Acute administration of dopaminergic drugs has differential effects on locomotion in larval zebrafish

Altered dopaminergic signaling causes behavioral changes in mammals. In general, dopaminergic receptor agonists increase locomotor activity, while antagonists decrease locomotor activity. In order to determine if zebrafish (a model organism becoming popular in pharmacology and toxicology) respond similarly, the acute effects of drugs known to target dopaminergic receptors in mammals were assessed in zebrafish larvae. Larvae were maintained in 96-well microtiter plates (1 larva/well). Non-lethal concentrations (0.2–50 µM) of dopaminergic agonists (apomorphine, SKF-38393, and quinpirole) and antagonists (butaclamol, SCH-23390, and haloperidol) were administered at 6 days post-fertilization (dpf). An initial experiment identified the time of peak effect of each drug (20–260 minutes post-dosing, depending on the drug). Locomotor activity was then assessed for 70 minutes in alternating light and dark at the time of peak effect for each drug to delineate dose-dependent effects. All drugs altered larval locomotion in a dose-dependent manner. Both the D1- and D2-like selective agonists (SKF-38393 and quinpirole, respectively) increased activity, while the selective antagonists (SCH-23390 and haloperidol, respectively) decreased activity. Both selective antagonists also blunted the response of the larvae to changes in lighting conditions at higher doses. The nonselective drugs had biphasic effects on locomotor activity: apomorphine increased activity at the low dose and at high doses, while butaclamol increased activity at low to intermediate doses, and decreased activity at high doses. This study demonstrates that (1) larval zebrafish locomotion can be altered by dopamine receptor agonists and antagonists, (2) receptor agonists and antagonists generally have opposite effects, and (3) drugs that target dopaminergic receptors in mammals appear, in general, to elicit similar locomotor responses in zebrafish larvae

Ozone induces glucose intolerance and systemic metabolic effects in young and aged brown Norway rats

Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2> 1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation

The natural history of HIV/AIDS in a major goldmining centre in South Africa: results of a biomedical and social survey

This paper presents the results of a cross-sectional biomedical and social survey, conducted in a major gold mining centre with a high prevalence of HIV infection. It also provides the baseline data for a comprehensive intervention programme. Our sample comprised a stratified random group of migrant mineworkers and of the resident adult population living in the community close to the mines and a small convenience sample of sex workers. In total, 2231 people between 13 and 59 years of age were interviewed using a structured questionnaire covering a wide range of psychological, behavioural and social issues. Blood and urine samples were collected and tested for the presence of HIV and syphilis antibodies and infection with Neisseria gonorrhoeae and Chlamydia trachomatis. The prevalence of HIV was high in all groups: 22% of the men and 37% of the women in the community, 29% of the mineworkers and 69% of the sex workers, were infected with HIV. The prevalence of other sexually transmitted infections (STIs), and especially syphilis, was also high in all four groups of people. Levels of migrancy were highest among mineworkers and sex workers. Migrants had a higher prevalence of casual partners than more permanent residents. More than 43 of the men in the study were circumcised and circumcision appears to offer some protection from HIV infection but not from other STIs. Knowledge about HIV was high but perceived vulnerability was low, which contributed to a high prevalence of unsafe behaviours. Social capital was also associated with HIV infection, with membership of sports clubs, youth clubs, burial societies and churches offering a protective effect against infection, while membership of stokvels (rotating credit associations) was associated with an increased chance of infection. Successful and sustainable intervention programmes must include a range of activities tailored to the needs of the community. Community-based peer education, focus group discussion and involvements of stakeholders should be complemented with syndromic management of STIs as well as periodic presumptive treatment of the sex workers, a partner notification system and training for local physicians

Potential for an intervention based on male circumcision in a South African township with high levels of HIV infection

The study aims to investigate the potential for an intervention based on male circumcision in a South African town with a high level of HIV infection. It draws on two cross-sectional studies conducted in August 2000 among a sample of 606 male adults aged 13-59 years, and in August 1999 among a sample of 723 male youth aged 14-24 years. A qualitative study was further conducted on perceptions and attitudes towards male circumcision using focus group discussions and in-depth interview. Among men aged 25-59 years, 36% reported being circumcised. The median reported age at circumcision was 20. A total of 42% of 14-24-year-old circumcised men reported having been circumcised in a medical setting. Circumcised and uncircumcised men did not differ in their sexual behaviour or in sociodemographic characteristics, apart from their age and ethnic group. Among 467 uncircumcised adult men, 59% said that they would be circumcised if circumcision reduced the chances of getting HIV and STDs. Focus group discussions showed that circumcision is still important to many people, and is seen as an essential part of the transition into adulthood. Reluctance to be circumcised was mainly related to the possibility of adverse outcomes of circumcision performed in non-medical settings, although initiation schools remain attractive for education and transmission of cultural values. Some misconceptions remain, however, especially about the preventative nature of circumcision for STD transmission. The cultural importance of male circumcision has weakened over the last century and when it is done it is often by a medical practitioner. An intervention that would include male circumcision seems feasible in communities such as the one where this study was conducted but needs to be carefully planned in order to ensure that participants understand that circumcision probably reduces, but certainly does not eliminate, the risk of HIV infection

Acute administration of dopaminergic drugs has differential effects on locomotion in larval zebrafish

Altered dopaminergic signaling causes behavioral changes in mammals. In general, dopaminergic receptor agonists increase locomotor activity, while antagonists decrease locomotor activity. In order to determine if zebrafish (a model organism becoming popular in pharmacology and toxicology) respond similarly, the acute effects of drugs known to target dopaminergic receptors in mammals were assessed in zebrafish larvae. Larvae were maintained in 96-well microtiter plates (1 larva/well). Non-lethal concentrations (0.2–50 µM) of dopaminergic agonists (apomorphine, SKF-38393, and quinpirole) and antagonists (butaclamol, SCH-23390, and haloperidol) were administered at 6 days post-fertilization (dpf). An initial experiment identified the time of peak effect of each drug (20–260 minutes post-dosing, depending on the drug). Locomotor activity was then assessed for 70 minutes in alternating light and dark at the time of peak effect for each drug to delineate dose-dependent effects. All drugs altered larval locomotion in a dose-dependent manner. Both the D1- and D2-like selective agonists (SKF-38393 and quinpirole, respectively) increased activity, while the selective antagonists (SCH-23390 and haloperidol, respectively) decreased activity. Both selective antagonists also blunted the response of the larvae to changes in lighting conditions at higher doses. The nonselective drugs had biphasic effects on locomotor activity: apomorphine increased activity at the low dose and at high doses, while butaclamol increased activity at low to intermediate doses, and decreased activity at high doses. This study demonstrates that (1) larval zebrafish locomotion can be altered by dopamine receptor agonists and antagonists, (2) receptor agonists and antagonists generally have opposite effects, and (3) drugs that target dopaminergic receptors in mammals appear, in general, to elicit similar locomotor responses in zebrafish larvae