Maureen Kelly

Effects of progesterone and testosterone on cocaine self-administration and cocaine discrimination by female rhesus monkeys.

The neuroactive steroid hormone progesterone attenuates cocaines abuse-related effects in women and in rodents under some conditions, but the effects of testosterone are unknown. We compared the acute effects of progesterone (0.1, 0.2, and 0.3 mg/kg, intramuscularly (i.m.)), testosterone (0.001, 0.003, and 0.01 mg/kg, i.m.), and placebo on cocaine self-administration and cocaine discrimination dose–effect curves in female rhesus monkeys. Cocaine self-administration (0.03 mg/kg per inj.) was maintained on a fixed ratio 30 schedule of reinforcement, and monkeys had unlimited access to cocaine for 2 h each day. Cocaine doses were administered in an irregular order during each dose–effect curve determination, and the same dose order was used in each subject in all treatment conditions. Blood samples for hormone analysis were collected at the end of each test session. Banana-flavored food pellets (1 g) were also available in three 1-h daily sessions. In drug discrimination studies, the effects of pretreatment with progesterone (0.032–0.32 mg/kg, i.m.) and testosterone (0.001–0.01 mg/kg, i.m.) on the discriminative stimulus effects of cocaine (0.18 mg/kg, i.m.) were examined. Progesterone and testosterone did not alter cocaine discrimination, and did not substitute for cocaine. In contrast, progesterone and testosterone each significantly decreased cocaine self-administration, and produced a downward and rightward shift in the cocaine self-administration dose–effect curve. These findings are concordant with clinical reports that progesterone administration may decrease ratings of positive subjective effects of cocaine in women, and suggest the possible value of neuroactive steroid hormones for the treatment of cocaine abuse and reduction of risk for relapse.

Effects of Estradiol on Cocaine Self-Administration and Cocaine Discrimination by Female Rhesus Monkeys

The ovarian steroid hormone, estradiol, enhances the reinforcing and locomotor activating effects of cocaine in rodents under some conditions. The present study evaluated the acute effects of estradiol benzoate (E2β) on cocaine self-administration and cocaine discrimination in female rhesus monkeys. Cocaine self-administration (0.10 mg/kg/inj., i.v.) was maintained on a fixed-ratio (FR) 30 schedule of reinforcement, and monkeys had access to cocaine during one 2-h session each day. E2β in a cyclodextrin vehicle (0.00001–0.01 mg/kg, i.m.) was administered 30 min before test sessions conducted twice each week. Cocaine doses were administered in an irregular order during each dose–effect curve determination (0.001–0.3 mg/kg/inj.). Blood samples were collected after test sessions to determine 17β-estradiol levels. Banana-flavored food pellets were available on an FR 30 schedule in three 1-h sessions each day. Five monkeys were trained to discriminate cocaine (0.18 mg/kg, i.m.) from saline in a two-key food-reinforced procedure, and the effects of pretreatment with E2β in cyclodextrin and in sesame oil were studied. Acute administration of E2β did not consistently alter the cocaine self-administration or drug discrimination dose–effect curves in comparison to saline control treatment. Females also did not self-administer E2β (0.00001–0.10 mg/kg, i.v.) above saline levels. Finally, E2β (0.0001–0.01 mg/kg, i.m.) did not substitute for cocaine in monkeys trained to discriminate cocaine from saline. Taken together, these data suggest that over the dose range studied, estradiol administration does not consistently alter the abuse-related effects of cocaine in female rhesus monkeys.

The Effects of Cocaine on Gonadal Steroid Hormones and LH in Male and Female Rhesus Monkeys

Cocaine stimulates significant increases in estradiol, testosterone (T), and luteinizing hormone (LH) in rhesus monkeys, but the temporal interactions between the gonadal steroid hormones and LH have not been determined. The effects of i.v. cocaine (0.8 mg/kg) or saline placebo administration on estradiol, T, and LH were compared in follicular phase female and male rhesus monkeys. Samples for hormone analysis were collected at 2-min intervals for 20 min, then at 10-min intervals for 50 min. Peak plasma cocaine levels were detected at 4 min and pharmacokinetic analyses showed no significant gender differences. Baseline hormone levels were equivalent before saline and cocaine administration, and saline did not alter LH or estradiol levels. In females, when baseline estradiol levels were low (<100 pg/ml), LH increased significantly within 8 min after cocaine administration (P<0.05), but when baseline estradiol levels were high (>100 pg/ml), LH levels did not change significantly after cocaine administration. Estradiol and T increased significantly after LH, within 16 min after cocaine administration (P<0.01–0.001). In males, significant LH increases were detected at 16 min after cocaine administration (P<0.05–0.001), but estradiol and T did not change significantly. Thus, cocaine may stimulate significant increases in estradiol and T in females but not in males. These rapid hormonal changes may contribute to cocaines abuse-related effects, as well as to disruptions of the menstrual cycle during chronic cocaine administration.

Filtered-Push: A Map-Reduce Platform for Collaborative Taxonomic Data Management

The Filtered-Push project aims to establish a cross-institutional infrastructure to help biologists (especially taxonomists) share and improve digitized natural history collection data via the exchange and management of specimen record annotations. Three challenges commonly confront the holders of data documenting specimens collected in the field: the identification of the organism and the annotation of records that arose from a single collection event but where parts of the organism have been distributed and are held as duplicates in multiple institutions; the quality control of new annotations [2]; and, more generally, the dissemination of annotations of specimen records, whether or not representing duplicate specimens. Addressing these can accelerate the rate of digital capture of data from paper records (such as handwritten labels attached to pinned insects or pasted on herbarium sheets with dried plants) and provide mechanisms for the global community of biologists to improve the quality of the data.

The effects of heroin on prolactin levels in male rhesus monkeys: use of cumulative-dosing procedures.

There is considerable evidence that mu opioid receptors are involved in the regulation of anterior pituitary function. For example, in nonhuman primates and humans, mu agonists generally increase prolactin (PRL) levels. In contrast, mu antagonists decrease or have no effect on PRL levels. The goal of this study was to assess the potential utility of cumulative-dosing procedures to evaluate the endocrine effects of mu opioid receptor ligands. The effects of single and multiple, cumulative doses of the mu agonist heroin and the mu-selective antagonist quadazocine on PRL levels were investigated in four male rhesus monkeys. Cumulative dose-response curves were determined by infusing increasing drug doses at 60 min intervals over 290 min. Blood samples for PRL analysis were collected at 25 and 50 min after each cumulative infusion. Samples were collected at similar time points following single drug dose administration. Heroin (0.01-0.32 mg/kg, IV) administration dose-dependently increased PRL levels. Maximum levels of heroin-induced PRL levels were equivalent after single and cumulative doses. Quadazocine alone (0.032-1.0 mg/kg, IM) did not alter PRL levels significantly. However, quadazocine (0.1 mg/kg, IM) antagonized heroin-stimulated increases in PRL levels and produced a significant rightward shift in the heroin dose-effect curve. These data suggest that a cumulative-dosing procedure similar to that used in behavioral pharmacology may be useful to study the endocrine pharmacology of mu opioids in rhesus monkeys.

Acute Effects of Nalmefene on LH, Prolactin, and Testosterone in Male Rhesus Monkeys

The effects of the long-acting opioid antagonist, nalmefene [17-N-cyclopropylmethyl-3,14-beta-dihydroxy-4, 5-alpha-epoxy-6-methylene morphinan hydrochloride] on LH, T, and prolactin release in rhesus monkeys are unknown. The acute effects of nalmefene (0.01 and 0.10 mg/kg, IV) or placebo on LH, PRL, and T were studied, and samples were collected at 10-min intervals for 360 min to permit cluster analysis of pulsatile release patterns. LH increased significantly within 30 min after nalmefene, and remained significantly above baseline levels for 50 to 60 min (p < 0.05). Testosterone increased significantly within 70 to 80 min after nalmefene, and remained significantly above baseline for 60 min (p < 0.05). Although nalmefene antagonizes opioid agonists for 6-8 h, inhibitory feedback by testosterone appeared to limit the duration of its antagonism of endogenous opioid inhibition of LHRH and stimulation of LH. Nalmefene did not change LH or PRL pulse frequency or amplitude significantly in comparison to placebo administration.

Semantic Annotation of Mutable Data

Electronic annotation of scientific data is very similar to annotation of documents. Both types of annotation amplify the original object, add related knowledge to it, and dispute or support assertions in it. In each case, annotation is a framework for discourse about the original object, and, in each case, an annotation needs to clearly identify its scope and its own terminology. However, electronic annotation of data differs from annotation of documents: the content of the annotations, including expectations and supporting evidence, is more often shared among members of networks. Any consequent actions taken by the holders of the annotated data could be shared as well. But even those current annotation systems that admit data as their subject often make it difficult or impossible to annotate at fine-enough granularity to use the results in this way for data quality control. We address these kinds of issues by offering simple extensions to an existing annotation ontology and describe how the results support an interest-based distribution of annotations. We are using the result to design and deploy a platform that supports annotation services overlaid on networks of distributed data, with particular application to data quality control. Our initial instance supports a set of natural science collection metadata services. An important application is the support for data quality control and provision of missing data. A previous proof of concept demonstrated such use based on data annotations modeled with XML-Schema.

Towards Automated Design, Analysis and Optimization of Declarative Curation Workflows

Data curation is increasingly important. Our previous work on a Kepler curation package has demonstrated advantages that come from automating data curation pipelines by using workflow systems. However, manually designed curation workflows can be error-prone and inefficient due to a lack of user understanding of the workflow system, misuse of actors, or human error. Correcting problematic workflows is often very time-consuming. A more proactive workflow system can help users avoid such pitfalls. For example, static analysis before execution can be used to detect the potential problems in a workflow and help the user to improve workflow design. In this paper, we propose a declarative workflow approach that supports semi-automated workflow design, analysis and optimization. We show how the workflow design engine helps users to construct data curation workflows, how the workflow analysis engine detects different design problems of workflows and how workflows can be optimized by exploiting parallelism.